Association of germline genetic variants with TMPRSS2-ERG fusion status in prostate cancer

Abstract

Introduction: Oncogenic activation of ERG resulting from TMPRSS2-ERG gene fusion is a key molecular genetic alteration in prostate cancer (CaP). The frequency of ERG fusion is variable by race; however, there are limited data available on germline polymorphisms associating with ERG fusion status. The goal of this study is to identify the inherited risk variants associating with ERG status of CaP. Materials and Methods: SNP genotyping was performed on the Illumina platform using Infinium Oncoarray SNP chip on blood derived genomic DNA samples from 400 patients treated by radical prostatectomy at a single military institution. ERG status was determined in whole mounted prostate specimens by immuno-histochemistry (IHC) for ERG protein expression. Data analysis approaches included association analyses based on EMMAX and imputation by IMPUTE2. Imputed SNPs were validated by ddPCR. Results: SNP genotyping analysis using imputation identified rs34349373 (p 4.68 × 10-8) and rs2055272 (p 5.62 × 10-8) in TBC1D22B to be significantly associated with ERG fusion status in index tumor and non-index tumor foci. Imputed SNP rs2055272 was further experimentally validated by ddPCR with 98.04% (100/102) concordance. Initial discovery analysis based on SNPs on Oncoarray SNP chip, showed significant (p 10-5) association for SNPs (rs6698333, rs1889877, rs3798999, rs10215144, rs3818136, rs9380660 and rs1792695) with ERG fusion status. The study also replicated two previously known ERG fusion associated SNPs (rs11704416 in chromsome 22; rs16901979 in chromosome 8). Conclusions: This study identified SNPs associated with ERG status of CaP. Impact: The findings may contribute towards defining the underlying genetics of ERG positive and ERG negative CaP patients.

Analysis of a large prostate cancer family identifies novel and recurrent gene fusion events providing evidence for inherited predisposition

“…In fact, these 'common' ETV1 fusions were not observed at all in TCGA tumour samples. It thus appears that the frequency of fusion events in PcTas9 is considerably higher than the frequency normally observed in Caucasian tumour cohorts (~40%–50%) 3–6 and suggests an underlying inherited predisposition to the formation of these events in this family. In fact, there is now a strong body of evidence supporting this theory, 3,12–15 including two recent and very diverse studies 29,30 .…”

“…It thus appears that the frequency of fusion events in PcTas9 is considerably higher than the frequency normally observed in Caucasian tumour cohorts (~40%–50%) 3–6 and suggests an underlying inherited predisposition to the formation of these events in this family. In fact, there is now a strong body of evidence supporting this theory, 3,12–15 including two recent and very diverse studies 29,30 . A transcriptome‐wide association study by Emami et al 29 observed a positive correlation between imputed TMPRSS2 expression levels in normal prostate tissue (as predicted by germline cis ‐expression quantitative trait loci) and ERG expression in TMPRSS2:ERG fusion‐positive tumour samples 29 .…”

“…Fusion prevalence does, however, vary between studies and cohorts of different ethnicities. For example, the fusion is detected at the highest prevalence in Caucasian (~40%–50%), followed by African American (~25%–35%) and Asian (~15%–30%) populations 3–6 …”

“…Despite the frequency of PrCa gene fusions, little is known about what drives these events. One theory is that inherited genetic variation predisposes men to gene fusions 3,12–15 . Hofer et al 12 observed a sibling recurrence risk ratio of up to 18.9 in a cohort of 33 PrCa families in which TMPRSS2:ERG fusion events were examined.…”

“…Two subsequent studies exploring potential associations between TMPRSS2:ERG fusions and common PrCa risk variants found a further nine variants to be significantly associated with the presence or absence of the fusion event 14,15 . A recent genome‐wide association study identified a further nine inherited risk variants associated with ERG status, a proxy for the presence of a TMPRSS2:ERG fusion event 3 …”