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Khalique, S. Pettitt, S.J. Kelly, G. Tunariu, N. Natrajan, R. Banerjee, S. Lord, C.J. (2020). Longitudinal analysis of a secondary BRCA2 mutation using digital droplet PCR. The journal of pathology: clinical research, Vol.6 (1), pp. 3-11.

Khalique, S. Lord, C.J. Banerjee, S. Natrajan, R. (2020). Translational genomics of ovarian clear cell carcinoma. Seminars in cancer biology, Vol.61, pp. 121-131.

Yap, T.A. O'Carrigan, B. Penney, M.S. Lim, J.S. Brown, J.S. de Miguel Luken, M.J. Tunariu, N. Perez-Lopez, R. Rodrigues, D.N. Riisnaes, R. Figueiredo, I. Carreira, S. Hare, B. McDermott, K. Khalique, S. Williamson, C.T. Natrajan, R. Pettitt, S.J. Lord, C.J. Banerji, U. Pollard, J. Lopez, J. de Bono, J.S. (2020). Phase I Trial of First-in-Class ATR Inhibitor M6620 (VX-970) as Monotherapy or in Combination With Carboplatin in Patients With Advanced Solid Tumors. J clin oncol, , pp. JCO1902404-JCO1902404. show abstract

PURPOSE: Preclinical studies demonstrated that ATR inhibition can exploit synthetic lethality (eg, in cancer cells with impaired compensatory DNA damage responses through ATM loss) as monotherapy and combined with DNA-damaging drugs such as carboplatin. PATIENTS AND METHODS: This phase I trial assessed the ATR inhibitor M6620 (VX-970) as monotherapy (once or twice weekly) and combined with carboplatin (carboplatin on day 1 and M6620 on days 2 and 9 in 21-day cycles). Primary objectives were safety, tolerability, and maximum tolerated dose; secondary objectives included pharmacokinetics and antitumor activity; exploratory objectives included pharmacodynamics in timed paired tumor biopsies. RESULTS: Forty patients were enrolled; 17 received M6620 monotherapy, which was safe and well tolerated. The recommended phase II dose (RP2D) for once- or twice-weekly administration was 240 mg/m2. A patient with metastatic colorectal cancer harboring molecular aberrations, including ATM loss and an ARID1A mutation, achieved RECISTv1.1 complete response and maintained this response, with a progression-free survival of 29 months at last assessment. Twenty-three patients received M6620 with carboplatin, with mechanism-based hematologic toxicities at higher doses, requiring dose delays and reductions. The RP2D for combination therapy was M6620 90 mg/m2 with carboplatin AUC5. A patient with advanced germline BRCA1 ovarian cancer achieved RECISTv1.1 partial response and Gynecologic Cancer Intergroup CA125 response despite being platinum refractory and PARP inhibitor resistant. An additional 15 patients had RECISTv1.1 stable disease as best response. Pharmacokinetics were dose proportional and exceeded preclinical efficacious levels. Pharmacodynamic studies demonstrated substantial inhibition of phosphorylation of CHK1, the downstream ATR substrate. CONCLUSION: To our knowledge, this report is the first of an ATR inhibitor as monotherapy and combined with carboplatin. M6620 was well tolerated, with target engagement and preliminary antitumor responses observed..

Dalton, W.B. Helmenstine, E. Walsh, N. Gondek, L.P. Kelkar, D.S. Read, A. Natrajan, R. Christenson, E.S. Roman, B. Das, S. Zhao, L. Leone, R.D. Shinn, D. Groginski, T. Madugundu, A.K. Patil, A. Zabransky, D.J. Medford, A. Lee, J. Cole, A.J. Rosen, M. Thakar, M. Ambinder, A. Donaldson, J. DeZern, A.E. Cravero, K. Chu, D. Madero-Marroquin, R. Pandey, A. Hurley, P.J. Lauring, J. Park, B.H. (2019). Hotspot SF3B1 mutations induce metabolic reprogramming and vulnerability to serine deprivation. Journal of clinical investigation, Vol.129 (11), pp. 4708-4723.

Krasny, L. Bland, P. Kogata, N. Wai, P. Howard, B. Natrajan, R. Huang, P. (2018). SWATH mass spectrometry as a tool for quantitative profiling of the matrisome. Journal of proteomics, . show abstract

Natrajan, R. Tutt, A.N. Lord, C.J. (2018). Driver Oncogenes but Not as We Know Them: Targetable Fusion Genes in Breast Cancer. Cancer discov, Vol.8 (3), pp. 272-275. show abstract

Khalique, S. Naidoo, K. Attygalle, A.D. Kriplani, D. Daley, F. Lowe, A. Campbell, J. Jones, T. Hubank, M. Fenwick, K. Matthews, N. Rust, A.G. Lord, C.J. Banerjee, S. Natrajan, R. (2018). Optimised ARID1A immunohistochemistry is an accurate predictor ofARID1Amutational status in gynaecological cancers. The journal of pathology: clinical research, Vol.4 (3), pp. 154-166.

Ng, C.K. Piscuoglio, S. Geyer, F.C. Burke, K.A. Pareja, F. Eberle, C.A. Lim, R.S. Natrajan, R. Riaz, N. Mariani, O. Norton, L. Vincent-Salomon, A. Wen, Y.H. Weigelt, B. Reis-Filho, J.S. (2017). The Landscape of Somatic Genetic Alterations in Metaplastic Breast Carcinomas. Clinical cancer research, Vol.23 (14), pp. 3859-3870.

Wilkerson, P.M. Dedes, K.J. Samartzis, E.P. Dedes, I. Lambros, M.B. Natrajan, R. Gauthier, A. Piscuoglio, S. Töpfer, C. Vukovic, V. Daley, F. Weigelt, B. Reis-Filho, J.S. (2017). Preclinical evaluation of the PARP inhibitor BMN-673 for the treatment of ovarian clear cell cancer. Oncotarget, Vol.8 (4), pp. 6057-6066.

Showeil, R. Romano, C. Valganon, M. Lambros, M. Trivedi, P. Van Noorden, S. Sriraksa, R. El-Kaffash, D. El-Etreby, N. Natrajan, R. Foroni, L. Osborne, R. El-Bahrawy, M. (2016). The status of epidermal growth factor receptor in borderline ovarian tumours. Oncotarget, Vol.7 (9), pp. 10568-10577.

Krasny, L. Paul, A. Wai, P. Howard, B.A. Natrajan, R.C. Huang, P.H. (2016). Comparative proteomic assessment of matrisome enrichment methodologies. Biochemical journal, Vol.473 (21), pp. 3979-3995. show abstract

Campbell, J. Ryan, C.J. Brough, R. Bajrami, I. Pemberton, H.N. Chong, I.Y. Costa-Cabral, S. Frankum, J. Gulati, A. Holme, H. Miller, R. Postel-Vinay, S. Rafiq, R. Wei, W. Williamson, C.T. Quigley, D.A. Tym, J. Al-Lazikani, B. Fenton, T. Natrajan, R. Strauss, S.J. Ashworth, A. Lord, C.J. (2016). Large-Scale Profiling of Kinase Dependencies in Cancer Cell Lines. Cell reports, Vol.14 (10), pp. 2490-2501.

Miller, R.E. Brough, R. Bajrami, I. Williamson, C.T. McDade, S. Campbell, J. Kigozi, A. Rafiq, R. Pemberton, H. Natrajan, R. Joel, J. Astley, H. Mahoney, C. Moore, J.D. Torrance, C. Gordan, J.D. Webber, J.T. Levin, R.S. Shokat, K.M. Bandyopadhyay, S. Lord, C.J. Ashworth, A. (2016). Synthetic Lethal Targeting of ARID1A -Mutant Ovarian Clear Cell Tumors with Dasatinib. Molecular cancer therapeutics, Vol.15 (7), pp. 1472-1484.

Natrajan, R. Weigelt, B. (2016). Risk Stratification and Intrinsic Subtype Classification of Breast Cancer: a Multi-Parameter Test to Rule Them All?. Journal of the national cancer institute, Vol.108 (9), pp. djw118-djw118.

Wong, J.P. Todd, J.R. Finetti, M.A. McCarthy, F. Broncel, M. Vyse, S. Luczynski, M.T. Crosier, S. Ryall, K.A. Holmes, K. Payne, L.S. Daley, F. Wai, P. Jenks, A. Tanos, B. Tan, A.-. Natrajan, R.C. Williamson, D. Huang, P.H. (2016). Dual Targeting of PDGFRα and FGFR1 Displays Synergistic Efficacy in Malignant Rhabdoid Tumors. Cell reports, Vol.17 (5), pp. 1265-1275.

Maguire, S.L. Peck, B. Wai, P.T. Campbell, J. Barker, H. Gulati, A. Daley, F. Vyse, S. Huang, P. Lord, C.J. Farnie, G. Brennan, K. Natrajan, R. (2016). Three-dimensional modelling identifies novel genetic dependencies associated with breast cancer progression in the isogenic MCF10 model. The journal of pathology, Vol.240 (3), pp. 315-328.

Morrison, E. Wai, P. Leonidou, A. Bland, P. Khalique, S. Farnie, G. Daley, F. Peck, B. Natrajan, R. (2016). Utilizing Functional Genomics Screening to Identify Potentially Novel Drug Targets in Cancer Cell Spheroid Cultures. J vis exp, (118). show abstract

Carvalho, D. Taylor, K. Burford, A. Nowak, I. Mackay, A. Vinci, M. Bjerke, L. Molinari, V. Nandhabalan, M. Ingram, W. Jury, A. Natrajan, R. Jones, D. Pfister, S. Shats, L. Moore, A. Jacques, T. Popov, S. Jones, C. (2015). HG-09 * INFANTILE GLIOBLASTOMA WITH SARCOMATOUS HISTOLOGY DRIVEN BY ETV6:NTRK3 FUSIONS ARE SENSITIVE TO TRK INHIBITION BY PHA-848125. Neuro-oncology, Vol.17 (suppl 3), pp. iii12-iii12.

Weigelt, B. Ng, C.K. Shen, R. Popova, T. Schizas, M. Natrajan, R. Mariani, O. Stern, M.-. Norton, L. Vincent-Salomon, A. Reis-Filho, J.S. (2015). Metastatic breast carcinomas display genomic and transcriptomic heterogeneity. Modern pathology, Vol.28 (3), pp. 340-351.

Maguire, S.L. Leonidou, A. Wai, P. Marchiò, C. Ng, C.K. Sapino, A. Salomon, A.-. Reis-Filho, J.S. Weigelt, B. Natrajan, R.C. (2015). SF3B1mutations constitute a novel therapeutic target in breast cancer. The journal of pathology, Vol.235 (4), pp. 571-580.

Weigelt, B. Ng, C.K. Shen, R. Popova, T. Schizas, M. Natrajan, R. Mariani, O. Stern, M.-. Norton, L. Vincent-Salomon, A. Reis-Filho, J.S. (2015). Erratum: Metastatic breast carcinomas display genomic and transcriptomic heterogeneity. Modern pathology, Vol.28 (4), pp. 607-607.

Schouten, P.C. Grigoriadis, A. Kuilman, T. Mirza, H. Watkins, J.A. Cooke, S.A. van Dyk, E. Severson, T.M. Rueda, O.M. Hoogstraat, M. Verhagen, C.V. Natrajan, R. Chin, S.-. Lips, E.H. Kruizinga, J. Velds, A. Nieuwland, M. Kerkhoven, R.M. Krijgsman, O. Vens, C. Peeper, D. Nederlof, P.M. Caldas, C. Tutt, A.N. Wessels, L.F. Linn, S.C. (2015). Robust BRCA1-like classification of copy number profiles of samples repeated across different datasets and platforms. Molecular oncology, Vol.9 (7), pp. 1274-1286.

Natrajan, R.C. (2015). Breast cancer heterogeneity: parallel evolution or conscious uncoupling?. The journal of pathology, Vol.237 (1), pp. 1-3.

Martelotto, L.G. De Filippo, M.R. Ng, C.K. Natrajan, R. Fuhrmann, L. Cyrta, J. Piscuoglio, S. Wen, H.-. Lim, R.S. Shen, R. Schultheis, A.M. Wen, Y.H. Edelweiss, M. Mariani, O. Stenman, G. Chan, T.A. Colombo, P.-. Norton, L. Vincent-Salomon, A. Reis-Filho, J.S. Weigelt, B. (2015). Genomic landscape of adenoid cystic carcinoma of the breast. The journal of pathology, Vol.237 (2), pp. 179-189.

Ng, C.K. Martelotto, L.G. Gauthier, A. Wen, H.-. Piscuoglio, S. Lim, R.S. Cowell, C.F. Wilkerson, P.M. Wai, P. Rodrigues, D.N. Arnould, L. Geyer, F.C. Bromberg, S.E. Lacroix-Triki, M. Penault-Llorca, F. Giard, S. Sastre-Garau, X. Natrajan, R. Norton, L. Cottu, P.H. Weigelt, B. Vincent-Salomon, A. Reis-Filho, J.S. (2015). Intra-tumor genetic heterogeneity and alternative driver genetic alterations in breast cancers with heterogeneous HER2 gene amplification. Genome biology, Vol.16 (1).

Maley, C.C. Koelble, K. Natrajan, R. Aktipis, A. Yuan, Y. (2015). An ecological measure of immune-cancer colocalization as a prognostic factor for breast cancer. Breast cancer research, Vol.17 (1).

Bajrami, I. Frankum, J.R. Konde, A. Miller, R.E. Rehman, F.L. Brough, R. Campbell, J. Sims, D. Rafiq, R. Hooper, S. Chen, L. Kozarewa, I. Assiotis, I. Fenwick, K. Natrajan, R. Lord, C.J. Ashworth, A. (2014). Genome-wide profiling of genetic synthetic lethality identifies CDK12 as a novel determinant of PARP1/2 inhibitor sensitivity. Cancer res, Vol.74 (1), pp. 287-297. show abstract

Natrajan, R. Wilkerson, P.M. Marchiò, C. Piscuoglio, S. Ng, C.K. Wai, P. Lambros, M.B. Samartzis, E.P. Dedes, K.J. Frankum, J. Bajrami, I. Kopec, A. Mackay, A. A'hern, R. Fenwick, K. Kozarewa, I. Hakas, J. Mitsopoulos, C. Hardisson, D. Lord, C.J. Kumar-Sinha, C. Ashworth, A. Weigelt, B. Sapino, A. Chinnaiyan, A.M. Maher, C.A. Reis-Filho, J.S. (2014). Characterization of the genomic features and expressed fusion genes in micropapillary carcinomas of the breast. J pathol, Vol.232 (5), pp. 553-565. show abstract

Micropapillary carcinoma (MPC) is a rare histological special type of breast cancer, characterized by an aggressive clinical behaviour and a pattern of copy number aberrations (CNAs) distinct from that of grade- and oestrogen receptor (ER)-matched invasive carcinomas of no special type (IC-NSTs). The aims of this study were to determine whether MPCs are underpinned by a recurrent fusion gene(s) or mutations in 273 genes recurrently mutated in breast cancer. Sixteen MPCs were subjected to microarray-based comparative genomic hybridization (aCGH) analysis and Sequenom OncoCarta mutation analysis. Eight and five MPCs were subjected to targeted capture and RNA sequencing, respectively. aCGH analysis confirmed our previous observations about the repertoire of CNAs of MPCs. Sequencing analysis revealed a spectrum of mutations similar to those of luminal B IC-NSTs, and recurrent mutations affecting mitogen-activated protein kinase family genes and NBPF10. RNA-sequencing analysis identified 17 high-confidence fusion genes, eight of which were validated and two of which were in-frame. No recurrent fusions were identified in an independent series of MPCs and IC-NSTs. Forced expression of in-frame fusion genes (SLC2A1-FAF1 and BCAS4-AURKA) resulted in increased viability of breast cancer cells. In addition, genomic disruption of CDK12 caused by out-of-frame rearrangements was found in one MPC and in 13% of HER2-positive breast cancers, identified through a re-analysis of publicly available massively parallel sequencing data. In vitro analyses revealed that CDK12 gene disruption results in sensitivity to PARP inhibition, and forced expression of wild-type CDK12 in a CDK12-null cell line model resulted in relative resistance to PARP inhibition. Our findings demonstrate that MPCs are neither defined by highly recurrent mutations in the 273 genes tested, nor underpinned by a recurrent fusion gene. Although seemingly private genetic events, some of the fusion transcripts found in MPCs may play a role in maintenance of a malignant phenotype and potentially offer therapeutic opportunities..

