A mechanism based classification of human prostate cancer
Supervisor(s): Professor Colin Cooper
Section of Molecular Carcinogenesis
Team: Cell Transformation
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Summary
We are proposing to put in place a new classification system for human prostate cancer, based on current knowledge of the underlying mechanism of development of this disease. The intention is that this classification system should be used alongside conventional predictors of aggressive disease and tumour progression to improve patient management and choice of therapeutic treatment. This molecular biology project will have clinical links to the Royal Marsden NHS Foundation Trust, be underpinned by the core infrastructure of the National Cancer Research Institute (NCRI) South of England Prostate Cancer Collaborative, and have international links through the TransAtlantic Prostate Group.
It has recently been discovered that alterations in members of the ETS-gene family (specifically ERG, ETV1, ETV4 and ETV5) are involved in the development of human prostate cancer [1]. Deletion of the PTEN suppressor gene [2], and amplification of the MYC gene [3] have also been reported in primary human prostate cancer. Additionally we have demonstrated that amplification of the androgen-receptor (AR) gene is observed in around 10% of early disease (unpublished). We have already set up Florescence in situ Hybridisation (FISH) assays for assessing AR, ETS and PTEN status [4]. The proposed project will involve a number of components:
Component 1. First, a microarray-based Comparative Genomic Hybridisation (CGH) screen will be performed on a series of 100 frozen cancer specimens and the data linked to clinical outcome. These analyses will allow an assessment of whether there are other regions of genetic gain and loss that could provide clinically useful information.
Component 2. Secondly, genetic alterations including AR and MYC gene status (and any new alterations identified in the above CGH studies) will be assessed using FISH assays in 4 independent series of prostate cancers representing over 1300 patients. This component of the study will validate whether genetic alterations, either alone or in combination, can be used as novel prognostic markers.
Component 3. Finally, individual gene markers identified in ‘Component 2’ will be verified as clinically useful in studies linked to randomized radiotherapy trials and to active surveillance trials. Current successes of this approach include the discovery that duplication of ERG rearrangement, in an alteration called 2+Edel, is an independent marker of very poor clinical outcome [5].
References
- Clark, J.P., Cooper, C.S. (2009) ETS gene fusions in prostate cancer. Nat Rev Urol Vol 6, No 8, p429-439
- Verhagen, P.C., et al. (2006) The PTEN gene in locally progressive prostate cancer is preferentially inactivated by bi-allelic gene deletion. J Pathol Vol 208, No 5, p699-707
- Ishkanian, A.S., et al. (2009) High-resolution array CGH identifies novel regions of genomic alteration in intermediate-risk prostate cancer. Prostate Vol 69, No 10, p1091-1100
- Attard, G. et al. (2009) Characterisation of ERG, AR and PTEN gene status in circulating tumour cells from patients with castration resistant prostate cancer. Cancer Res Vol 69, No 7, p2912-2918
- Attard, G. et al. (2008) Duplication of the fusion of TMPRSS2 to ERG sequences identifies fatal human prostate cancer. Oncogene Vol 27, No 3, p253-263
