Somatic mutations in the DNA repairome in prostate cancers in African Americans and Caucasians

Abstract

Most hereditary tumors show aberrations in DNA repair genes or their regulators. In contrast, only a minority of sporadic tumors show alterations in these genes. As a result, genomic instability is currently considered an enhancer of tumorigenesis rather than an obligatory event in this process. However, tumor heterogeneity presents a significant technical challenge for most cancer genomics studies performed at less than 100× mean resolution depth. To address the importance of genomic instability in prostate carcinogenesis and tumor progression, we performed ultrahigh depth exome sequencing of 124 DNA damage repair/response (repairome) genes in 63 tumors and matched normal tissue samples in African Americans and Caucasians. The average sequence depth was 712-fold for DNA isolated from normal tissue and 368-fold for FFPE tumors. We identified 671 somatic mutations in tumors from African Americans and 762 somatic mutations in tumors in Caucasians. The most frequently mutated DNA repairome genes were EXO1,

Systematic Literature Review of the Epidemiology of Advanced Prostate Cancer and Associated Homologous Recombination Repair Gene Alterations

“…Research has suggested there may be important differences between African-American men with PC versus Caucasian men. [35][36][37][38] Additionally, NCCN guidelines recommends Ashkenazi Jewish population for genetic testing. 5 Studies lacked consistency for the specific HRRm assessed.…”

Immune Inflammation Pathways as Therapeutic Targets to Reduce Lethal Prostate Cancer in African American Men

“…A proposed feature of prostate tumors in African American men that may play a prominent role in differential response to treatment is a deficiency in DNA damage repair capacity. Both germline and somatic alterations to DNA damage repair pathways have now been found in prostate tumors across multiple studies [66,[105][106][107]. Tumors from African American men were reported to have a significantly lower level of DNA repair capacity when compared to those from European American men.…”

Race as a Contributor to Stromal Modulation of Tumor Progression

“…Genomic instability contributes to tumorigenesis and both germline and somatic mutations are amenable to novel therapeutic approaches. Somatic mutations of DNA repair and response mechanisms in PCa patients differ between AA and EA populations [ 66 ]. Although mutations of major DNA pathways were present in both AA and EA PCa tumors, AA men had a larger number of somatic mutations [ 66 ].…”

“…Somatic mutations of DNA repair and response mechanisms in PCa patients differ between AA and EA populations [ 66 ]. Although mutations of major DNA pathways were present in both AA and EA PCa tumors, AA men had a larger number of somatic mutations [ 66 ]. The consequences of these somatic alterations in cancer cells (or premalignant epithelial cells) on neighboring stromal partners including fibroblasts are currently not known.…”