Mutational Landscape of Aggressive Prostate Tumors in African American Men

Abstract

Prostate cancer is the most frequently diagnosed and second most fatal non-skin cancer among men in the United States. African American men are two times more likely to develop and die of prostate cancer compared with men of other ancestries. Previous whole genome or exome tumor sequencing studies of prostate cancer have primarily focused on men of European ancestry. In this study, we sequenced and characterized somatic mutations in aggressive (Gleason ≥7, stage ≥T2b) prostate tumors from 24 African American patients. We describe the locations and prevalence of small somatic mutations (up to 50 bases in length), copy number aberrations, and structural rearrangements in the tumor genomes compared with patient-matched normal genomes. We observed several mutation patterns consistent with previous studies, such as large copy number aberrations in chromosome 8 and complex rearrangement chains. However, TMPRSS2-ERG gene fusions and PTEN losses occurred in only 21% and 8% of the African American patients, respectively, far less common than in patients of European ancestry. We also identified mutations that appeared specific to or more common in African American patients, including a novel CDC27-OAT gene fusion occurring in 17% of patients. The genomic aberrations reported in this study warrant further investigation of their biological significance in the incidence and clinical outcomes of prostate cancer in African Americans.

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

“…These studies will inform whether alterations in these genes may be enriched in certain ancestral groups. Recent studies have implicated prostate tumor location, differential gene expression, and somatic genomic events such as LSAMP deletions in prostate cancers in AA men (2–4,42–44). 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.…”

Prevalence and Prognostic Significance of PTEN Loss in African-American and European-American Men Undergoing Radical Prostatectomy

“…It is clear that ERG rearrangement is significantly less common in the AA population [7, 8]. However, the relative rate of PTEN loss in AA PCa has only been examined in a few small cohorts [8–10]. In addition, it is unknown whether ERG rearrangement and/or PTEN loss are prognostic in AA PCa since most large cohorts with clinical follow-up information studied to date are predominantly EA men.…”

“…TMA 2 included a nested case-control study comparing men with and without biochemical recurrence who underwent RP from 1993 to 2001. TMA 3 included consecutive RPs from 2000 to 2004 not included in the previous microarrays; subjects with Gleason score >6 were specifically selected, as in previous studies, owing to their higher risk of recurrence and metastasis, with the aim of evaluating the association of these genomic risk factors with the most clinically relevant cancers [10]. Because TMA 2 and 3 were not designed explicitly for comparison by race, and the RP population at our institution has been predominantly EA, all three TMAs cumulatively ultimately yielded 936 EA men with available PTEN/ERG status and clinical follow-up (Supplementary Table 1), compared to 169 AA men.…”

“…To increase the study power, we included an additional population of AA men who underwent RP from 2006 to 2010 with Gleason score ≥4 + 3 (Supplementary Table 2). Again, higher-grade cancers were selected to identify the association between these genomic alterations and clinically relevant disease [10]. These men were not considered in the prevalence analysis owing to a lack of matched EA samples.…”

How the future of clinical cancer diagnostics can contribute to overcoming race-associated cancer disparities

“…A growing body of evidence also support that there are race-associated differences in the molecular biology of cancer, with the likely consequence of expanding the diversity of molecular subtypes and contributing to disparities. Moreover, recent research studying somatic cancer gene mutations and copy number variation indicates that well-known and clinically actionable cancer-driver gene aberrations are overall found at significantly lower frequency in African American cancers [10][11][12]. Underscoring that somatic gene aberrations driving African American cancers remain understudied and possibly undocumented.…”