Garcia-Murillas, I. Sharpe, R. Pearson, A. Campbell, J. Natrajan, R. Ashworth, A. Turner, N.C. (2014). An siRNA screen identifies the GNAS locus as a driver in 20q amplified breast cancer. Oncogene, Vol.33 (19), pp. 2478-2486. show abstract

Dryden, N.H. Broome, L.R. Dudbridge, F. Johnson, N. Orr, N. Schoenfelder, S. Nagano, T. Andrews, S. Wingett, S. Kozarewa, I. Assiotis, I. Fenwick, K. Maguire, S.L. Campbell, J. Natrajan, R. Lambros, M. Perrakis, E. Ashworth, A. Fraser, P. Fletcher, O. (2014). Unbiased analysis of potential targets of breast cancer susceptibility loci by Capture Hi-C. Genome res, Vol.24 (11), pp. 1854-1868. show abstract

Piscuoglio, S. Ng, C.K. Martelotto, L.G. Eberle, C.A. Cowell, C.F. Natrajan, R. Bidard, F.-. De Mattos-Arruda, L. Wilkerson, P.M. Mariani, O. Vincent-Salomon, A. Weigelt, B. Reis-Filho, J.S. (2014). Integrative genomic and transcriptomic characterization of papillary carcinomas of the breast. Molecular oncology, Vol.8 (8), pp. 1588-1602.

Shiu, K.-. Wetterskog, D. Mackay, A. Natrajan, R. Lambros, M. Sims, D. Bajrami, I. Brough, R. Frankum, J. Sharpe, R. Marchio, C. Horlings, H. Reyal, F. van der Vijver, M. Turner, N. Reis-Filho, J.S. Lord, C.J. Ashworth, A. (2014). Integrative molecular and functional profiling of ERBB2-amplified breast cancers identifies new genetic dependencies. Oncogene, Vol.33 (5), pp. 619-631. show abstract

Wetterskog, D. Wilkerson, P.M. Rodrigues, D.N. Lambros, M.B. Fritchie, K. Andersson, M.K. Natrajan, R. Gauthier, A. Di Palma, S. Shousha, S. Gatalica, Z. Toepfer, C. Vukovic, V. A'Hern, R. Weigelt, B. Vincent-Salomon, A. Stenman, G. Rubin, B.P. Reis-Filho, J.S. (2013). Mutation profiling of adenoid cystic carcinomas from multiple anatomical sites identifies mutations in the RAS pathway, but no KIT mutations. Histopathology, Vol.62 (4), pp. 543-550.

Eccles, S.A. Aboagye, E.O. Ali, S. Anderson, A.S. Armes, J. Berditchevski, F. Blaydes, J.P. Brennan, K. Brown, N.J. Bryant, H.E. Bundred, N.J. Burchell, J.M. Campbell, A.M. Carroll, J.S. Clarke, R.B. Coles, C.E. Cook, G.J. Cox, A. Curtin, N.J. Dekker, L.V. dos Santos Silva, I. Duffy, S.W. Easton, D.F. Eccles, D.M. Edwards, D.R. Edwards, J. Evans, D.G. Fenlon, D.F. Flanagan, J.M. Foster, C. Gallagher, W.M. Garcia-Closas, M. Gee, J.M. Gescher, A.J. Goh, V. Groves, A.M. Harvey, A.J. Harvie, M. Hennessy, B.T. Hiscox, S. Holen, I. Howell, S.J. Howell, A. Hubbard, G. Hulbert-Williams, N. Hunter, M.S. Jasani, B. Jones, L.J. Key, T.J. Kirwan, C.C. Kong, A. Kunkler, I.H. Langdon, S.P. Leach, M.O. Mann, D.J. Marshall, J.F. Martin, L.A. Martin, S.G. Macdougall, J.E. Miles, D.W. Miller, W.R. Morris, J.R. Moss, S.M. Mullan, P. Natrajan, R. O’Connor, J.P. O’Connor, R. Palmieri, C. Pharoah, P.D. Rakha, E.A. Reed, E. Robinson, S.P. Sahai, E. Saxton, J.M. Schmid, P. Smalley, M.J. Speirs, V. Stein, R. Stingl, J. Streuli, C.H. Tutt, A.N. Velikova, G. Walker, R.A. Watson, C.J. Williams, K.J. Young, L.S. Thompson, A.M. (2013). Critical research gaps and translational priorities for the successful prevention and treatment of breast cancer. Breast cancer research, Vol.15 (5).

Horlings, H.M. Weigelt, B. Anderson, E.M. Lambros, M.B. Mackay, A. Natrajan, R. Ng, C.K. Geyer, F.C. van de Vijver, M.J. Reis-Filho, J.S. (2013). Genomic profiling of histological special types of breast cancer. Breast cancer research and treatment, Vol.142 (2), pp. 257-269.

Natrajan, R. Wilkerson, P. (2013). From Integrative Genomics to Therapeutic Targets. Cancer research, Vol.73 (12), pp. 3483-3488.

Piscuoglio, S. Ng, C.K. Martelotto, L.G. Cowell, C.F. Natrajan, R. Bidard, F.-. Wilkerson, P.M. Mariani, O. Vincent-Salomon, A. Weigelt, B. Reis-Filho, J.S. (2013). Abstract P4-04-08: Genomic and transcriptomic characterization of papillary carcinomas of the breast. Poster session abstracts, .

Natrajan, R.C. Leonidou, A. Brough, R. Frankum, J. Wai, P.T. Ng, C.K. Reis-Filho, J.S. Lord, C.J. Ashworth, A. (2013). Abstract S4-02: Integrated genomic analyses of members of protein kinase C family identifies subtype specific alterations as novel therapeutic targets. General session abstracts, .

Patani, N. Lambros, M.B. Natrajan, R. Dedes, K.J. Geyer, F.C. Ward, E. Martin, L.-. Dowsett, M. Reis-Filho, J.S. (2012). Non-existence of caveolin-1 gene mutations in human breast cancer. Breast cancer res treat, Vol.131 (1), pp. 307-310. show abstract

Wetterskog, D. Angeles Lopez-Garcia, M. Lambros, M.B. A'Hern, R. Geyer, F.C. Milanezi, F. Cabral, M.C. Natrajan, R. Gauthier, A. Shiu, K.-. Orr, N. Shousha, S. Gatalica, Z. Mackay, A. Palacios, J. S Reis-Filho, J. Weigelt, B. (2012). Adenoid cystic carcinomas constitute a genomically distinct subgroup of triple-negative and basal-like breast cancers. Journal of pathology, Vol.226 (1), pp. 84-96.

Duprez, R. Wilkerson, P.M. Lacroix-Triki, M. Lambros, M.B. MacKay, A. A'Hern, R. Gauthier, A. Pawar, V. Colombo, P.-. Daley, F. Natrajan, R. Ward, E. MacGrogan, G. Arbion, F. Michenet, P. Weigelt, B. Vincent-Salomon, A. Reis-Filho, J.S. (2012). Immunophenotypic and genomic characterization of papillary carcinomas of the breast. J pathol, Vol.226 (3), pp. 427-441. show abstract

Papillary carcinomas are a special histological type of breast cancer and have a relatively good outcome. We characterized the genomic and phenotypic characteristics of papillary carcinomas to determine whether they would constitute an entity distinct from grade- and oestrogen receptor (ER)-matched invasive ductal carcinomas of no special type (IDC-NSTs). The phenotype of 63 papillary carcinomas of the breast and grade- and ER-matched IDC-NSTs was determined by immunohistochemistry. DNA of sufficient quality was extracted from 49 microdissected papillary carcinomas and 49 microdissected grade- and ER-matched IDC-NSTs. These samples were subjected to high-resolution microarray-based comparative genomic hybridization (aCGH) and Sequenom MassARRAY sequencing analysis of 19 known oncogenes. Papillary carcinomas were predominantly of low histological grade, expressed immunohistochemical markers consistent with a luminal phenotype, and a lower rate of lymph node metastasis and p53 expression than grade- and ER-matched IDC-NSTs. Papillary carcinomas displayed less genomic aberrations than grade- and ER-matched IDC-NSTs; however, the patterns of gene copy number aberrations found in papillary carcinomas were similar to those of ER- and grade-matched IDC-NSTs, including 16q losses. Furthermore, PIK3CA mutations were found in 43% and 29% of papillary carcinomas and grade- and ER-matched IDC-NSTs, respectively. The genomic profiles of encapsulated, solid and invasive papillary carcinomas, the three morphological subtypes, were remarkably similar. Our results demonstrate that papillary carcinomas are a homogeneous special histological type of breast cancer. The similarities in the genomic profiles of papillary carcinomas and grade- and ER-matched IDC-NSTs suggest that papillary carcinomas may be best positioned as part of the spectrum of ER-positive breast cancers, rather than as a distinct entity. Furthermore, the good prognosis of papillary carcinomas may stem from the low rates of lymph node metastasis and p53 expression, low number of gene copy number aberrations and high prevalence of PIK3CA mutations..

Geyer, F.C. de Biase, D. Lambros, M.B. Ragazzi, M. Lopez-Garcia, M.A. Natrajan, R. Mackay, A. Kurelac, I. Gasparre, G. Ashworth, A. Eusebi, V. Reis-Filho, J.S. Tallini, G. (2012). Genomic profiling of mitochondrion-rich breast carcinoma: chromosomal changes may be relevant for mitochondria accumulation and tumour biology. Breast cancer res treat, Vol.132 (1), pp. 15-28. show abstract

Oncocytic carcinomas are composed of mitochondrion-rich cells. Though recognised by the WHO classification as a histological special type of breast cancer, their status as a discrete pathological entity remains a matter of contention. Given that oncocytic tumours of other anatomical sites display distinct clinico-pathological and molecular features, we sought to define the molecular genetic features of mitochondrion-rich breast tumours and to compare them with a series of histological grade- and oestrogen receptor status-matched invasive ductal carcinomas of no special type. Seventeen mitochondrion-rich breast carcinomas, including nine bona fide oncocytic carcinomas, were profiled with antibodies against oestrogen, progesterone and androgen receptors, HER2, Ki67, GCDFP-15, chromogranin, epithelial membrane antigen, cytokeratin 7, cytokeratin 14, CD68 and mitochondria antigen. These tumours were microdissected and DNA extracted from samples with >70% of tumour cells. Fourteen cases yielded DNA of sufficient quality/quantity and were subjected to high-resolution microarray comparative genomic hybridisation analysis. The genomic profiles were compared to those of 28 grade- and oestrogen receptor status-matched invasive ductal carcinomas of no special type. Oncocytic and other mitochondrion-rich tumours did not differ significantly between themselves. As a group, mitochondrion-rich carcinomas were immunophenotypically heterogenous. Recurrent copy number changes were similar to those described in unselected breast cancers. However, unsupervised and supervised analysis identified a subset of mitochondrion-rich cancers, which often displayed gains of 11q13.1-q13.2 and 19p13. Changes in the latter two chromosomal regions have been shown to be associated with oncocytic tumours of the kidney and thyroid, respectively, and host several nuclear genes with specific mitochondrial function. Our results indicate that in a way akin to oncocytic tumours of other anatomical sites, at least a subset of mitochondrion-rich breast carcinomas may be underpinned by a distinct pattern of chromosomal changes potentially relevant for mitochondria accumulation and constitute a discrete molecular entity..

Hernandez, L. Wilkerson, P.M. Lambros, M.B. Campion-Flora, A. Rodrigues, D.N. Gauthier, A. Cabral, C. Pawar, V. Mackay, A. A'Hern, R. Marchiò, C. Palacios, J. Natrajan, R. Weigelt, B. Reis-Filho, J.S. (2012). Genomic and mutational profiling of ductal carcinomas in situ and matched adjacent invasive breast cancers reveals intra-tumour genetic heterogeneity and clonal selection. J pathol, Vol.227 (1), pp. 42-52. show abstract

Natrajan, R. Mackay, A. Lambros, M.B. Weigelt, B. Wilkerson, P.M. Manie, E. Grigoriadis, A. A'Hern, R. van der Groep, P. Kozarewa, I. Popova, T. Mariani, O. Turaljic, S. Furney, S.J. Marais, R. Rodruigues, D.-. Flora, A.C. Wai, P. Pawar, V. McDade, S. Carroll, J. Stoppa-Lyonnet, D. Green, A.R. Ellis, I.O. Swanton, C. van Diest, P. Delattre, O. Lord, C.J. Foulkes, W.D. Vincent-Salomon, A. Ashworth, A. Stern, M.H. Reis-Filho, J.S. (2012). A whole-genome massively parallel sequencing analysis of BRCA1 mutant oestrogen receptor-negative and -positive breast cancers. J pathol, Vol.227 (1), pp. 29-41. show abstract

Geyer, F.C. Lacroix-Triki, M. Colombo, P.-. Patani, N. Gauthier, A. Natrajan, R. Lambros, M.B. Khalifeh, I. Albarracin, C. Orru, S. Marchio, C. Sapino, A. Mackay, A. Weigelt, B. Schmitt, F.C. Wesseling, J. Sneige, N. Reis-Filho, J.S. (2012). Molecular evidence in support of the neoplastic and precursor nature of microglandular adenosis. Histopathology, Vol.60 (6B), pp. E115-E130.

Brough, R. Bajrami, I. Vatcheva, R. Natrajan, R. Reis-Filho, J.S. Lord, C.J. Ashworth, A. (2012). APRIN is a cell cycle specific BRCA2-interacting protein required for genome integrity and a predictor of outcome after chemotherapy in breast cancer. Embo journal, Vol.31 (5), pp. 1160-1176.

Daemen, A. Wolf, D.M. Korkola, J.E. Griffith, O.L. Frankum, J.R. Brough, R. Jakkula, L.R. Wang, N.J. Natrajan, R. Reis-Filho, J.S. Lord, C.J. Ashworth, A. Spellman, P.T. Gray, J.W. van't Veer, L.J. (2012). Cross-platform pathway-based analysis identifies markers of response to the PARP inhibitor olaparib. Breast cancer research and treatment, Vol.135 (2), pp. 505-517.

Grigoriadis, A. Mackay, A. Noel, E. Wu, P.J. Natrajan, R. Frankum, J. Reis-Filho, J.S. Tutt, A. (2012). Molecular characterisation of cell line models for triple-negative breast cancers. Bmc genomics, Vol.13.

