TMPRSS2-ERG fusions linked to prostate cancer racial health disparities: A focus on Africa

Abstract

Background: The androgen-regulated gene TMPRSS2 to the ETS transcription factor gene ERG fusion is the most common genomic alteration acquired during prostate tumorigenesis and biased toward men of European ancestry. In contrast, African American men present with more advanced disease, yet their tumors are less likely to acquire TMPRSS2-ERG. Data for Africa is scarce.

Methods: RNA was made available for genomic analyses from 181 prostate tissue biopsy cores from Black South African men, 94 with and 87 without pathological evidence for prostate cancer. Reverse transcription polymerase chain reaction was used to screen for the TMPRSS2-ERG fusion, while transcript junction coordinates and isoform frequencies, including novel gene fusions, were determined using targeted RNA sequencing.

Results: Here we report a frequency of 13% for TMPRSS2-ERG in tumors from Black South Africans. Present in 12/94 positive versus 1/87 cancer negative prostate tissue cores, this suggests a 92.62% predictivity for a positive cancer diagnosis (P = 0.0031). At a frequency of almost half that reported for African Americans and roughly a quarter of that reported for men of European ancestry, acquisition of TMPRSS2-ERG appears to be inversely associated with aggressive prostate cancer. Further support was provided by linking the presence of TMPRSS2-ERG to low-grade disease in younger patients (P = 0.0466), with higher expressing distal ERG fusion junction coordinates.

Conclusions: Only the second study of its kind for the African continent, we support a link between TMPRSS2-ERG status and prostate cancer racial health disparity beyond the borders of the United States. We call for urgent evaluation of androgen deprivation therapy within Africa.

Keywords: African ancestry; TMPRSS2- ERG; early-onset; fusion gene; prostate cancer; racial health disparity.

Figure 1

Summary of TMPRSS2‐ERG fusion gene diagnosis. (A) Schematic representation of the fusion gene resulting from a genomic rearrangement within TMPRSS2 intron 1 and ERG intron 3. Locations of forward TMPRSS2 and reverse ERG PCR primers are shown as arrows. (B) Difference in age at diagnosis for TMPRSS2‐ERG positive versus negative low‐grade (ISUP 1 and 2) and high‐grade (ISUP 3 to 5) tumors

Figure 2

TMPRSS2‐ERG fusion gene isoforms detected in 12 prostate tumors from African patients. (A) TMPRSS2 and ERG gene structures and TMPRSS2‐ERG fusion isoform prevalence across all patients based on the GENCODE v27 comprehensive exon annotation. Bar charts quantify the number of samples expressing each isoform. For simplicity, TMPRSS2 junctions beyond exon 1 are depicted with exon 1a. Black line represents retained intronic sequence. (B) Isoform prevalence, represented as fusion position between TMPRSS2 and ERG for each patient. Light and dark blue panels denote proximal and distal ERG junction positions. (C) Boxplot of TMPRSS2‐ERG expression relative to ERG fusion position. (D) Boxplot of patient age at diagnosis relative to ERG fusion position. Each dot represents a single patient sample [Color figure can be viewed at wileyonlinelibrary.com]