Evidence for Molecular Differences in Prostate Cancer between African American and Caucasian Men

Abstract

Purpose To compare the frequency of ERG rearrangement, PTEN deletion, SPINK1 overexpression, and SPOP mutation in prostate cancer in African American and Caucasian men. Experimental design Dominant tumor nodules from radical prostatectomy specimens of 105 African American men (AAM) were compared to 113 dominant nodules from Caucasian men (CaM). Clinical and pathologic characteristics of the two groups were similar. SPINK1 overexpression was evaluated by immunohistochemistry, ERG rearrangement and PTEN deletion by FISH, and SPOP mutation by Sanger sequencing. Results ERG rearrangement was identified in 48/113 tumors (42.5%) in CaM and 29/105 tumors (27.6%) in AAM (p=0.024). PTEN deletion was seen in 19/96 tumors (19.8%) in CaM and 7/101 tumors (6.9%) in AAM (p=0.011). SPINK1 overexpression was present in 9/110 tumors (8.2%) in CaM and 25/105 tumors (23.4%) in AAM (p=0.002). SPOP mutation was identified in 8/78 (10.3%) tumors in CaM and 4/88 (4.5%) tumors in AAM (p=0.230). When adjusted for age, BMI, Gleason score, and pathologic stage, ERG rearrangement and SPINK1 overexpression remain significantly different (p=0.018 and p=0.008, respectively), and differences in PTEN deletion and SPOP mutation approach significance (p=0.061 and p=0.087, respectively). Conclusions Significant molecular differences exist between prostate cancers in AAM and CaM. SPINK1 overexpression, an alteration associated with more aggressive prostate cancers, was more frequent in AAM, while ERG rearrangement and PTEN deletion were less frequent in this cohort. Further investigation is warranted to determine if these molecular differences explain some of the disparity in incidence and mortality between these two ethnic groups.

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

“…Given that the TCGA data set comprises higher frequencies of Gleason 8 and higher tumors in comparison to the AAPC cohort, these copy number differences were less pronounced when stratified by Gleason score yet persisted at certain loci (Supplemental Table 3 and Supplemental Figure 2). For example, overall, PTEN deletions were more common in the TCGA cohort (32%) compared to the AAPC cohort (6%), consistent with previous reports, and this difference remained when examining Gleason 7 and Gleason 8 (or higher) tumors (Supplemental Figure 2) (2). We note that focal copy number gains at 17q25.3, a locus containing the gene fatty acid synthase ( FASN ) and a significant amplification by GISTIC analysis in the AAPC cohort, occur in 12.7% of AAPC tumors in contrast to 1% in the TCGA dataset (p = 0.0001, Fisher’s exact test; Supplemental Figures 1B and 3) (14,15).…”

“…To extend the finding of ERF copy number loss, we assessed three prostate cancer cohorts for ERF deletion by FISH analysis. Only 1 of 105 cases of localized prostate cancer in African-Americans in a previously published cohort demonstrated hemizygous ERF deletion (2). None of 33 cases of localized prostate cancer in the predominantly white Early Detection Research Network (EDRN) cohort showed deletion in ERF .…”

A Biopsy-based 17-gene Genomic Prostate Score Predicts Recurrence After Radical Prostatectomy and Adverse Surgical Pathology in a Racially Diverse Population of Men with Clinically Low- and Intermediate-risk Prostate Cancer

“…Several studies have highlighted molecular differences in PCa in AA and Caucasian men [22] including prevalence of transmembrane protease, serine 2/v-ets avian erythroblastosis virus E26 oncogene homolog (TMPRSS2-ERG) fusions [23] and phosphatase and tensin homolog (PTEN) deletions [24], and gene expression patterns [25]. Studies also suggest that increased androgen signaling is seen in AA men [26].…”

A Prospective Investigation of PTEN Loss and ERG Expression in Lethal Prostate Cancer

“…Importantly, the association of PTEN loss with lethal events among ERG fusion-negative tumors was much stronger than that seen for PTEN loss considered without ERG status, and this association remained strong even when considering tumors with heterogeneous PTEN loss. Finally, white men primarily comprise our cohort (97%), so our results may not be generalizable to other racial/ethnic groups, in which ERG expression and PTEN loss may be less frequent (45)(46)(47)(48)(49)(50).…”