Mackay, A.G. Natrajan, R. Maher, C. Lambros, M. Weigelt, B. Nava-Rodrigues, D. Wilkerson, P. CampionFlora, A. Kozarewa, I. Fenwick, K. Campbell, J. Chen, L. Lord, C.J. Gauthier, A. Pawar, V. Mariani, O. Vincent-Salomon, A. Reis-Filho, J. (2012). Abstract 5076: Integrative genomic and transcriptomic analysis of metaplastic carcinomas of the breast. Molecular and cellular biology, .

Ng, C.K. Gauthier, A. Mackay, A. Lambros, M.B. Rodrigues, D.N. Arnoud, L. Lacroix-Triki, M. Penault-Llorca, F. Baranzelli, M.C. Sastre-Garau, X. Lord, C.J. Zvelebil, M. Mitsopoulos, C. Ashworth, A. Natrajan, R. Weigelt, B. Delattre, O. Cottu, P. Reis-Filho, J.S. Vincent-Salomon, A. (2012). Abstract PD05-08: Genomic characterisation of invasive breast cancers with heterogeneous HER2 gene amplification. Poster discussion abstracts, .

Gauthier, A. Lambros, M. Rodrigues, D.N. Arnould, L. Lacroix-Tikri, M. Penault-Llorca, F. Baranzelli, M.-. Sastre, X. Natrajan, R. Delattre, O. Cottu, P. Reis-Filho, J.S. Vincent-Salomon, A. (2012). Abstract 8: Genomic analyses of heterogeneous HER2 3+ invasive ductal carcinomas of the breast. Molecular and cellular biology, .

Natrajan, R. Mackay, A. Wilkerson, P.M. Lambros, M.B. Wetterskog, D. Arnedos, M. Shiu, K.-. Geyer, F.C. Langerød, A. Kreike, B. Reyal, F. Horlings, H.M. van de Vijver, M.J. Palacios, J. Weigelt, B. Reis-Filho, J.S. (2012). Functional characterization of the 19q12 amplicon in grade III breast cancers. Breast cancer res, Vol.14 (2), p. R53. show abstract

INTRODUCTION: The 19q12 locus is amplified in a subgroup of oestrogen receptor (ER)-negative grade III breast cancers. This amplicon comprises nine genes, including cyclin E1 (CCNE1), which has been proposed as its 'driver'. The aim of this study was to identify the genes within the 19q12 amplicon whose expression is required for the survival of cancer cells harbouring their amplification. METHODS: We investigated the presence of 19q12 amplification in a series of 313 frozen primary breast cancers and 56 breast cancer cell lines using microarray comparative genomic hybridisation (aCGH). The nine genes mapping to the smallest region of amplification on 19q12 were silenced using RNA interference in phenotypically matched breast cancer cell lines with (MDA-MB-157 and HCC1569) and without (Hs578T, MCF7, MDA-MB-231, ZR75.1, JIMT1 and BT474) amplification of this locus. Genes whose silencing was selectively lethal in amplified cells were taken forward for further validation. The effects of cyclin-dependent kinase 2 (CDK2) silencing and chemical inhibition were tested in cancer cells with and without CCNE1 amplification. RESULTS: 19q12 amplification was identified in 7.8% of ER-negative grade III breast cancer. Of the nine genes mapping to this amplicon, UQCRFS1, POP4, PLEKHF1, C19ORF12, CCNE1 and C19ORF2 were significantly over-expressed when amplified in primary breast cancers and/or breast cancer cell lines. Silencing of POP4, PLEKHF1, CCNE1 and TSZH3 selectively reduced cell viability in cancer cells harbouring their amplification. Cancer cells with CCNE1 amplification were shown to be dependent on CDK2 expression and kinase activity for their survival. CONCLUSIONS: The 19q12 amplicon may harbour more than a single 'driver', given that expression of POP4, PLEKHF1, CCNE1 and TSZH3 is required for the survival of cancer cells displaying their amplification. The observation that cancer cells harbouring CCNE1 gene amplification are sensitive to CDK2 inhibitors provides a rationale for the testing of these chemical inhibitors in a subgroup of patients with ER-negative grade III breast cancers..

Dedes, K.J. Natrajan, R. Lambros, M.B. Geyer, F.C. Lopez-Garcia, M.A. Savage, K. Jones, R.L. Reis-Filho, J.S. (2011). Down-regulation of the miRNA master regulators Drosha and Dicer is associated with specific subgroups of breast cancer. Eur j cancer, Vol.47 (1), pp. 138-150. show abstract

Geyer, F.C. Lacroix-Triki, M. Savage, K. Arnedos, M. Lambros, M.B. MacKay, A. Natrajan, R. Reis-Filho, J.S. (2011). β-Catenin pathway activation in breast cancer is associated with triple-negative phenotype but not with CTNNB1 mutation. Mod pathol, Vol.24 (2), pp. 209-231. show abstract

Aberrant β-catenin expression as determined by assessment of its subcellular localization constitutes a surrogate marker of Wnt signalling pathway activation and has been reported in a subset of breast cancers. The association of β-catenin/Wnt pathway activation with clinical outcome and the mechanisms leading to its activation in breast cancers still remain a matter of controversy. The aims of this study were to address the distribution of β-catenin expression in invasive breast cancers, the correlations between β-catenin expression and clinicopathological features and survival of breast cancer patients, and to determine whether aberrant β-catenin expression is driven by CTNNB1 (β-catenin encoding gene) activating mutations. Immunohistochemistry was performed on a tissue microarray containing 245 invasive breast carcinomas from uniformly treated patients, using two anti-β-catenin monoclonal antibodies. Selected samples were subjected to CTNNB1 exon 3 mutation analysis by direct gene sequencing. A good correlation between the two β-catenin antibodies was observed (Spearman's r >0.62, P<0.001). Respectively, 31 and 11% of the cases displayed lack/reduction of β-catenin membranous expression and nuclear accumulation. Complete lack of β-catenin expression was significantly associated with invasive lobular carcinoma histological type. Subgroup analysis of non-lobular cancers or non-lobular grade 3 carcinomas revealed that lack/reduction of β-catenin membranous expression and/or nuclear accumulation were significantly associated with oestrogen receptor negativity, absence of HER2 gene amplification and overexpression, lack/reduction of E-cadherin expression and tumours of triple-negative and basal-like phenotype. Univariate survival analysis revealed a significant association between β-catenin nuclear expression and shorter metastasis-free and overall survival in the whole cohort; however, β-catenin nuclear expression was not an independent predictor of outcome in multivariate analysis. No CTNNB1 mutations were identified in the 28 selected breast carcinomas analysed. In conclusion, β-catenin/Wnt pathway activation is preferentially found in triple-negative/basal-like breast carcinomas, is associated with poor clinical outcome and is unlikely to be driven by CTNNB1 mutations in breast cancer..

Natrajan, R. Reis-Filho, J.S. (2011). Next-generation sequencing applied to molecular diagnostics. Expert rev mol diagn, Vol.11 (4), pp. 425-444. show abstract

Brough, R. Frankum, J.R. Sims, D. Mackay, A. Mendes-Pereira, A.M. Bajrami, I. Costa-Cabral, S. Rafiq, R. Ahmad, A.S. Cerone, M.A. Natrajan, R. Sharpe, R. Shiu, K.-. Wetterskog, D. Dedes, K.J. Lambros, M.B. Rawjee, T. Linardopoulos, S. Reis-Filho, J.S. Turner, N.C. Lord, C.J. Ashworth, A. (2011). Functional viability profiles of breast cancer. Cancer discov, Vol.1 (3), pp. 260-273. show abstract

Hungermann, D. Schmidt, H. Natrajan, R. Tidow, N. Poos, K. Reis, J.S. Brandt, B. Buerger, H. Korsching, E. (2011). Influence of whole arm loss of chromosome 16q on gene expression patterns in oestrogen receptor-positive, invasive breast cancer. J pathol, Vol.224 (4), pp. 517-528. show abstract

A whole chromosome arm loss of 16q belongs to the most frequent and earliest chromosomal alterations in invasive and in situ breast cancers of all common subtypes. Besides E-cadherin, several putative tumour suppressor genes residing on 16q in breast cancer have been investigated. However, the significance of these findings has remained unclear. Thus, other mechanisms leading to gene loss of function (eg haploinsufficiency, or distortion of multiple regulative subnetworks) remain to be tested as a hypothesis. To define the effect on gene expression of whole-arm loss of chromosome 16q in invasive breast cancer, we performed global gene expression analysis on a series of 18 genetically extensively characterized invasive ductal breast carcinomas and verified the results by quantitative real-time PCR (qRT-PCR). The distribution of the differential genes across the genome and their expression status was studied. A second approach by qRT-PCR in an independent series of 30 breast carcinomas helped to narrow down the observed effect. Whole-arm chromosome 16q losses, irrespective of other chromosomal changes, are associated with decreased expression of a number of candidate genes located on 16q (eg CDA08, CGI-128, SNTB2, NQO1, SF3B3, KIAA0174, ATBF1, GABARAPL2, KARS, GCSH, MBTPS1 and ZDHHC7) in breast carcinomas with a low degree of genetic instability. qRT-PCR provided evidence to suggest that the expression of these genes was reduced in a gene dosage-dependent manner. The differential expression of the candidate genes according to the chromosomal 16q-status vanished in genetically advanced breast cancer cases and changed ER status. These results corroborate previous reports about the importance of whole-arm loss of chromosome 16q in breast carcinogenesis and give evidence for the first time that haploinsufficiency, in the sense of a gene dosage effect, might be an important contributing factor in the early steps of breast carcinogenesis. Copyright (C) 2011 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd..

Wilkerson, P.M. Dedes, K.J. Wetterskog, D. Mackay, A. Lambros, M.B. Mansour, M. Frankum, J. Lord, C.J. Natrajan, R. Ashworth, A. Reis-Filho, J.S. (2011). Functional characterization of EMSY gene amplification in human cancers. J pathol, Vol.225 (1), pp. 29-42. show abstract

Lambros, M.B. Wilkerson, P.M. Natrajan, R. Patani, N. Pawar, V. Vatcheva, R. Mansour, M. Laschet, M. Oelze, B. Orr, N. Muller, S. Reis, J.S. (2011). High-throughput detection of fusion genes in cancer using the Sequenom MassARRAY platform. Lab invest, Vol.91 (10), pp. 1491-1501. show abstract

Lambros, M.B. Wilkerson, P.M. Natrajan, R. Patani, N. Pawar, V. Vatcheva, R. Mansour, M. Laschet, M. Oelze, B. Orr, N. Muller, S. Reis-Filho, J.S. (2011). High-throughput detection of fusion genes in cancer using the Sequenom MassARRAY platform. Laboratory investigation; a journal of technical methods and pathology, Vol.91 (10), pp. 1491-1501. show abstract

Williams, R.D. Al-Saadi, R. Natrajan, R. Mackay, A. Chagtai, T. Little, S. Hing, S.N. Fenwick, K. Ashworth, A. Grundy, P. Anderson, J.R. Dome, J.S. Perlman, E.J. Jones, C. Pritchard-Jones, K. (2011). Molecular Profiling Reveals Frequent Gain of MYCN and Anaplasia-Specific Loss of 4q and 14q in Wilms Tumor. Gene chromosome canc, Vol.50 (12), pp. 982-995. show abstract

Robinson, D.R. Kalyana-Sundaram, S. Wu, Y.-. Shankar, S. Cao, X. Ateeq, B. Asangani, I.A. Iyer, M. Maher, C.A. Grasso, C.S. Lonigro, R.J. Quist, M. Siddiqui, J. Mehra, R. Jing, X. Giordano, T.J. Sabel, M.S. Kleer, C.G. Palanisamy, N. Natrajan, R. Lambros, M.B. Reis-Filho, J.S. Kumar-Sinha, C. Chinnaiyan, A.M. (2011). Functionally recurrent rearrangements of the MAST kinase and Notch gene families in breast cancer. Nature medicine, Vol.17 (12), pp. 1646-U163.

Tan, D.S. Iravani, M. McCluggage, W.G. Lambros, M.B. Milanezi, F. Mackay, A. Gourley, C. Geyer, F.C. Vatcheva, R. Millar, J. Thomas, K. Natrajan, R. Savage, K. Fenwick, K. Williams, A. Jameson, C. El-Bahrawy, M. Gore, M.E. Gabra, H. Kaye, S.B. Ashworth, A. Reis-Filho, J.S. (2011). Genomic analysis reveals the molecular heterogeneity of ovarian clear cell carcinomas. Clin cancer res, Vol.17 (6), pp. 1521-1534. show abstract

Sharpe, R. Pearson, A. Herrera-Abreu, M.T. Johnson, D. Mackay, A. Welti, J.C. Natrajan, R. Reynolds, A.R. Reis-Filho, J.S. Ashworth, A. Turner, N.C. (2011). FGFR signaling promotes the growth of triple-negative and basal-like breast cancer cell lines both in vitro and in vivo. Clin cancer res, Vol.17 (16), pp. 5275-5286. show abstract

Daemen, A. Wolf, D.M. Korkola, J.E. Griffith, O.L. Frankum, J.R. Jakkula, L.R. Wang, N.J. Natrajan, R. Reis-Filho, J.S. Lord, C.J. Ashworth, A. Gray, J.W. Spellman, P.T. van't Veer, L. (2011). P1-06-22: Identification of Biomarkers in Breast Cancer for Prediction of Response to PARP Inhibitor Olaparib. Poster session abstracts, .

Wilkerson, P. Dedes, K.J. Wetterskog, D. Natrajan, R. Lambros, M.B. Mackay, A. Lord, C.J. Ashworth, A. Reis-Filho, J.S. (2011). Abstract 3917: EMSY amplification and overexpression is not associated with defective homologous recombination and does not predict sensitivity to cisplatin or PARP inhibitors. Cellular and molecular biology, .

Natrajan, R. Maher, C.A. Lambros, M.B. Pawar, V. Wetterskog, D. Marchio, C. Barbashina, V. Geyer, F.C. Fenwick, K. Kozarewa, I. Mackay, A. Hakas, J. Mitsopoulos, K. Hardisson, D. Sapino, A. Vincent-Salomon, A. Lord, C.J. Chinniayan, A. Ashworth, A. Reis-Filho, J.S. (2011). Abstract 4829: Massively parallel RNA sequencing analysis of micropapillary carcinomas of the breast. Cellular and molecular biology, .

Chong, I. Wetterskog, D. Shiu, K.-. Meijer, T. Natrajan, R. Maryou, L. Reis-Filho, J. Lord, L.J. David, C. Ashworth, A. (2011). Abstract 3039: Identification of a novel biomarker of resistance to lapatinib common to both breast and oesophagogastric cancer. Cellular and molecular biology, .

Wetterskog, D. Shiu, K.-. Chong, I. Meijer, T. Natrajan, R. Lord, C.J. Ashworth, A. Reis-Filho, J.S. (2011). Abstract 4987: Identification of novel genes and pathways involved in resistance to HER2-targeting agents in breast cancer. Cellular and molecular biology, .

