Bio-medical Sciences and Engineering MS Thesis Defense by Tunç Morova

August 29, 2018






Title: Androgen receptor binding sites are highly mutated in prostate cancer


Speaker: Tunç Morova


Time: 27.06.2018 – 10:30


Place: ENG B15

Koç University

Rumeli Feneri Yolu

Sariyer, Istanbul


Thesis Committee Members:

Assoc. Prof. Nathan A. LACK (Advisor, Koç University)

Prof. Dr. Attila GÜRSOY (Koç University)

Assist. Prof. Öznur TAŞTAN (Sabanci University)




Cancer arises through the sequential accumulation of mutations that induce neoplastic transformation and uncontrolled proliferation. These somatic mutations however do not occur in a normal distribution across the genome and are affected by several variables including GC content, replication time, distance to telomere and chromatin compaction. Recent study demonstrated that TF binding to DNA increases the rate of mutations due the impairment of nuclear excision repair mechanism. On the other hand, Prostate cancer (PCa) is the most frequently diagnosed cancer in European men and the second leading cause of cancer-related death. Androgen receptor (AR) mediated transcription is critical at all stages of PCa progression. Following activation, AR binds to specific DNA response elements where it recruits numerous co-activators that induce gene transcription. Given properties of AR makes it an ideal model to study TF mediated DNA damage characteristics and frequency. Therefore, our aim is to investigate how TF binding affects somatic mutations in Prostate Cancer. To test this we analyzed clinical whole genome sequencing data to investigate both the type and frequency of mutations at ARBS. We demonstrated that PCa has the highest frequency of mutations at ARBS of any cancer type. Further, among all transcription factors tested, AR had the highest mutation frequency in PCa. Interestingly, we also found a novel mutation signature at ARBS that is different from the remainder of the genome. Specifically, there was a markedly higher rate of TpG->ApG mutations potentially mediated by spontaneous depurination. This mutational signature is independent of the nucleotide composition of ARBS. While speculative, we believe the higher rate of mutations occurs due to an inability of the Base Excision Repair machinery to access the spontaneous mutations at ARBS and not DSB. Herein we reveal distinct mutation phenomena in prostate cancer patients that require validation and further investigation.