Whole-exome sequencing of over 4100 men of African ancestry and prostate cancer risk

Abstract

Prostate cancer is the most common non-skin cancer in males, with a ∼1.5-2-fold higher incidence in African American men when compared with whites. Epidemiologic evidence supports a large heritable contribution to prostate cancer, with over 100 susceptibility loci identified to date that can explain ∼33% of the familial risk. To explore the contribution of both rare and common variation in coding regions to prostate cancer risk, we sequenced the exomes of 2165 prostate cancer cases and 2034 controls of African ancestry at a mean coverage of 10.1×. We identified 395 220 coding variants down to 0.05% frequency [57% non-synonymous (NS), 42% synonymous and 1% gain or loss of stop codon or splice site variant] in 16 751 genes with the strongest associations observed in SPARCL1 on 4q22.1 (rs13051, Ala49Asp, OR = 0.78, P = 1.8 × 10(-6)) and PTPRR on 12q15 (rs73341069, Val239Ile, OR = 1.62, P = 2.5 × 10(-5)). In gene-level testing, the two most significant genes were C1orf100 (P = 2.2 × 10(-4)) and GORAB (P = 2.3 × 10(-4)). We did not observe exome-wide significant associations (after correcting for multiple hypothesis testing) in single variant or gene-level testing in the overall case-control or case-case analyses of disease aggressiveness. In this first whole-exome sequencing study of prostate cancer, our findings do not provide strong support for the hypothesis that NS coding variants down to 0.5-1.0% frequency have large effects on prostate cancer risk in men of African ancestry. Higher-coverage sequencing efforts in larger samples will be needed to study rarer variants with smaller effect sizes associated with prostate cancer risk.

Exome Sequencing of African-American Prostate Cancer Reveals Loss-of-Function ERF Mutations

“…Our study suggests that there are still unexplained reasons for the aggressive nature of prostate cancer in AA men that is only partially explained by the genomic studies to date. Additional studies focused on metastatic CRPC samples from AA men and development of methodologies to integrate analyses of somatic and germline data may improve our understanding of the nature of aggressive prostate cancer in these patients (23,45–47). Our results suggest that inclusion of sufficient numbers of patients of African ancestry in cancer genomic studies may enable the discovery of new cancer genes and inform the inclusion of diverse populations towards precision cancer medicine (48).…”

The 22Rv1 prostate cancer cell line carries mixed genetic ancestry: Implications for prostate cancer health disparities research using pre‐clinical models

“…Because 22Rv1 was derived from a xenograft of CWR22R cells which was serially propagated in mice, it would be appropriate to also assign this mixed ancestral racial classification to the CWR22R cell line. The implications of 22Rv1 and CWR22R carrying AFR genetic ancestry are far reaching as genetic factors associated with AFR ancestry have been recently linked to prostate tumor aggressive properties . Further studies are needed to determine if these cell lines carry any of these factors.…”

“…Recent studies have provided compelling evidence in support of the notion that PCa health disparities result from the interplay of multiple factors, including biological/genetic factors . For instance, several recent studies have reported genomic differences between AA men with PCa and Caucasian or European American (EA) with PCa, suggesting a potential role for biological mediators in driving PCa mortality disparities . Understanding how these mediators contribute to increased PCa mortality in AA men requires mechanistic functional studies in pre‐clinical cellular and animal models of PCa.…”

Disparities in prostate cancer incidence and mortality rates: Solvable or not?

“…To date, to the best of our knowledge, four reported GWAS studies have been conducted with a primary focus on MAA from 2007–2016, as 10% of all GWAS PCa studies over the last decade. From these investigations: genetic variant/s in a number of chromosomal regions such as, 8q24 (working in conjunction with another variant) was twice more prevalent in MAA compared to MEA, a novel risk variant, rs7210100 in the 17q21 region was unique to African‐Americans, while its functionality is unknown with respect to PCa, it is reported to be associated to the breast cancer susceptibility gene, BRAC1; a risk variant in 10p14 was most prevalent in Ghanaian men while sub‐analysis associated SNPs at 5q31.3 with high Gleason score and finally, Rand et al reported PCa associations to the gene SPARCL1 on 4q22.1 and PTPRR on 12q15.…”