Mackay, A. Weigelt, B. Grigoriadis, A. Kreike, B. Natrajan, R. A'Hern, R. Tan, D.S. Dowsett, M. Ashworth, A. Reis-Filho, J.S. (2011). Microarray-based class discovery for molecular classification of breast cancer: analysis of interobserver agreement. J natl cancer inst, Vol.103 (8), pp. 662-673. show abstract

BACKGROUND: Breast cancers can be classified by hierarchical clustering using an "intrinsic" gene list into one of at least five molecular subtypes: basal-like, HER2, luminal A, luminal B, and normal breast-like. Five different intrinsic gene lists composed of varying numbers of genes have been used for molecular subtype identification and classification of breast cancers. The aim of this study was to determine the objectivity and interobserver reproducibility of the assignment of molecular subtype classes by hierarchical cluster analysis. METHODS: Three publicly available breast cancer datasets (n = 779) were subjected to two-way average-linkage hierarchical cluster analysis using five distinct intrinsic gene lists. We used free-marginal Kappa statistics to analyze interobserver agreement among five breast cancer researchers for the whole classification and for each molecular subtype separately according to each intrinsic gene list for each breast cancer dataset. RESULTS: None of the classification systems tested produced almost perfect agreement (Kappa ≥ 0.81) among observers. However, substantial interobserver agreement (70.8% to 76.1% of the samples and free-marginal Kappa scores from 0.635 to 0.701) was consistently observed in all datasets for four molecular subtypes (luminal, basal-like, HER2, and normal breast-like). When luminal cancers were subdivided (luminal A, B, and C), none of the classification systems produced substantial agreement (Kappa ≥ 0.61) in all the datasets analyzed. Analysis of each subtype separately revealed that only two (basal-like and HER2) could be reproducibly identified by independent observers (Kappa ≥ 0.81). CONCLUSIONS: Assignment of molecular subtype classes of breast cancer based on the analysis of dendrograms obtained with hierarchical cluster analysis is subjective and shows modest interobserver reproducibility. For the development of a molecular taxonomy, objective definitions for each molecular subtype and standardized methods for their identification are required..

Xu, H. Yan, M. Patra, J. Natrajan, R. Yan, Y. Swagemakers, S. Tomaszewski, J.M. Verschoor, S. Millar, E.K. van der Spek, P. Reis-Filho, J.S. Ramsay, R.G. O'Toole, S.A. McNeil, C.M. Sutherland, R.L. McKay, M.J. Fox, S.B. (2011). Enhanced RAD21 cohesin expression confers poor prognosis and resistance to chemotherapy in high grade luminal, basal and HER2 breast cancers. Breast cancer res, Vol.13 (1), p. R9. show abstract

Ha, K.C. Lalonde, E. Li, L. Cavallone, L. Natrajan, R. Lambros, M.B. Mitsopoulos, C. Hakas, J. Kozarewa, I. Fenwick, K. Lord, C.J. Ashworth, A. Vincent-Salomon, A. Basik, M. Reis-Filho, J.S. Majewski, J. Foulkes, W.D. (2011). Identification of gene fusion transcripts by transcriptome sequencing in BRCA1-mutated breast cancers and cell lines. Bmc med genomics, Vol.4, p. 75. show abstract

BACKGROUND: Gene fusions arising from chromosomal translocations have been implicated in cancer. However, the role of gene fusions in BRCA1-related breast cancers is not well understood. Mutations in BRCA1 are associated with an increased risk for breast cancer (up to 80% lifetime risk) and ovarian cancer (up to 50%). We sought to identify putative gene fusions in the transcriptomes of these cancers using high-throughput RNA sequencing (RNA-Seq). METHODS: We used Illumina sequencing technology to sequence the transcriptomes of five BRCA1-mutated breast cancer cell lines, three BRCA1-mutated primary tumors, two secretory breast cancer primary tumors and one non-tumorigenic breast epithelial cell line. Using a bioinformatics approach, our initial attempt at discovering putative gene fusions relied on analyzing single-end reads and identifying reads that aligned across exons of two different genes. Subsequently, latter samples were sequenced with paired-end reads and at longer cycles (producing longer reads). We then refined our approach by identifying misaligned paired reads, which may flank a putative gene fusion junction. RESULTS: As a proof of concept, we were able to identify two previously characterized gene fusions in our samples using both single-end and paired-end approaches. In addition, we identified three novel in-frame fusions, but none were recurrent. Two of the candidates, WWC1-ADRBK2 in HCC3153 cell line and ADNP-C20orf132 in a primary tumor, were confirmed by Sanger sequencing and RT-PCR. RNA-Seq expression profiling of these two fusions showed a distinct overexpression of the 3' partner genes, suggesting that its expression may be under the control of the 5' partner gene's regulatory elements. CONCLUSIONS: In this study, we used both single-end and paired-end sequencing strategies to discover gene fusions in breast cancer transcriptomes with BRCA1 mutations. We found that the use of paired-end reads is an effective tool for transcriptome profiling of gene fusions. Our findings suggest that while gene fusions are present in some BRCA1-mutated breast cancers, they are infrequent and not recurrent. However, private fusions may still be valuable as potential patient-specific biomarkers for diagnosis and treatment..

Tanas, M.R. Sboner, A. Oliveira, A.M. Erickson-Johnson, M.R. Hespelt, J. Hanwright, P.J. Flanagan, J. Luo, Y. Fenwick, K. Natrajan, R. Mitsopoulos, C. Zvelebil, M. Hoch, B.L. Weiss, S.W. Debiec-Rychter, M. Sciot, R. West, R.B. Lazar, A.J. Ashworth, A. Reis-Filho, J.S. Lord, C.J. Gerstein, M.B. Rubin, M.A. Rubin, B.P. (2011). Identification of a disease-defining gene fusion in epithelioid hemangioendothelioma. Sci transl med, Vol.3 (98), p. 98ra82. show abstract

Turner, N. Pearson, A. Sharpe, R. Lambros, M. Geyer, F. Lopez-Garcia, M.A. Natrajan, R. Marchio, C. Iorns, E. Mackay, A. Gillett, C. Grigoriadis, A. Tutt, A. Reis, J.S. Ashworth, A. (2010). FGFR1 Amplification Drives Endocrine Therapy Resistance and Is a Therapeutic Target in Breast Cancer. Cancer res, Vol.70 (5), pp. 2085-2094. show abstract

Weigelt, B. Geyer, F.C. Natrajan, R. Lopez-Garcia, M.A. Ahmad, A.S. Savage, K. Kreike, B. Reis-Filho, J.S. (2010). The molecular underpinning of lobular histological growth pattern: a genome-wide transcriptomic analysis of invasive lobular carcinomas and grade- and molecular subtype-matched invasive ductal carcinomas of no special type. J pathol, Vol.220 (1), pp. 45-57. show abstract

Invasive lobular carcinoma (ILC) is the most frequent special type of breast cancer. The majority of these tumours are of low histological grade, express hormone receptors, and lack HER2 expression. The pleomorphic variant of ILCs (PLCs) is characterized by atypical cells with pleomorphic nuclei and is reported to have an aggressive clinical behaviour. Expression profiling studies have demonstrated that classic ILCs preferentially display a luminal phenotype, whereas PLCs may be of luminal, HER2 or molecular apocrine subtypes. The aims of this study were two-fold: to determine the transcriptomic characteristics of lobular carcinomas and to define the genome-wide transcriptomic differences between classic ILCs and PLCs. To define the transcriptomic characteristics of ILCs, minimizing the impact of histological grade and molecular subtype on the analysis, we subjected a series of grade- and molecular subtype-matched ILCs and invasive ductal carcinomas (IDCs) to genome-wide gene expression profiling using oligonucleotide microarrays. Hierarchical clustering analysis demonstrated that ILCs formed a separate cluster and a supervised analysis revealed that 5.8% of the transcriptionally regulated genes were significantly differentially expressed in ILCs compared to grade- and molecular subtype-matched IDCs. ILCs displayed down-regulation of E-cadherin and of genes related to actin cytoskeleton remodelling, protein ubiquitin, DNA repair, cell adhesion, TGF-beta signalling; and up-regulation of transcription factors/immediate early genes, lipid/prostaglandin biosynthesis genes, and cell migration-associated genes. Supervised analysis of classic ILCs and PLCs demonstrated that less than 0.1% of genes were significantly differentially expressed between these tumour subtypes. Our results demonstrate that ILCs differ from grade- and molecular subtype-matched IDCs in the expression of genes related to cell adhesion, cell-to-cell signalling, and actin cytoskeleton signalling. However, classic ILCs and PLCs are remarkably similar at the molecular level and should be considered as part of a spectrum of lesions..

Klingbeil, P. Natrajan, R. Everitt, G. Vatcheva, R. Marchio, C. Palacios, J. Buerger, H. Reis-Filho, J.S. Isacke, C.M. (2010). CD44 is overexpressed in basal-like breast cancers but is not a driver of 11p13 amplification. Breast cancer res treat, Vol.120 (1), pp. 95-109. show abstract

Molyneux, G. Geyer, F.C. Magnay, F.-. McCarthy, A. Kendrick, H. Natrajan, R. Mackay, A. Grigoriadis, A. Tutt, A. Ashworth, A. Reis-Filho, J.S. Smalley, M.J. (2010). BRCA1 basal-like breast cancers originate from luminal epithelial progenitors and not from basal stem cells. Cell stem cell, Vol.7 (3), pp. 403-417. show abstract

Turner, N. Pearson, A. Sharpe, R. Lambros, M. Geyer, F. Lopez-Garcia, M.A. Natrajan, R. Marchio, C. Iorns, E. Mackay, A. Gillett, C. Grigoriadis, A. Tutt, A. Reis-Filho, J.S. Ashworth, A. (2010). FGFR1 amplification drives endocrine therapy resistance and is a therapeutic target in breast cancer. Cancer research, Vol.70 (5), pp. 2085-2094. show abstract

Geyer, F.C. Weigelt, B. Natrajan, R. Lambros, M.B. de Biase, D. Vatcheva, R. Savage, K. Mackay, A. Ashworth, A. Reis-Filho, J.S. (2010). Molecular analysis reveals a genetic basis for the phenotypic diversity of metaplastic breast carcinomas. J pathol, Vol.220 (5), pp. 562-573. show abstract

Cancers may be composed of multiple populations of submodal clones sharing the same initiating genetic lesions, followed by the acquisition of divergent genetic hits. Intra-tumour genetic heterogeneity has profound implications for cancer clinical management. To determine the extent of intra-tumour genetic heterogeneity in breast cancers, and whether the morphological diversity of breast cancers is underpinned by divergent genetic aberrations, we analysed the genomic profiles of microdissected, morphologically distinct components of six metaplastic breast carcinomas, tumours characterized by the presence of morphological areas with divergent differentiation. Each morphologically distinct component was separately microdissected and subjected to high-resolution microarray-based comparative genomic hybridization. Each component was also analysed by immunohistochemistry and in situ hybridization. Clonal relationship between the distinct components was tested by TP53 sequencing and human androgen receptor (HUMARA) X-chromosome inactivation assay. In the majority of cases, all morphologically distinct components from each case were clonal and displayed remarkably similar genetic profiles. In two cases, however, morphologically distinct components harboured specific genetic aberrations. In an adenosquamous carcinoma, the differences were such that only 20% of the genome harboured similar copy number changes. The squamous component displayed EGFR gene amplification, EGFR over-expression and lack of expression of hormone receptors, whereas the lobular component displayed the reverse pattern. The components of a biphasic spindle cell carcinoma harboured similar gains, losses, amplifications of 9p23 and 17q12 (HER2) and identical TP53 mutations, suggesting that these were relatively early events in the development of this tumour; however, each component displayed divergent focal amplifications. Importantly, the metastatic deposit of this case, despite harbouring a TP53 mutation identical to that found in the primary tumour, harboured additional specific focal amplifications. This proof-of-principle study provides direct evidence of intra-tumour genetic heterogeneity in breast cancers, and shows that in some cases morphological diversity may be underpinned by distinct genetic aberrations..

Weigelt, B. Mackay, A. A'hern, R. Natrajan, R. Tan, D.S. Dowsett, M. Ashworth, A. Reis-Filho, J.S. (2010). Breast cancer molecular profiling with single sample predictors: a retrospective analysis. Lancet oncol, Vol.11 (4), pp. 339-349. show abstract

Natrajan, R. Weigelt, B. Mackay, A. Geyer, F.C. Grigoriadis, A. Tan, D.S. Jones, C. Lord, C.J. Vatcheva, R. Rodriguez-Pinilla, S.M. Palacios, J. Ashworth, A. Reis-Filho, J.S. (2010). An integrative genomic and transcriptomic analysis reveals molecular pathways and networks regulated by copy number aberrations in basal-like, HER2 and luminal cancers. Breast cancer res treat, Vol.121 (3), pp. 575-589. show abstract

Shiu, K.K. Natrajan, R. Geyer, F.C. Ashworth, A. Reis, J.S. (2010). DNA amplifications in breast cancer: genotypic-phenotypic correlations. Future oncol, Vol.6 (6), pp. 967-984. show abstract

Shiu, K.-. Natrajan, R. Geyer, F.C. Ashworth, A. Reis-Filho, J.S. (2010). DNA amplifications in breast cancer: genotypic–phenotypic correlations. Future oncology, Vol.6 (6), pp. 967-984.

Geyer, F.C. Lambros, M.B. Natrajan, R. Mehta, R. Mackay, A. Savage, K. Parry, S. Ashworth, A. Badve, S. Reis-Filho, J.S. (2010). Genomic and immunohistochemical analysis of adenosquamous carcinoma of the breast. Mod pathol, Vol.23 (7), pp. 951-960. show abstract

Breast adenosquamous carcinomas are rare tumours characterized by well-developed gland formation intimately admixed with solid nests of squamous cells immersed in a highly cellular spindle cell stroma. A low-grade variant has been described that is associated with a better prognosis. Here we studied five cases of adenosquamous carcinomas to determine their genetic profiles and to investigate whether the spindle cell component of these cancers could at least in part stem from the glandular/epithelial components. Five adenosquamous carcinomas of the breast were subjected to (1) immunohistochemical analysis, (2) microdissection and genetic analysis with a high-resolution microarray comparative genomic hybridization platform, and (3) chromogenic in situ hybridization. All cases displayed a triple-negative immunophenotype, consistently expressed 'basal' keratins and showed variable levels of epidermal growth factor receptor expression. Microarray comparative genomic hybridization analysis of two of the cases revealed multiple low-level gains and losses affecting several chromosomal arms. Case 1 displayed gains of the whole of chromosome 7, and case 2 harboured a focal, high-level amplification of 7p12, encompassing the epidermal growth factor receptor gene, which was associated with strong and intense membranous epidermal growth factor receptor expression. Chromogenic in situ hybridization revealed that the genetic features found in the epithelial cells were also present in a minority of the spindle cells of the stromal component, in particular in those near the epithelial clusters, indicating that some of the spindle cells are clonal and derived from the epithelial component of the tumour. In conclusion, breast adenosquamous carcinomas are triple-negative cancers that express 'basal' keratins. These tumours harbour complex genetic profiles. Some of the spindle cells in adenosquamous carcinomas are derived from the epithelial component, suggesting that adenosquamous carcinomas may also be part of the group of metaplastic breast carcinomas with spindle cell metaplastic elements..

Weigelt, B. Mackay, A. Natrajan, R. Tan, D.S. Dowsett, M. Ashworth, A. Reis, J.S. (2010). The importance of gene-centring microarray data Reply. Lancet oncol, Vol.11 (8), pp. 720-721.

