Androjen reseptörü baglanma noktaları prostat kanserinde sıkça mutasyona uğramıştır.

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 in melanoma due the impairment of nuclear excision repair mechanism. However, it is unclear if this phenomenon is specific to only high-mutation rate cancers or certain chromosomal regions. 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. However, despite the importance of AR signaling in prostate cancer it plays no role in almost all other cancer types. Given this specificity, the AR is an ideal model to study TF mediated DNA damage characteristics and frequency. Therefore, the aim of this work was to investigate how TF binding affects somatic mutations in prostate cancer (PCa). To test this, we analyzed whole genome sequencing data from prostate primary PCa (n=196) to investigate both the type and frequency of mutations at AR binding sites (ARBS). We demonstrated that PCa has the highest frequency of mutations at ARBS of any cancer type. Further, among all TF tested, ARBS had by far the highest mutation frequency. 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.