Biomarkers of Genomic Instability in African Americans and Caucasians - Beyond the Abstract

Most experts regard genomic instability as a mere enhancer of carcinogenesis rather than an obligatory event in this process. However, most of the evidence comes from next-generation sequencing (NGS) studies performed at 30-100× mean resolution depth. At this depth, somatic mutations present at less than 10-20% of the tumor cells remain elusive (due to low p-value), and the tumor is misclassified as wild type for each gene.

To address this technical problem, we decided to focus only on the 124 DNA repair/response genes (“DNA repairome”), which are expected to be the drivers of genomic instability. Limiting the analysis to only a small fraction of the genome allowed us to increase resolution depth to 300-800x on average without a significant financial burden. This method allowed us to discover that all prostate tumors have somatic mutations in the DNA repairome. Therefore, we infer that genomic instability is universal in prostate cancer. This is a paradigm shift. Further, there is no reason to believe that genomic instability is not universal in other types of tumors.

 

Specifically, we deep sequenced the exons of 124 genes involved in the DNA damage repair/response in 52 prostate cancers (PCa) and matched normal tissue samples (peripheral blood lymphocytes) at very high resolution (312–768 average read depth). We found 1433 somatic mutations in these tumors (24–38 somatic mutations per patient, depending on race and Gleason score). We further discovered that all prostate tumors had somatic mutations in DNA repair/response genes, regardless of the Gleason score.

Another major goal of this study was to examine the issue of health disparities in PCa: African Americans have the highest incidence of PCa in the world, and among the highest mortalities. We found that African Americans have different somatic mutations than Caucasians, especially in genes such as XPC, ATR, and MBD4. We thus hypothesize that part of this health disparity between African Americans and Caucasians may be due to specific somatic mutations of the DNA repairome.

The high number of somatic DNA repair mutations that we identified in prostate tumors significantly expands the percentage of patients that can benefit from a synthetic lethality approach. The caveat is that in contrast to e.g. BRCA1/BRCA2 deletions, the functional effect of a missense somatic mutation needs to be ascertained before these patients can become eligible for a synthetic lethality therapeutic approach. However, many of the somatic mutations that we found have been characterized before, functionally, and/or epidemiologically, and some are also prevalent in each prostate tumor. Even if we only focus on these previously characterized mutations, our preliminary analysis indicates that up to a third of the prostate cancer patients can benefit from a synthetic lethality approach. 

This study shows that all prostate tumors have somatic mutations in the DNA repairome. We further observed that the well-known difference in PCa incidence and mortality between African Americans and Caucasians may have a genetic basis, specifically involving the DNA repairome. Tumors in African Americans, compared with Caucasians, had distinct mutations in the DNA repairome and a higher rate of somatic mutations overall. Our study also expands the potential usefulness of the synthetic lethality approach. In our opinion, if validated, these data can be used to select important biomarkers of prostate cancer progression, mortality and racial disparities, and to guide therapeutic options.

Written by: Nick Makridakis, PhD, 1Globe Health Institute, Boston, Massachusetts, Twitter: @bioathenian

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