Turner, N. Lambros, M.B. Horlings, H.M. Pearson, A. Sharpe, R. Natrajan, R. Geyer, F.C. van Kouwenhove, M. Kreike, B. Mackay, A. Ashworth, A. van de Vijver, M.J. Reis-Filho, J.S. (2010). Integrative molecular profiling of triple negative breast cancers identifies amplicon drivers and potential therapeutic targets. Oncogene, Vol.29 (14), pp. 2013-2023. show abstract

Weigelt, B. Mackay, A. Natrajan, R. Tan, D.S. Dowsett, M. Ashworth, A. Reis-Filho, J.S. (2010). The importance of gene-centring microarray data – Authors' reply. The lancet oncology, Vol.11 (8), pp. 720-721.

Lopez-Garcia, M.A. Geyer, F.C. Natrajan, R. Kreike, B. Mackay, A. Grigoriadis, A. Reis-Filho, J.S. Weigelt, B. (2010). Transcriptomic analysis of tubular carcinomas of the breast reveals similarities and differences with molecular subtype-matched ductal and lobular carcinomas. J pathol, Vol.222 (1), pp. 64-75. show abstract

Lambros, M.B. Natrajan, R. Geyer, F.C. Lopez-Garcia, M.A. Dedes, K.J. Savage, K. Lacroix-Triki, M. Jones, R.L. Lord, C.J. Linardopoulos, S. Ashworth, A. Reis-Filho, J.S. (2010). PPM1D gene amplification and overexpression in breast cancer: a qRT-PCR and chromogenic in situ hybridization study. Mod pathol, Vol.23 (10), pp. 1334-1345. show abstract

PPM1D (protein phosphatase magnesium-dependent 1δ) maps to the 17q23.2 amplicon and is amplified in ∼8% of breast cancers. The PPM1D gene encodes a serine threonine phosphatase, which is involved in the regulation of several tumour suppressor pathways, including the p53 pathway. Along with others, we have recently shown that PPM1D is one of the drivers of the 17q23.2 amplicon and a promising therapeutic target. Here we investigate whether PPM1D is overexpressed when amplified in breast cancers and the correlations between PPM1D overexpression and amplification with clinicopathological features and survival of breast cancer patients from a cohort of 245 patients with invasive breast cancer treated with therapeutic surgery followed by adjuvant anthracycline-based chemotherapy. mRNA was extracted from representative sections of tumours containing >50% of tumour cells and subjected to TaqMan quantitative real-time PCR using primers for PPM1D and for two housekeeping genes. PPM1D overexpression was defined as the top quartile of expression levels. Chromogenic in situ hybridization with in-house-generated probes for PPM1D was performed. Amplification was defined as >50% of cancer cells with >5 signals per nucleus/large gene clusters. PPM1D overexpression and amplification were found in 25 and 6% of breast cancers, respectively. All cases harbouring PPM1D amplification displayed PPM1D overexpression. PPM1D overexpression was inversely correlated with expression of TOP2A, EGFR and cytokeratins 5/6 and 17. PPM1D amplification was significantly associated with HER2 overexpression, and HER2, TOP2A and CCND1 amplification. No association between PPM1D gene amplification and PPM1D mRNA overexpression with survival was observed. In conclusion, PPM1D is consistently overexpressed when amplified; however, PPM1D overexpression is more pervasive than gene amplification. PPM1D overexpression and amplification are associated with tumours displaying luminal or HER2 phenotypes. Co-amplification of PPM1D and HER2/TOP2A and CCND1 are not random events and may suggest the presence of a 'firestorm' genetic profile..

Lacroix-Triki, M. Suarez, P.H. MacKay, A. Lambros, M.B. Natrajan, R. Savage, K. Geyer, F.C. Weigelt, B. Ashworth, A. Reis-Filho, J.S. (2010). Mucinous carcinoma of the breast is genomically distinct from invasive ductal carcinomas of no special type. J pathol, Vol.222 (3), pp. 282-298. show abstract

Mucinous carcinomas are a rare entity accounting for up to 2% of all breast cancers, which have been shown to display a gene expression profile distinct from that of invasive ductal carcinomas of no special type (IDC-NSTs). Here, we have defined the genomic aberrations that are characteristic of this special type of breast cancer and have investigated whether mucinous carcinomas might constitute a genomic entity distinct from IDC-NSTs. Thirty-five pure and 11 mixed mucinous breast carcinomas were assessed by immunohistochemistry using antibodies against oestrogen receptor (ER), progesterone receptor, HER2, Ki67, cyclin D1, cortactin, Bcl-2, p53, E-cadherin, basal markers, neuroendocrine markers, and WT1. Fifteen pure mucinous carcinomas and 30 grade- and ER-matched IDC-NSTs were microdissected and subjected to high-resolution microarray-based comparative genomic hybridization (aCGH). In addition, the distinct components of seven mixed mucinous carcinomas were microdissected separately and subjected to aCGH. Pure mucinous carcinomas consistently expressed ER (100%), lacked HER2 expression (97.1%), and showed a relatively low level of genetic instability. Unsupervised hierarchical cluster analysis revealed that pure mucinous carcinomas were homogeneous and preferentially clustered together, separately from IDC-NSTs. They less frequently harboured gains of 1q and 16p and losses of 16q and 22q than grade- and ER-matched IDC-NSTs, and no pure mucinous carcinoma displayed concurrent 1q gain and 16q loss, a hallmark genetic feature of low-grade IDC-NSTs. Finally, both components of all but one mixed mucinous carcinoma displayed similar patterns of genetic aberrations and preferentially clustered together with pure mucinous carcinomas on unsupervised clustering analysis. Our results demonstrate that mucinous carcinomas are more homogeneous between themselves at the genetic level than IDC-NSTs. Both components of mixed mucinous tumours are remarkably similar at the molecular level to pure mucinous cancers, suggesting that mixed mucinous carcinomas may be best classified as variants of mucinous cancers rather than of IDC-NSTs..

Dedes, K.J. Lopez-Garcia, M.-. Geyer, F.C. Lambros, M.B. Savage, K. Vatcheva, R. Wilkerson, P. Wetterskog, D. Lacroix-Triki, M. Natrajan, R. Reis-Filho, J.S. (2010). Cortactin gene amplification and expression in breast cancer: a chromogenic in situ hybridisation and immunohistochemical study. Breast cancer res treat, Vol.124 (3), pp. 653-666. show abstract

Amplification of 11q13 is found in approximately 15% of breast cancers. Cyclin D1 (CCND1) has been reported to be the 'driver' of this amplicon, however, multiple genes map to the smallest region of amplification of 11q13. Out of these genes, cortactin (CTTN) has been shown to be consistently overexpressed at the mRNA level in tumours harbouring 11q13 amplification. The aims of this study are to define whether CTTN is consistently co-amplified with the main core of the 11q13 amplicon, whether it is consistently overexpressed when amplified and to determine correlations between CTTN amplification and overexpression with clinicopathological features of breast cancers and survival of breast cancer patients. CTTN and CCND1 chromogenic in situ hybridisation (CISH) probes and a validated monoclonal antibody against CTTN were applied to a tissue microarray of a cohort of breast cancers from patients treated with anthracycline-based chemotherapy. CTTN and CCND1 amplifications were found in 12.3 and 12.4% of cases, respectively. All cases harbouring CTTN amplification also displayed CCND1 amplification. High expression of CTTN was found in 10.8% of cases and was associated with CTTN amplification, expression of 'basal' markers and topoisomerase IIα. Exploratory subgroup analysis of tumours devoid of 11q13 amplification revealed that high expression of CTTN in the absence of CTTN gene amplification was associated with lymph node negative disease, lack of hormone receptors and FOXA1, expression of 'basal' markers, high Ki-67 indices, p53 nuclear expression, and basal-like and triple negative phenotypes. CTTN expression and CTTN gene amplification were not associated with disease-, metastasis-free and overall survival. In conclusion, CTTN is consistently co-amplified with CCND1 and expressed at higher levels in breast cancers harbouring 11q13 amplification, suggesting that CTTN may also constitute one of the drivers of this amplicon. CTTN expression is not associated with the outcome of breast cancer patients treated with anthracycline-based chemotherapy..

Dedes, K.J. Wetterskog, D. Mendes-Pereira, A.M. Natrajan, R. Lambros, M.B. Geyer, F.C. Vatcheva, R. Savage, K. Mackay, A. Lord, C.J. Ashworth, A. Reis-Filho, J.S. (2010). PTEN deficiency in endometrioid endometrial adenocarcinomas predicts sensitivity to PARP inhibitors. Sci transl med, Vol.2 (53), p. 53ra75. show abstract

Dedes, K.J. Wetterskog, D. Mendes-Pereira, A.M. Vatcheva, R. Natrajan, R. Lambros, M.B. Lord, C.J. Ashworth, A. Reis-Filho, J.S. (2010). Preclinical evaluation of PARP inhibition as a treatment for endometrioid endometrial carcinomas. Journal of clinical oncology, Vol.28 (15).

Tan, D.S. Lambros, M.B. Rayter, S. Natrajan, R. Vatcheva, R. Gao, Q. Marchiò, C. Geyer, F.C. Savage, K. Parry, S. Fenwick, K. Tamber, N. Mackay, A. Dexter, T. Jameson, C. McCluggage, W.G. Williams, A. Graham, A. Faratian, D. El-Bahrawy, M. Paige, A.J. Gabra, H. Gore, M.E. Zvelebil, M. Lord, C.J. Kaye, S.B. Ashworth, A. Reis-Filho, J.S. (2009). PPM1D is a potential therapeutic target in ovarian clear cell carcinomas. Clin cancer res, Vol.15 (7), pp. 2269-2280. show abstract

PURPOSE: To identify therapeutic targets in ovarian clear cell carcinomas, a chemoresistant and aggressive type of ovarian cancer. EXPERIMENTAL DESIGN: Twelve ovarian clear cell carcinoma cell lines were subjected to tiling path microarray comparative genomic hybridization and genome-wide expression profiling analysis. Regions of high-level amplification were defined and genes whose expression levels were determined by copy number and correlated with gene amplification were identified. The effects of inhibition of PPM1D were assessed using short hairpin RNA constructs and a small-molecule inhibitor (CCT007093). The prevalence of PPM1D amplification and mRNA expression was determined using chromogenic in situ hybridization and quantitative real-time reverse transcription-PCR in a cohort of pure ovarian clear cell carcinomas and on an independent series of unselected epithelial ovarian cancers. RESULTS: Array-based comparative genomic hybridization analysis revealed regions of high-level amplification on 1q32, 1q42, 2q11, 3q24-q26, 5p15, 7p21-p22, 11q13.2-q13.4, 11q22, 17q21-q22, 17q23.2, 19q12-q13, and 20q13.2. Thirty-four genes mapping to these regions displayed expression levels that correlated with copy number gains/amplification. PPM1D had significantly higher levels of mRNA expression in ovarian clear cell carcinoma cell lines harboring gains/amplifications of 17q23.2. PPM1D inhibition revealed that PPM1D expression and phosphatase activity are selectively required for the survival of ovarian clear cell carcinoma cell lines with 17q23.2 amplification. PPM1D amplification was significantly associated with ovarian clear cell carcinoma histology (P = 0.0003) and found in 10% of primary ovarian clear cell carcinomas. PPM1D expression levels were significantly correlated with PPM1D gene amplification in primary ovarian clear cell carcinomas. CONCLUSION: Our data provide strong circumstantial evidence that PPM1D is a potential therapeutic target for a subgroup of ovarian clear cell carcinomas..

Drake, K.M. Ruteshouser, E.C. Natrajan, R. Harbor, P. Wegert, J. Gessler, M. Pritchard-Jones, K. Grundy, P. Dome, J. Huff, V. Jones, C. Aldred, M.A. (2009). Loss of heterozygosity at 2q37 in sporadic Wilms' tumor: putative role for miR-562. Clin cancer res, Vol.15 (19), pp. 5985-5992. show abstract

Natrajan, R. Lambros, M.B. Geyer, F.C. Marchio, C. Tan, D.S. Vatcheva, R. Shiu, K.-. Hungermann, D. Rodriguez-Pinilla, S.M. Palacios, J. Ashworth, A. Buerger, H. Reis-Filho, J.S. (2009). Loss of 16q in high grade breast cancer is associated with estrogen receptor status: Evidence for progression in tumors with a luminal phenotype?. Genes chromosomes cancer, Vol.48 (4), pp. 351-365. show abstract

Natrajan, R. Lambros, M.B. Rodríguez-Pinilla, S.M. Moreno-Bueno, G. Tan, D.S. Marchió, C. Vatcheva, R. Rayter, S. Mahler-Araujo, B. Fulford, L.G. Hungermann, D. Mackay, A. Grigoriadis, A. Fenwick, K. Tamber, N. Hardisson, D. Tutt, A. Palacios, J. Lord, C.J. Buerger, H. Ashworth, A. Reis-Filho, J.S. (2009). Tiling path genomic profiling of grade 3 invasive ductal breast cancers. Clinical cancer research : an official journal of the american association for cancer research, Vol.15 (8), pp. 2711-2722. show abstract

Marchio, C. Iravan, M. Natrajan, R. Lambros, M.B. Geyer, F.C. Savage, K. Parry, S. Tamber, N. Fenwick, K. Mackay, A. Schmitt, F.C. Bussolati, G. Ellis, I. Ashworth, A. Sapino, A. Reis, J.S. (2009). Mixed micropapillary-ductal carcinomas of the breast: a genomic and immunohistochemical analysis of morphologically distinct components. J pathol, Vol.218 (3), pp. 301-315. show abstract

Micropapillary carcinomas (MPCs) can present as a rare histological special type of breast cancer; however, this histological type is more frequently found admixed with invasive ductal carcinomas of no special type (IDC-NSTs). We have previously demonstrated that pure MPCs constitute a distinct entity at the morphological and genetic levels. Here, we sought to determine whether mixed MPCs have genomic aberrations similar to those found in pure MPCs, and to investigate whether the distinct morphological components of MPCs harbour different genetic aberrations. Using high-resolution microarray comparative genomic hybridization (aCGH), we profiled a series of 10 MPCs of mixed histology and 20 IDC-NSTs matched for grade and oestrogen receptor (ER) status. In addition, we generated tissue microarrays containing a series of 24 pure and 40 mixed MPCs and performed immunohistochemical analysis with ER, progesterone receptor (PR), Ki-67, HER2, cytokeratin (CK) 5/6, CK14, CK17, EGFR, topoisomerase-II alpha, cyclin D1, caveolin-1 and E-cadherin antibodies. In situ hybridization was employed to evaluate the prevalence of HER2, TOP2A, EGFR, CCND1, MYC and FGFR1 gene amplification. Our results demonstrate that mixed MPCs harbour similar patterns of genomic aberrations and phenotype (82.5% luminal and 17.5% HER2) compared to pure MPCs. A comparison between the distinct morphological components of mixed MPCs in a pairwise fashion revealed that both components harbour strikingly similar genomic profiles. When compared to grade- and ER-matched IDC-NSTs, mixed MPCs significantly more frequently harboured amplification of multiple regions on 8q (adjusted Fisher's p value <0.05). Furthermore, mixed MPCs displayed higher proliferative rates than grade- and ER-matched IDC-NST.s. Our results suggest that micropapillary differentiation in breast cancer may identify a subgroup of more aggressive ER-positive breast carcinomas, even in those featuring a mixed histology, and that mixed MPCs are more closely related to pure MPCs than to IDC-NSTs. Copyright (C) 2009 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd..

