PacRim7 7th PacRim Meeting Poster Presentations (1) (52 abstracts)
Androgen receptor binding sites are highly mutated in prostate cancer
Tunç Morova 1, , Mehmet Gönen 1, , Kush Dalal 3 , Attila Gursoy 2 , Özlem Keskin 2 & Nathan A Lack 1,
1School of Medicine, Koç University, Istanbul, Turkey; 2College of Engineering, Koç University, Istanbul, Turkey; 3Vancouver Prostate Centre, University of British Columbia, Vancouver, Canada.
Androgen receptor (AR) signalling is essential to nearly all prostate cancer cells. Any alterations to AR-mediated transcription can have a profound effect on prostate carcinogenesis and tumour growth. While the AR protein has been extensively studied, little is know about mutations to the non-coding regions where AR binds to DNA. Using clinical whole genome sequencing, we demonstrate that AR binding sites have a dramatically increased rate of mutations that is greater than any other transcription factor and specific to only prostate cancer. Demonstrating this may be common to lineage-specific transcription factors, estrogen receptor binding sites also had an elevated rate of mutations in breast cancer. Based on the mutations observed at the binding site of AR and other related transcription factors, we propose that AR occupancy impairs access of base excision repair enzymes to endogenous DNA damage. To identify critical binding sites we systematically tested enhancer activity at every clinical AR binding site. From this we demonstrated that approximately 10% of the binding sites have enhancer activity. Combining these results with chromosomal confirmation capture approaches, we link specific somatic mutations at enhancer sites to alterations in gene regulation. Overall, this work demonstrates that non-coding mutations at AR binding sites can play a critical role in prostate cancer.
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Oncology Abstracts
ISSN 2631-4657 (online)
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