Molecular profiling of ETS and non‐ETS aberrations in prostate cancer patients from northern India

Abstract

BACKGROUNDMolecular stratification of prostate cancer (PCa) based on genetic aberrations including ETS or RAF gene‐rearrangements, PTEN deletion, and SPINK1 over‐expression show clear prognostic and diagnostic utility. Gene rearrangements involving ETS transcription factors are frequent pathogenetic somatic events observed in PCa. Incidence of ETS rearrangements in Caucasian PCa patients has been reported, however, occurrence in Indian population is largely unknown. The aim of this study was to determine the prevalence of the ETS and RAF kinase gene rearrangements, SPINK1 over‐expression, and PTEN deletion in this cohort.METHODSIn this multi‐center study, formalin‐fixed paraffin embedded (FFPE) PCa specimens (n = 121) were procured from four major medical institutions in India. The tissues were sectioned and molecular profiling was done using immunohistochemistry (IHC), RNA in situ hybridization (RNA‐ISH) and/or fluorescence in situ hybridization (FISH).RESULTS ERG over‐expression was detected in 48.9% (46/94) PCa specimens by IHC, which was confirmed in a subset of cases by FISH. Among other ETS family members, while ETV1 transcript was detected in one case by RNA‐ISH, no alteration in ETV4 was observed. SPINK1 over‐expression was observed in 12.5% (12/96) and PTEN deletion in 21.52% (17/79) of the total PCa cases. Interestingly, PTEN deletion was found in 30% of the ERG‐positive cases (P = 0.017) but in only one case with SPINK1 over‐expression (P = 0.67). BRAF and RAF1 gene rearrangements were detected in ∼1% and ∼4.5% of the PCa cases, respectively.CONCLUSIONSThis is the first report on comprehensive molecular profiling of the major spectrum of the causal aberrations in Indian men with PCa. Our findings suggest that ETS gene rearrangement and SPINK1 over‐expression patterns in North Indian population largely resembled those observed in Caucasian population but differed from Japanese and Chinese PCa patients. The molecular profiling data presented in this study could help in clinical decision‐making for the pursuit of surgery, diagnosis, and in selection of therapeutic intervention. Prostate 75:1051–1062, 2015. © 2015 The Authors. The Prostate, published by Wiley Periodicals, Inc.

Differential expression of Annexin 2, SPINK1, and Hsp60 predict progression of prostate cancer through bifurcated WHO Gleason score categories in African American men

“…SPINK1/TATI is known to be produced in the prostate and in prostate cancer, and its production increases with a higher tumor grade . Strongly increased SPINK1 expression is found in about 10% of all prostate cancers, and serum concentrations of SPINK1 are increased in more than 40% of patients with advanced prostate cancer . Increased SPINK1/TATI expression was observed in our cancer groups compared to controls (normals).…”

Epigenetic silencing of miRNA-338-5p and miRNA-421 drives SPINK1-positive prostate cancer

“…Clinical specimens were collected after obtaining written informed consent from the patients and Institutional Review Board approvals from the King George's Medical University, Lucknow and Indian Institute of Technology, Kanpur, India. A total of 20 PCa specimens were selected for this study based on the SPINK1 and TMPRSS2-ERG status, confirmed by qPCR, immunohistochemistry and Fluorescent in situ hybridization (FISH) for gene rearrangement (64). The PCa specimens used in this study were collected from men who underwent needle core biopsies and transurethral resection of the prostate (TURP) to relieve obstructive symptoms from locally advanced disease between year 2014 and 2016.…”

“…Majority of the PCa patients harbor gene rearrangements between members of the ETS transcription factor family and the androgen-regulated transmembrane protease serine 2 (TMPRSS2), most recurrent (~50%) being TMPRSS2-ERG, a gene fusion involving the v-ets erythroblastosis virus E26 oncogene homolog (ERG) (5,7). The ERG transcription factor encoded by TMPRSS2-ERG fusion is known to drive cell invasion and metastases, induce DNA damage in vitro, and focal pre-cancerous prostatic intraepithelial neoplasia (PIN) lesions in transgenic mice (8,9).…”

Status of TMPRSS2–ERG fusion in prostate cancer patients from India: correlation with clinico-pathological details and TMPRSS2 Met160Val polymorphism

“…The frequency of ERG-positive tumors in our study (26%) is similar to that in the study by Rawal et al 22 who have reported a low frequency; eight cases were ERG positive (27%) by FISH in a total cohort of 30 samples from a single medical institution in North India. However, Ateeq et al 23 detected ERG overexpression by IHC in 46 of 94 (48.9%) PCa cases from northern India; this was subsequently confirmed in a much smaller subset (17 samples) by FISH.…”