Marchiò, C. Iravani, M. Natrajan, R. Lambros, M.B. Geyer, F.C. Savage, K. Parry, S. Tamber, N. Fenwick, K. Mackay, A. Schmitt, F.C. Bussolati, G. Ellis, I. Ashworth, A. Sapino, A. Reis‐Filho, J.S. (2009). Mixed micropapillary–ductal carcinomas of the breast: a genomic and immunohistochemical analysis of morphologically distinct components. The journal of pathology, Vol.218 (3), pp. 301-315.

Geyer, F.C. Kushner, Y.B. Lambros, M.B. Natrajan, R. Mackay, A. Tamber, N. Fenwick, K. Purnell, D. Ashworth, A. Walker, R.A. Reis, J.S. (2009). Microglandular adenosis or microglandular adenoma? A molecular genetic analysis of a case associated with atypia and invasive carcinoma. Histopathology, Vol.55 (6), pp. 732-743. show abstract

Geyer, F.C. Kushner, Y.B. Lambros, M.B. Natrajan, R. Mackay, A. Tamber, N. Fenwick, K. Purnell, D. Ashworth, A. Walker, R.A. Reis-Filho, J.S. (2009). Microglandular adenosis or microglandular adenoma? A molecular genetic analysis of a case associated with atypia and invasive carcinoma. Histopathology, Vol.55 (6), pp. 732-743.

Natrajan, R. Lambros, M.B. Rodriguez-Pinilla, S.M. Moreno-Bueno, G. Tan, D.S. Marchio, C. Vatcheva, R. Rayter, S. Mahler-Araujo, B. Fulford, L.G. Hungermann, D. Mackay, A. Grigoriadis, A. Fenwick, K. Tamber, N. Hardisson, D. Tutt, A. Palacios, J. Lord, C.J. Buerger, H. Ashworth, A. Reis, J.S. (2009). Tiling Path Genomic Profiling of Grade 3 Invasive Ductal Breast Cancers. Clin cancer res, Vol.15 (8), pp. 2711-2722. show abstract

Stephens, P.J. McBride, D.J. Lin, M.-. Varela, I. Pleasance, E.D. Simpson, J.T. Stebbings, L.A. Leroy, C. Edkins, S. Mudie, L.J. Greenman, C.D. Jia, M. Latimer, C. Teague, J.W. Lau, K.W. Burton, J. Quail, M.A. Swerdlow, H. Churcher, C. Natrajan, R. Sieuwerts, A.M. Martens, J.W. Silver, D.P. Langerød, A. Russnes, H.E. Foekens, J.A. Reis-Filho, J.S. van 't Veer, L. Richardson, A.L. Børresen-Dale, A.-. Campbell, P.J. Futreal, P.A. Stratton, M.R. (2009). Complex landscapes of somatic rearrangement in human breast cancer genomes. Nature, Vol.462 (7276), pp. 1005-1010. show abstract

Iorns, E. Lord, C.J. Grigoriadis, A. McDonald, S. Fenwick, K. Mackay, A. Mein, C.A. Natrajan, R. Savage, K. Tamber, N. Reis-Filho, J.S. Turner, N.C. Ashworth, A. (2009). Integrated functional, gene expression and genomic analysis for the identification of cancer targets. Plos one, Vol.4 (4), p. e5120. show abstract

Natrajan, R. Warren, W. Messahel, B. Reis-Filho, J.S. Brundler, M.-. Dome, J.S. Grundy, P.E. Vujanic, G. Pritchard-Jones, K. Jones, C. (2008). Complex patterns of chromosome 9 alterations including the p16INK4a locus in Wilms tumours. J clin pathol, Vol.61 (1), pp. 95-102. show abstract

Arriola, E. Marchio, C. Tan, D.S. Drury, S.C. Lambros, M.B. Natrajan, R. Rodriguez-Pinilla, S.M. Mackay, A. Tamber, N. Fenwick, K. Jones, C. Dowsett, M. Ashworth, A. Reis-Filho, J.S. (2008). Genomic analysis of the HER2/TOP2A amplicon in breast cancer and breast cancer cell lines. Lab invest, Vol.88 (5), pp. 491-503. show abstract

HER2 and TOP2A are targets for the therapeutic agents trastuzumab and anthracyclines and are frequently amplified in breast cancers. The aims of this study were to provide a detailed molecular genetic analysis of the 17q12-q21 amplicon in breast cancers harbouring HER2/TOP2A co-amplification and to investigate additional recurrent co-amplifications in HER2/TOP2A-co-amplified cancers. In total, 15 breast cancers with HER2 amplification, 10 of which also harboured TOP2A amplification, as defined by chromogenic in situ hybridisation, and 6 breast cancer cell lines known to be amplified for HER2 were subjected to high-resolution microarray-based comparative genomic hybridisation analysis. This revealed that the genomes of 12 cases were characterised by at least one localised region of clustered, relatively narrow peaks of amplification, with each cluster confined to a single chromosome arm (ie 'firestorm' pattern) and 3 cases displayed many narrow segments of duplication and deletion affecting the vast majority of chromosomes (ie 'sawtooth' pattern). The smallest region of amplification (SRA) on 17q12 in the whole series extended from 34.73 to 35.48 Mb, and encompassed HER2 but not TOP2A. In HER2/TOP2A-co-amplified samples, the SRA extended from 34.73 to 36.54 Mb, spanning a region of approximately 1.8 Mb. Apart from HER2 and TOP2A, this region encompassed four additional genes whose expression levels as defined by quantitative real-time PCR are significantly higher in HER2/TOP2A-co-amplified vs HER2-amplified breast cancers: CASC3, CDC6, RARA and SMARCE1. Of the cell lines studied, SKBR3 and UACC812 showed HER2/TOP2A co-amplification. In conclusion, this is the first detailed genome-wide characterisation of HER2/TOP2A-amplified breast cancers; cell lines were identified that can be used to model these cancers in vitro. The 17q12 amplicon is complex and harbours multiple genes that may be associated with breast cancer development and progression, and potentially exploitable as therapeutic targets..

Reis-Filho, J.S. Natrajan, R. Vatcheva, R. Lambros, M.B. Marchió, C. Mahler-Araújo, B. Paish, C. Hodi, Z. Eusebi, V. Ellis, I.O. (2008). Is acinic cell carcinoma a variant of secretory carcinoma? A FISH study using ETV6'split apart' probes. Histopathology, Vol.52 (7), pp. 840-846. show abstract

Reis-Filho, J.S. Drury, S. Lambros, M.B. Marchio, C. Johnson, N. Natrajan, R. Salter, J. Levey, P. Fletcher, O. Peto, J. Ashworth, A. Dowsett, M. (2008). ESR1 gene amplification in breast cancer: a common phenomenon?. Nat genet, Vol.40 (7), pp. 809-810.

Marchiò, C. Iravani, M. Natrajan, R. Lambros, M.B. Savage, K. Tamber, N. Fenwick, K. Mackay, A. Senetta, R. Di Palma, S. Schmitt, F.C. Bussolati, G. Ellis, L.O. Ashworth, A. Sapino, A. Reis-Filho, J.S. (2008). Genomic and immunophenotypical characterization of pure micropapillary carcinomas of the breast. J pathol, Vol.215 (4), pp. 398-410. show abstract

Marchiò, C. Natrajan, R. Shiu, K.K. Lambros, M.B. Rodriguez-Pinilla, S.M. Tan, D.S. Lord, C.J. Hungermann, D. Fenwick, K. Tamber, N. Mackay, A. Palacios, J. Sapino, A. Buerger, H. Ashworth, A. Reis-Filho, J.S. (2008). The genomic profile of HER2-amplified breast cancers: the influence of ER status. J pathol, Vol.216 (4), pp. 399-407. show abstract

Edwards, S.L. Brough, R. Lord, C.J. Natrajan, R. Vatcheva, R. Levine, D.A. Boyd, J. Reis-Filho, J.S. Ashworth, A. (2008). Resistance to therapy caused by intragenic deletion in BRCA2. Nature, Vol.451 (7182), pp. 1111-1115. show abstract

Natrajan, R. Little, S.E. Sodha, N. Reis-Filho, J.S. Mackay, A. Fenwick, K. Ashworth, A. Perlman, E.J. Dome, J.S. Grundy, P.E. Pritchard-Jones, K. Jones, C. (2007). Analysis by array CGH of genomic changes associated with the progression or relapse of Wilms' tumour. J pathol, Vol.211 (1), pp. 52-59. show abstract

Little, S.E. Bax, D.A. Rodriguez-Pinilla, M. Natrajan, R. Messahel, B. Pritchard-Jones, K. Vujanic, G.M. Reis-Filho, J.S. Jones, C. (2007). Multifaceted dysregulation of the epidermal growth factor receptor pathway in clear cell sarcoma of the kidney. Clin cancer res, Vol.13 (15 Pt 1), pp. 4360-4364. show abstract

Natrajan, R. Williams, R.D. Grigoriadis, A. Mackay, A. Fenwick, K. Ashworth, A. Dome, J.S. Grundy, P.E. Pritchard-Jones, K. Jones, C. (2007). Delineation of a 1Mb breakpoint region at 1p13 in Wilms tumors by fine-tiling oligonucleotide array CGH. Genes chromosomes cancer, Vol.46 (6), pp. 607-615. show abstract

Lambros, M.B. Natrajan, R. Reis-Filho, J.S. (2007). Chromogenic and fluorescent in situ hybridization in breast cancer. Hum pathol, Vol.38 (8), pp. 1105-1122. show abstract

Tan, D.S. Lambros, M.B. Natrajan, R. Reis-Filho, J.S. (2007). Getting it right: designing microarray (and not 'microawry') comparative genomic hybridization studies for cancer research. Lab invest, Vol.87 (8), pp. 737-754. show abstract

Marchio, C. Iravani, M. Natrajan, R. Lambros, M. James, M. Savage, K. Mackay, A. Fenwick, K. Tamber, N. Schmitt, F.C. Ashworth, A. Ellis, I. Sapino, A. Bussolati, G. Reis, J.S. (2007). Molecular genetics and immunophenotypical characterization of micropapillary carcinomas of the breast. Virchows arch, Vol.451 (2), pp. 145-146.

Arriola, E. Lambros, M. Marchio, C. Tan, D. Natrajan, R. Rodriguez-Pinilla, S.M. Tamber, N. Fenwick, K. Mackay, A. Jones, C. Ashworth, A. Reis-Filho, J.S. (2007). Her2/TOP2A amplicon in breast: A microarray-based and chromogenic in situ hybridisation analysis. Virchows arch, Vol.451 (2), pp. 141-141.

Natrajan, R. Pinilla, S.M. Marchio, C. Vatcheva, R. Savage, K. Mackay, A. Fenwick, K. Tamber, N. Palacios, J. Ashworth, A. Reis, J.S. (2007). Near tiling microarray-based CGH identifies CCNE1 amplification in basal-like breast cancer. Virchows arch, Vol.451 (2), pp. 136-137.

Natrajan, R. Reis-Filho, J.S. Little, S.E. Messahel, B. Brundler, M.-. Dome, J.S. Grundy, P.E. Vujanic, G.M. Pritchard-Jones, K. Jones, C. (2006). Blastemal expression of type I insulin-like growth factor receptor in Wilms' tumors is driven by increased copy number and correlates with relapse. Cancer res, Vol.66 (23), pp. 11148-11155. show abstract

Little, S.E. Vuononvirta, R. Reis-Filho, J.S. Natrajan, R. Iravani, M. Fenwick, K. Mackay, A. Ashworth, A. Pritchard-Jones, K. Jones, C. (2006). Array CGH using whole genome amplification of fresh-frozen and formalin-fixed, paraffin-embedded tumor DNA. Genomics, Vol.87 (2), pp. 298-306. show abstract

Lambros, M.B. Simpson, P.T. Jones, C. Natrajan, R. Westbury, C. Steele, D. Savage, K. Mackay, A. Schmitt, F.C. Ashworth, A. Reis, J.S. (2006). Unlocking pathology archives for molecular genetic studies: a reliable method to generate probes for chromogenic and fluorescent in situ hybridization. Lab invest, Vol.86 (4), pp. 398-408. show abstract

Chromogenic (CISH) and fluorescent ( FISH) in situ hybridization have emerged as reliable techniques to identify amplifications and chromosomal translocations. CISH provides a spatial distribution of gene copy number changes in tumour tissue and allows a direct correlation between copy number changes and the morphological features of neoplastic cells. However, the limited number of commercially available gene probes has hindered the use of this technique. We have devised a protocol to generate probes for CISH that can be applied to formalin-fixed, paraffin-embedded tissue sections (FFPETS). Bacterial artificial chromosomes ( BACs) containing fragments of human DNA which map to specific genomic regions of interest are amplified with phi 29 polymerase and random primer labelled with biotin. The genomic location of these can be readily confirmed by BAC end pair sequencing and FISH mapping on normal lymphocyte metaphase spreads. To demonstrate the reliability of the probes generated with this protocol, four strategies were employed: (i) probes mapping to cyclin D1 (CCND1) were generated and their performance was compared with that of a commercially available probe for the same gene in a series of 10 FFPETS of breast cancer samples of which five harboured CCND1 amplification; (ii) probes targeting cyclin-dependent kinase 4 were used to validate an amplification identified by microarray-based comparative genomic hybridization (aCGH) in a pleomorphic adenoma; (iii) probes targeting fibroblast growth factor receptor 1 and CCND1 were used to validate amplifications mapping to these regions, as defined by aCGH, in an invasive lobular breast carcinoma with FISH and CISH; and (iv) gene-specific probes for ETV6 and NTRK3 were used to demonstrate the presence of t(12; 15)(p12; q25) translocation in a case of breast secretory carcinoma with dual colour FISH. In summary, this protocol enables the generation of probes mapping to any gene of interest that can be applied to FFPETS, allowing correlation of morphological features with gene copy number..

Lambros, M.B. Simpson, P.T. Jones, C. Natrajan, R. Westbury, C. Steele, D. Savage, K. Mackay, A. Schmitt, F.C. Ashworth, A. Reis-Filho, J.S. (2006). Unlocking pathology archives for molecular genetic studies: a reliable method to generate probes for chromogenic and fluorescent in situ hybridization. Laboratory investigation, Vol.86 (4), pp. 398-408.

Natrajan, R. Williams, R.D. Hing, S.N. Mackay, A. Reis-Filho, J.S. Fenwick, K. Iravani, M. Valgeirsson, H. Grigoriadis, A. Langford, C.F. Dovey, O. Gregory, S.G. Weber, B.L. Ashworth, A. Grundy, P.E. Pritchard-Jones, K. Jones, C. (2006). Array CGH profiling of favourable histology Wilms tumours reveals novel gains and losses associated with relapse. J pathol, Vol.210 (1), pp. 49-58. show abstract

Natrajan, R. Little, S.E. Reis-Filho, J.S. Hing, L. Messahel, B. Grundy, P.E. Dome, J.S. Schneider, T. Vujanic, G.M. Pritchard-Jones, K. Jones, C. (2006). Amplification and overexpression of CACNA1E correlates with relapse in favorable histology Wilms' tumors. Clin cancer res, Vol.12 (24), pp. 7284-7293. show abstract

Williams, R.D. Hing, S.N. Greer, B.T. Whiteford, C.C. Wei, J.S. Natrajan, R. Kelsey, A. Rogers, S. Campbell, C. Pritchard-Jones, K. Khan, J. (2004). Prognostic classification of relapsing favorable histology Wilms tumor using cDNA microarray expression profiling and support vector machines. Genes chromosomes cancer, Vol.41 (1), pp. 65-79. show abstract

Natrajan, R. Louhelainen, J. Williams, S. Laye, J. Knowles, M.A. (2003). High-resolution deletion mapping of 15q13 2-q21 1 in transitional cell carcinoma of the bladder. Cancer research, Vol.63 (22), pp. 7657-7662.

