Intermediate phenotypes and mapping causal variants; IGFBP-2, IGFBP-5 and breast cancer risk
Supervisor(s): Professor Alan Ashworth
Section: Breakthrough Breast Cancer Research Centre
Team: Gene Function
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Summary
Identifying women at high polygenic risk of developing breast cancer and, particularly identifying subgroups of women who may benefit disproportionately from targeted interventions remains a priority in breast cancer research. Studies based on intermediate phenotypes may provide a statistically efficient alternative to classical genetic association studies. The overall aim of this project is to inform future strategies for mapping genetic variants in relation to intermediate phenotypes, specifically:
- To develop and compare methodology to measure IGFBP-2 and IGFBP-5 levels in peripheral blood lymphocytes (buffy coat samples), in tissue culture breast cancer cell lines and in fresh frozen breast tumour tissue
- To test for an association between levels of IGFBP-2 and IGFBP-5 and (i) the breast cancer risk allele rs13387042 at 2q35, (ii) additional common variants within a 1 megabase region surrounding IGFBP-2 and IGFBP-5 and (iii) published variants within the IGFBP-2 and IGFBP-5 locus
- To fine map potential causal variants within the LD block containing rs13387042 in relation to (i) breast cancer and (ii) levels of IGFBP-2 and IGFBP-5
- To test for functional effects associated with these variants using qRT-PCR, pyro-sequencing, electromobility shift assays and chromatin immunoprecipitation
- Use genome wide SNP data to test for trans acting loci that are associated with levels of IGFBP-2 and IGFBP-5
References
- Fletcher, O., et al. (2005) Polymorphisms and circulating levels in the insulin-like growth factor system and risk of breast cancer: a systematic review. Cancer Epidemiol Biomarkers Prev Vol 14, No 1, p2-19
- Li, X., et al. (2007) Expression level of insulin-like growth factor binding protein 5 mRNA is a prognostic factor for breast cancer. Cancer Sci Vol 98, No 10, p1592-1596
- Wang, H., et al. (2008) IGFBP2 and IGFBP5 overexpression correlates with the lymph node metastasis in T1 breast carcinomas. Breast J Vol 14, No 3, p261-267
- Stacey, S.N., et al. (2007) Common variants on chromosomes 2q35 and 16q12 confer susceptibility to estrogen receptor-positive breast cancer. Nat Genet Vol 39, No 7, p865-869
- Dunning, A.M., et al. (2004) Polymorphisms associated with circulating sex hormone levels in postmenopausal women. J Natl Cancer Inst Vol 96, No 12, p936-945
- Palles, C., et al. (2008) Identification of genetic variants that influence circulating IGF1 levels: a targeted search strategy. Hum Mol Genet Vol 17, No 10, p1457-1464
