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, ATR, POLQ, NEIL3, ERCC6, BRCA2, BRCA1, XPC, JAG1, RPA1, POLE, ATM, and LIG1 in African American men, and POLQ, NEIL3, POLB, BRCA2, EXO1, ERCC6, ATR, RBBP8, BRCA1, ATM, JAG1, XPC, and POLE in Caucasians. We found that 89% of
tumors had at least one mutation in nucleotide excision repair pathway genes in African Americans, whereas >40% of
tumors had mutations in base excision repair pathway genes in Caucasians. We further identified a marginal increase in mutation rate in
tumors in African Americans with increasing age.
Tumors in Caucasians did not show a correlation with age, but a progressive increase in the mutation rate was observed at higher Gleason scores. Our data reveal significant differences in the molecular signatures in the
DNA repairome in
prostate cancer between African Americans and Caucasians. These data also have substantial implications regarding the well-known health disparities in
prostate cancer, such as the higher mortality in African Americans than Caucasians.