Natrajan, R. Sailem, H. Mardakheh, F.K. Arias Garcia, M. Tape, C.J. Dowsett, M. Bakal, C. Yuan, Y. Microenvironmental Heterogeneity Parallels Breast Cancer Progression: A Histology–Genomic Integration Analysis. Plos medicine, Vol.13 (2), pp. e1001961-e1001961.

Todd, J.R. Ryall, K.A. Vyse, S. Natrajan, R.C. Yuan, Y. Tan, A.C. Huang, P.H. Systematic analysis of tumour cell-extracellular matrix adhesion identifies independent prognostic factors in breast cancer. Oncotarget, . show abstract

Naidoo, K. Wai, P. Maguire, S. Daley, F. Haider, S. Kriplani, D. Campbell, J. Mirza, H. Grigoriadis, A. Tutt, A. Moseley, P. Abdel-Fatah, T. Chan, S. Madhusudan, S. Rhaka, E. Ellis, I. Lord, C. Yuan, Y. Green, A. Natrajan, R. Evaluation of CDK12 Protein Expression as a Potential Novel Biomarker for DNA Damage Response Targeted Therapies in Breast Cancer. Molecular cancer therapeutics, .

Bajrami, I. Marlow, R. van de Ven, M. Brough, R. Pemberton, H. Frankum, J. Song, F. Raquif, R. Konde, A. Krastev, D. Menon, M. Campbell, J. Gulati, A. Kumar, R. Pettitt, S. Gurden, M. Cardenosa, M. Chong, I. Gazinska, P. Wallberg, F. Sawyer, E. Martin, L. Dowsett, M. Linardopoulos, S. Natrajan, R. Ryan, C. Derksen, P. Jonkers, J. Tutt, A. Ashworth, A. Lord, C. E-cadherin/ROS1 inhibitor synthetic lethality in breast cancer. Cancer discovery, .

Read, A. Natrajan, R. Splicing dysregulation as a driver of breast cancer. Endocrine-related cancer, , pp. ERC-18-0068-ERC-18-0068.

Naidoo, K. Barrow-McGee, R. Procter, J. Gibson, A. Buus, R. Holgersen, E. Natrajan, R. Haider, S. Tutt, A. Real-time ex vivo perfusion of human lymph nodes invaded by cancer (REPLICANT): a feasibility study. Journal of pathology, .

Emad, A. Ray, T. Jensen, T.W. Parat, M. Natrajan, R. Sinha, S. Ray, P.S. An epithelial-mesenchymal-amoeboid transition gene signature reveals subtypes of breast cancer progression and metastasis. , . show abstract

Barry, P. Vatsiou, A. Spiteri Sagastume, I. Nichol, D. Cresswell, G. Acar, A. Trahearn, N. Hrebien, S. Garcia-Murillas, I. Chkhaidze, K. Ermini, L. Cottom, H. Zabaglo, L. Koelble, K. Khalique, S. Rusby, J. Muscara, F. Dowsett, M. Maley, C. Natrajan, R. Yuan, Y. Schiavon, G. Turner, N. Sottoriva, A. The spatio-temporal evolution of lymph node spread in early breast cancer. Clinical cancer research, .

Jones, C. Mackay, A. Izquierdo, E. Temelso, S. Carvalho, D. Molinari, V. Burford, A. Howell, L. Natrajan, R. Boult, J. Robinson, S. Infant high grade gliomas comprise multiple subgroups characterized by novel targetable gene fusions and favorable outcomes. Cancer discovery, .

Book Chapters

Leonidou, A. Peck, B. Natrajan, R. (2017). Identification and Validation of Driver Kinases from Next-Generation Sequencing Data. Methods in Molecular Biology. (pp. 179-195). Springer New York, ISBN: 9781493971527.

Conferences

Barrow-McGee, R.Procter, J.Owen, J.Woodman, N.Lombardelli, C.Kothari, A.Kovacs, T.Douek, M.George, S.Barry, P.Ramsey, K.Gibson, A.Buus, R.Holgerson, E.Natrajan, R.Haider, S.Shattock, M.J.Gillett, C.Tutt, A.N.Pinder, S.E.Naidoo, K. (2019). Normothermic Ex-Vivo Perfusion of Human Lymph Nodes: A Feasibility Study, JOURNAL OF PATHOLOGY, Vol.249, p.S16.

Piscuoglio, S.Ng, C.K.Geyer, F.C.Burke, K.A.Cowell, C.F.Martelotto, L.G.Natrajan, R.Popova, T.Maher, C.A.Lim, R.S.Bruijn, I.D.Mariani, O.Norton, L.Vincent-Salomon, A.Weigelt, B.Reis-Filho, J.S. (2017). Genomic and transcriptomic heterogeneity in metaplastic carcinomas of the breast, npj Breast Cancer, Vol.3 (1).

Piscuoglio, S.Ng, C.K.Cowell, C.F.Mariani, O.Martelotto, L.Natrajan, R.Lim, R.S.Maher, C.A.Vincent-Salomon, A.Weigelt, B.Reis-Filho, J.S. (2016). Abstract P6-03-10: Genomic and transcriptomic heterogeneity in metaplastic breast carcinomas, Presented at Abstracts: Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium; December 8-12, 2015; San Antonio, TX, Poster Session Abstracts, .

Carvalho, D.Taylor, K.Burford, A.Nowak, I.Mackay, A.Vinci, M.Bjerke, L.Molinari, V.Nandhabalan, M.Ingram, W.Jury, A.Natrajan, R.Jones, D.Pfister, S.Shats, L.Moore, A.Jacques, T.Popov, S.Jones, C. (2015). INFANTILE GLIOBLASTOMA WITH SARCOMATOUS HISTOLOGY DRIVEN BYETV6:NTRK3 FUSIONS ARE SENSITIVE TO TRK INHIBITION BY PHA-848125, NEURO-ONCOLOGY, Vol.17, p.12.

Maguire, S.Leonidou, A.Wai, P.Marchio, C.Ng, C.Sapino, A.Vincent-Salomon, A.Reis-Filho, J.Weigelt, B.Natrajan, R. (2015). Abstract A2-02: SF3B1 mutations constitute a novel therapeutic target in breast cancer, Presented at Abstracts: AACR Special Conference: Translation of the Cancer Genome; February 7-9, 2015; San Francisco, CA, Genomics and Target Discovery, .

Piscuoglio, S.Ng, C.K.Martelotto, L.G.Eberle, C.Cowell, C.F.Natrajan, R.Bidard, F.-.Wilkerson, P.M.Mariani, O.Vincent-Salomon, A.Weigelt, B.Reis-Filho, J.S. (2014). Papillary Carcinomas of the Breast Have Distinctive Transcriptomic Profiles and Are Not Underpinned by a Highly Recurrent Fusion Gene, LABORATORY INVESTIGATION, Vol.94, pp.75A-76A.

Martelotto, L.G.Ng, C.K.Lim, R.Piscuoglio, S.Natrajan, R.Wetterskog, D.Colombo, P.-.Reis-Filho, J.S.Vincent-Salomon, A.Weigelt, B. (2014). The Genomic Landscape of Adenoid Cystic Carcinoma of the Breast, MODERN PATHOLOGY, Vol.27, p.465A.

Maguire, S.Leonidou, A.Wai, P.Marchio, C.Ng, C.Weigelt, B.Sapino, A.Vincent-Solomon, A.Reis-Filho, J.Natrajan, R. (2014). SF3B1 K700E mutations are associated with alternative splicing in oestrogen receptor-positive breast cancer, VIRCHOWS ARCHIV, Vol.465, p.S24.

Maguire, S.Leonidou, A.Wai, P.Marchio, C.Ng, C.K.Weigelt, B.Sapino, A.Vincent-Salomon, A.Reis-Filho, J.S.Natrajan, R. (2014). SF3B1 mutations are associated with alternative splicing in ER-positive breast cancer, EUROPEAN JOURNAL OF CANCER, Vol.50, p.186.

Natrajan, R.Wilkerson, P.M.Marchio, C.Lambros, M.B.Ng, C.K.Topfer, C.Kozarewa, I.Hakas, J.Mitsopoulos, K.Hardisson, D.Lord, C.J.Weigelt, B.Ashworth, A.Sapino, A.Chinnaiyan, A.Maher, C.A.Reis-Filho, J.S. (2013). Functional Characterisation of Fusion Genes in Micropapillary Carcinomas of the Breast, LABORATORY INVESTIGATION, Vol.93, pp.57A-58A.

Ng, C.K.Gauthier, A.Wilkerson, P.M.Lambros, M.B.Arnoud, L.Lacroix-Triki, M.Penault-Llorca, F.Baranzelli, M.C.Sastre-Garau, X.Lord, C.J.Zvelebil, M.Mitsopoulos, C.Ashworth, A.Natrajan, R.Weigelt, B.Delattre, O.Cottu, P.Reis-Filho, J.S.Vincent-Salomon, A. (2013). Characterisation of the Genetic Heterogeneity of Invasive Breast Cancers with Heterogeneous HER2 Overexpression and Gene Amplification, MODERN PATHOLOGY, Vol.26, p.58A.

Garcia-Murillas, I.Pearson, A.Lambros, M.Natrajan, R.Segal, C.Dowsett, M.Turner, N.C. (2013). Abstract P2-08-01: Analysis of PIK3CA mutation abundance in primary breast cancer with droplet digital PCR identifies frequent sub-clonal PIK3CA mutations in ER negative and / or HER2 positive breast cancer, Presented at Abstracts: Thirty-Sixth Annual CTRC-AACR San Antonio Breast Cancer Symposium - Dec 10-14, 2013; San Antonio, TX, Poster Session Abstracts, .

Marchio, C.Rodrigues, D.N.Wilkerson, P.Lambros, M.B.Weigelt, B.Sapino, A.Mackay, A.Maher, C.Natrajan, R.Reis-Filho, J.S. (2012). Breast Micropapillary Carcinomas: RNA-Seq and Mutation Profiling, MODERN PATHOLOGY, Vol.25, p.53A.

Campion-Flora, A.Hernandez, L.Wilkerson, P.Lambros, M.B.Rodrigues, D.N.Gauthier, A.Mackay, A.Natrajan, R.Reis-Filho, J.S. (2012). Characterisation of the Repertoire of Gene Copy Number Changes and Gene Mutations in the Progression from In Situ to Invasive Breast Cancer, MODERN PATHOLOGY, Vol.25, pp.27A-28A.

Rodrigues, D.N.Wilkerson, P.Duprez, R.Mackay, A.Lambros, M.B.Gauthier, A.Mariani, O.Mansour, M.Natrajan, R.Weigelt, B.Vincent-Salomon, A.Reis-Filho, J.S. (2012). Integrative Analysis of Papillary Carcinomas of the Breast, MODERN PATHOLOGY, Vol.25, p.63A.

Reis-Filho, J.S.Mackay, A.Wilkerson, P.M.Lambros, M.B.Gauthier, A.Mariani, O.Duprez, R.Rodrigues, D.N.Mandour, M.Maher, C.Weigelt, B.Natrajan, R.Vincent-Salomon, A. (2012). Identification of Fusion Genes in Papillary Carcinomas of the Breast, MODERN PATHOLOGY, Vol.25, pp.61A-62A.

Geyer, F.C.Lacroix-Triki, M.Colombo, P.-.Patani, N.Gauthier, A.Natrajan, R.Lambros, M.B.Khalifch, I.Albarracin, C.Orru, S.Marchio, C.Sapino, A.Mackay, A.Weigeli, B.Schmitt, F.C.Wesseling, J.Sneige, N.Reis-Filho, J.S. (2012). Molecular Evidence in Support of the Neoplastic and Precursor Nature of Microglandular Adenosis, MODERN PATHOLOGY, Vol.25, p.41A.

Duprez, R.Wilkerson, P.Lacroix-Triki, M.Lambros, M.B.Mackay, A.Hern, R.A.Gauthier, A.Colombo, P.-.Daley, F.Natrajan, R.Ward, E.MacGrogan, G.Arbion, F.Michenet, P.Weigelt, B.Vincent-Saloman, A.Reis-Filho, J.S. (2012). Immunophenotypic and Genomic Characterisation of Papillary Carcinomas of the Breast, MODERN PATHOLOGY, Vol.25, p.35A.

Dedes, K.J.Wilkerson, P.Wetterskog, D.Lambros, M.B.Natrajan, R.Tan, D.S.Campion-Flora, A.Rodrigues, D.N.Gauthier, A.Daley, F.Lord, C.J.Kaye, S.B.Ashworth, A.Reis-Filho, J.S. (2012). PARP-Inhibitor Olaparib in the Treatment of Ovarian Clear Cell Cancer: Predictors of Sensitivity and Resistance, MODERN PATHOLOGY, Vol.25, p.265A.

Geyer, F.C.Lacroix-Triki, M.Colombo, P.-.Patani, N.Gauthier, A.Natrajan, R.Lambros, M.B.Khalifeh, I.Albarracin, C.Orru, S.Marchio, C.Sapino, A.Mackay, A.Weigelt, B.Schmitt, F.C.Wesseling, J.Sneige, N.Reis-Filho, J.S. (2012). Molecular Evidence in Support of the Neoplastic and Precursor Nature of Microglandular Adenosis, LABORATORY INVESTIGATION, Vol.92, p.41A.

Rodrigues, D.A.Wilkerson, P.Duprez, R.Mackay, A.Lambros, M.B.Gauthier, A.Mariani, O.Mansour, M.Natrajan, R.Weigelt, B.Vincent-Salomon, A.Reis-Filho, J.S. (2012). Integrative Analysis of Papillary Carcinomas of the Breast, LABORATORY INVESTIGATION, Vol.92, p.63A.

Hernandez, L.Lambros, M.B.Cabral, C.Vatcheva, R.Mackay, A.Wilkerson, P.Natrajan, R.Reis, J.S. (2011). Genomic Analysis of Matched In Situ to Invasive Ductal Carcinomas Provides Direct Evidence for Selection of Invasive Cancer Cells with Specific Genetic Aberrations, Presented at 100th Annual Meeting United States-and-Canadian-Academy-of-Pathology, San Antonio, TX. MODERN PATHOLOGY, Vol.24, p.42A.

Mackay, A.Weigelt, B.Grigoriadis, A.Kreike, B.Natrajan, R.A'Hern, R.Tan, D.S.Dowsett, M.Ashworth, A.Reis, J.S. (2011). Identification of Molecular Subtypes of Breast Cancer Using Hierarchical Clustering: Analysis of Inter-Observer Agreement., Presented at 100th Annual Meeting United States-and-Canadian-Academy-of-Pathology, San Antonio, TX. MODERN PATHOLOGY, Vol.24, p.53A.

Natrajan, R.Wetterskog, D.Lambros, M.B.Geyer, F.C.Mackay, A.Vatcheva, R.Reis, J.S. (2011). Functional Characterisation of the 19q12 Amplicon in Grade 3 Breast Cancers., Presented at 100th Annual Meeting United States-and-Canadian-Academy-of-Pathology, San Antonio, TX. MODERN PATHOLOGY, Vol.24, p.56A.

Wilkerson, P.Mackay, A.Lambros, M.B.Natrajan, R.Horlings, H.van de Vijver, M.J.Reis, J.S. (2011). Identification of Drivers of the 11q13 Amplicon., Presented at 100th Annual Meeting United States-and-Canadian-Academy-of-Pathology, San Antonio, TX. MODERN PATHOLOGY, Vol.24, p.71A.

Hernandez, L.Lambros, M.B.Cabral, C.Vatcheva, R.Mackay, A.Wilkerson, P.Natrajan, R.Reis, J.S. (2011). Genomic Analysis of Matched In Situ to Invasive Ductal Carcinomas Provides Direct Evidence for Selection of Invasive Cancer Cells with Specific Genetic Aberrations, Presented at 100th Annual Meeting of the United States and Canadian-Academy-of-Pathology, San Antonio, TX. LABORATORY INVESTIGATION, Vol.91, p.42A.

Mackay, A.Weigelt, B.Grigoriadis, A.Kreike, B.Natrajan, R.A'Hern, R.Tan, D.S.Dowsett, M.Ashworth, A.Reis, J.S. (2011). Identification of Molecular Subtypes of Breast Cancer Using Hierarchical Clustering: Analysis of Inter-Observer Agreement, Presented at 100th Annual Meeting of the United States and Canadian-Academy-of-Pathology, San Antonio, TX. LABORATORY INVESTIGATION, Vol.91, p.53A.

Natrajan, R.Wetterskog, D.Lambros, M.B.Geyer, P.C.Mackay, A.Vatcheva, R.Reis, J.S. (2011). Functional Characterisation of the 19q12 Amplicon in Grade 3 Breast Cancers, Presented at 100th Annual Meeting of the United States and Canadian-Academy-of-Pathology, San Antonio, TX. LABORATORY INVESTIGATION, Vol.91, p.56A.

Wilkerson, P.Mackay, A.Lambros, M.B.Natrajan, R.Horlings, H.van de Vijver, M.J.Reis, J.S. (2011). Identification of Drivers of the 11q13 Amplicon, Presented at 100th Annual Meeting of the United States and Canadian-Academy-of-Pathology, San Antonio, TX. LABORATORY INVESTIGATION, Vol.91, p.71A.

Lambros, M.B.Natrajan, R.Vatcheva, R.Gohlke, H.Plant, M.Muller, S.Reis, J.S. (2011). Massarray Technology: High Throughput Method for Unlocking the Presence of Recurrent Fusion Gene in Cancer, Presented at 100th Annual Meeting United States-and-Canadian-Academy-of-Pathology, San Antonio, TX. MODERN PATHOLOGY, Vol.24, p.451A.

Lambros, M.B.Natrajan, R.Vatcheva, R.Gohlke, H.Plant, M.Muller, S.Reis, J.S. (2011). Massarray Technology: High Throughput Method for Unlocking the Presence of Recurrent Fusion Gene in Cancer, Presented at 100th Annual Meeting of the United States and Canadian-Academy-of-Pathology, San Antonio, TX. LABORATORY INVESTIGATION, Vol.91, p.451A.

Patani, N.Dedes, K.J.Lambros, M.K.Natrajan, R.Reis-Filho, J.S.Dowsett, M. (2011). FREQUENCY AND DISTRIBUTION OF CAVEOLIN-1 MUTATIONS IN HUMAN BREAST CANCER, Presented at Conference on Improving Care and Knowledge through Translational Research (IMPAKT) Breast Cancer, Brussels, BELGIUM. ANNALS OF ONCOLOGY, Vol.22, p.35.

Natrajan, R.Geyer, F.Lambros, M.B.Lopez-Garcia, M.A.Savage, K.Reis-Filho, J.S. (2010). Drosha and Dicer Down-Regulation in Breast Cancer: A QRT-PCR Analysis, Presented at 99th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology, Washington, DC. LABORATORY INVESTIGATION, Vol.90, pp.63A-64A.

Abdel-Fatah, T.M.Powe, D.G.Lambros, M.Natrajan, R.Green, A.Reis-Filho, J.S.Ellis, I.O. (2010). Use of High Resolution Array Comparative Genomic Hybridization (aCGH) To Identify Mouse Double Minutes 4 (Mdm4) as an Early Genetic Change in Breast Cancer Development: Evaluation of Mdm4 as a New Prognostic and Predictive Marker, Presented at 99th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology, Washington, DC. MODERN PATHOLOGY, Vol.23, p.31A.

Muggerud, A.Horlings, H.Lambros, M.B.Natrajan, R.Mackay, A.Ashworth, A.van de Vijver, M.J.Reis-Filho, J.S. (2010). Integration of Microarray CGH and Expression Analysis Reveals Potential Breast Cancer Therapeutic Targets, Presented at 99th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology, Washington, DC. LABORATORY INVESTIGATION, Vol.90, p.63A.

Abdel-Fatah, T.M.Powe, D.G.Lambros, M.Natrajan, R.Green, A.Reis, J.S.Ellis, I.O. (2010). Use of High Resolution Array Comparative Genomic Hybridization (aCGH) To Identify Mouse Double Minutes 4 (Mdm4) as an Early Genetic Change in Breast Cancer Development: Evaluation of Mdm4 as a New Prognostic and Predictive Marker, Presented at 99th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology, Washington, DC. LABORATORY INVESTIGATION, Vol.90, p.31A.

Natrajan, R.Geyer, F.Lambros, M.B.Lopez-Garcia, M.A.Savage, K.Reis, J.S. (2010). Drosha and Dicer Down-Regulation in Breast Cancer: A QRT-PCR Analysis, Presented at 99th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology, Washington, DC. MODERN PATHOLOGY, Vol.23, pp.63A-64A.

Lacroix-Triki, M.Saurez, P.Lambros, M.B.Natrajan, R.Mackay, A.Geyer, F.C.Ashworth, A.Reis, J.S. (2010). Molecular Characterisation of Mucinous Carcinomas of the Breast - A Genomic Profiling Analysis, Presented at 99th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology, Washington, DC. LABORATORY INVESTIGATION, Vol.90, pp.57A-58A.

Lambros, M.B.Natrajan, R.Geyer, F.C.Lopez-Garcia, M.A.Savage, K.Lacroix-Triki, M.Reis, J.S. (2010). PPM1D Overexpression and Gene Amplification in Breast Cancers: A QRT-PCR and Chromogenic In Situ Hybridisation Study, Presented at 99th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology, Washington, DC. MODERN PATHOLOGY, Vol.23, p.58A.

Muggerud, A.Horlings, H.Lambros, M.B.Natrajan, R.Mackay, A.Ashworth, A.van de Vijver, M.J.Reis, J.S. (2010). Integration of Microarray CGH and Expression Analysis Reveals Potential Breast Cancer Therapeutic Targets, Presented at 99th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology, Washington, DC. MODERN PATHOLOGY, Vol.23, p.63A.

Weigelt, B.Geyer, F.C.Natrajan, R.Lopez-Garcia, M.A.Ahmad, A.S.Savage, K.Kreike, B.Reis, J.S. (2010). The Molecular Underpinning of Lobular Histological Growth Pattern: A Genome-Wide Transcriptomic Analysis of Invasive Lobular Carcinomas and Grade- and Molecular Subtype-Matched Invasive Ductal Carcinomas of No Special Type, Presented at 99th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology, Washington, DC. MODERN PATHOLOGY, Vol.23, p.77A.

Weigelt, B.Mackay, A.Natrajan, R.Tan, D.S.Ashworth, A.Reis, J.S. (2010). Breast Cancer Molecular Subtype Classification: A Comparison of Three Microarray-Based Single Sample Predictors, Presented at 99th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology, Washington, DC. MODERN PATHOLOGY, Vol.23, p.77A.

Natrajan, R.Lambros, M.B.Marchio, C.Tan, D.S.Vatcheva, R.Geyer, F.Shiu, K.K.Hungermann, D.Rodriguez-Pinilla, S.M.Palacios, J.Ashworth, A.Buerger, H.Reis-Filho, J.S. (2009). Loss of 16q in High Grade Breast Cancer Is Associated with ER Status: Evidence for Progression in Luminal Tumours?, Presented at 98th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology, Boston, MA. LABORATORY INVESTIGATION, Vol.89, p.59A.

Natrajan, R.Lambros, M.B.Marchio, C.Tan, D.S.Vatcheva, R.Geyer, F.Shiu, K.K.Hungermann, D.Rodriguez-Pinilla, S.M.Palacios, J.Ashworth, A.Buerger, H.Reis, J.S. (2009). Loss of 16q in High Grade Breast Cancer Is Associated with ER Status: Evidence for Progression in Luminal Tumours?, Presented at 98th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology, Boston, MA. MODERN PATHOLOGY, Vol.22, p.59A.

Natrajan, R.Rodriguez-Pinilla, S.M.Lambros, M.B.Tan, D.S.Marchio, C.Vatcheva, R.Rayter, S.Moreno-Bueno, G.Fulford, L.G.Mackay, A.Grigoriadis, A.Fenwick, K.Tamber, N.Hardisson, D.Tutt, A.Palacios, J.Buerger, H.Lord, C.J.Ashworth, A.Reis-Filho, J.S. (2009). Molecular Profiling of Grade III Invasive Ductal Breast Cancers Identifies PPM1D Amplification as a Therapeutic Target in Luminal and HER2 Tumours, Presented at 98th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology, Boston, MA. LABORATORY INVESTIGATION, Vol.89, p.59A.

Reis-Filho, J.S.de Biase, D.Lambros, M.B.Geyer, F.C.Ragazzi, M.Natrajan, R.Mackay, A.Tamber, N.Fenwick, K.Ashworth, A.Tallini, G.Eusebi, V. (2009). Genomic Profiling of Mitochondria-Rich Breast Cancer, Presented at 98th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology, Boston, MA. LABORATORY INVESTIGATION, Vol.89, p.64A.

Natrajan, R.Rodriguez-Pinilla, S.M.Lambros, M.B.Tan, D.S.Marchio, C.Vatcheva, R.Rayter, S.Moreno-Bueno, G.Fulford, L.G.Mackay, A.Grigoriadis, A.Fenwick, K.Tamber, N.Hardisson, D.Tutt, A.Palacios, J.Buerger, H.Lord, C.J.Ashworth, A.Reis, J.S. (2009). Molecular Profiling of Grade III Invasive Ductal Breast Cancers Identifies PPM1D Amplification as a Therapeutic Target in Luminal and HER2 Tumours, Presented at 98th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology, Boston, MA. MODERN PATHOLOGY, Vol.22, p.59A.

Reis, J.S.de Biase, D.Lambros, M.B.Geyer, F.C.Ragazzi, M.Natrajan, R.Mackay, A.Tamber, N.Fenwick, K.Ashworth, A.Tallini, G.Eusebi, V. (2009). Genomic Profiling of Mitochondria-Rich Breast Cancer, Presented at 98th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology, Boston, MA. MODERN PATHOLOGY, Vol.22, p.64A.

Turner, N.Lambros, M.Horlings, H.Pearson, A.Sharpe, R.Mackay, A.Natrajan, R.Geyer, F.van Kouwenhove, M.Kreike, B.Ashworth, A.van de Vijver, M.Reis, J. (2009). Integrative Molecular Profiling of Triple Negative Breast Cancers Identifies Potential Therapeutic Targets Including Amplifications of FGFR2, Presented at 32nd Annual San Antonio Breast Cancer Symposium, San Antonio, TX. CANCER RESEARCH, Vol.69 (24), p.695S.

Abdel-Fatah, T.M.Powe, D.G.Lambros, M.Natrajan, R.Reis, J.S.Ellis, I.O. (2009). High Resolution Array Comparative Genomic Hybridization (aCGH) of Breast Carcinoma Identifies Mouse Double Minutes 4 (Mdm4) as One of the Early Genetic Changes in Breast Cancer Development: Mdm4 Is a New Independent Prognostic and Predictive Marker, Presented at 32nd Annual San Antonio Breast Cancer Symposium, San Antonio, TX. CANCER RESEARCH, Vol.69 (24), p.705S.

Reis-Filho, J.S.Natrajan, R.Vatcheva, R.Lambros, M.B.Marchio, C.Mahler-Raujo, B.Iravani, M.Paish, C.Hodi, Z.Eusebi, V.Ellis, I.O. (2008). Is acinic cell carcinoma a variant of secretory carcinoma? A FISH study using ETV6 'split apart' probes, Presented at 97th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology, Denver, CO. MODERN PATHOLOGY, Vol.21, p.51A.

Reis-Filho, J.S.Natrajan, R.Vatcheva, R.Lambros, M.B.Marchio, C.Mahler-Araujo, B.Iravani, M.Paish, C.Hodi, Z.Eusebi, V.Ellis, I.O. (2008). Is acinic cell carcinoma a variant of secretory carcinoma? A FISH study using ETV6 'Split apart' probes, Presented at 97th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology, Denver, CO. LABORATORY INVESTIGATION, Vol.88, p.51A.

Arriola, E.Lambros, M.B.Marchio, C.Tan, D.Natrajan, R.Rodrigvez-Pinilla, S.M.Tamber, N.Fenwick, K.Mackay, A.Jones, C.Dowsett, M.Ashworth, A.Reis-Filho, J.S. (2007). HER2/TOP2A amplicon in breast cancer: a microarray-based and chromogenic in situ hybridisation analysis, Presented at 30th Annual San Antonio Breast Cancer Symposium, San Antonio, TX. BREAST CANCER RESEARCH AND TREATMENT, Vol.106, pp.S285-S286.

Natrajan, R.Rodriguez-Pinilla, S.M.Marchio, C.Moreno-Bueno, G.Vatcheva, R.Mahler-Araujo, B.Lambros, M.B.Mackay, V.A.Palacios, J.Ashworth, A.Reis-Filho, J.S. (2007). Array-CGH identifies CCNE1 amplification in ER/HER2 negative breast cancers, Presented at 30th Annual San Antonio Breast Cancer Symposium, San Antonio, TX. BREAST CANCER RESEARCH AND TREATMENT, Vol.106, p.S285.

Marchio, C.Iravani, M.Natrajan, R.Lambros, M.B.James, M.Savage, K.Mackay, A.Fenwick, K.Tamber, N.Schmitt, F.C.Ellis, I.Bussolati, G.Sapino, A.Ashworth, A.Reis-Filho, J.S. (2007). Molecular genetics and immunophenotypical characterisation of micropapillary carcinomas of the breast, Presented at 30th Annual San Antonio Breast Cancer Symposium, San Antonio, TX. BREAST CANCER RESEARCH AND TREATMENT, Vol.106, p.S286.

Natrajan, R.Little, S.E.Reis-Filho, J.S.Warren, W.Messahel, B.Brundler, M.-.Vujanic, G.Pritchard-Jones, K.Jones, C. (2006). Blastemal/stromal expression of IGF1R in Wilms tumours is driven by increased copy number and correlates with relapse, CANCER RESEARCH, Vol.66 (8).

Lambros, M.B.Simpson, P.T.Jones, C.Natrajan, R.Westbury, C.Steele, D.Savage, K.MacKay, A.Schmitt, F.C.Ashworth, A.Reis-Filho, J.S. (2006). Unlocking pathology archives for molecular genetic studies: A reliable method to generate probes for chromogenic and fluorescent in situ hybridisation, Presented at 26th International Congress of the International-Academy-of-Pathology, Montreal, CANADA. MODERN PATHOLOGY, Vol.19, pp.139-140.

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