TY - JOUR
T1 - Predisposition for TMPRSS2-ERG fusion in prostate cancer by variants in DNA repair genes
AU - Luedeke, Manuel
AU - Linnert, Carmen M.
AU - Hofer, Matthias D.
AU - Surowy, Harald M.
AU - Rinckleb, Antje E.
AU - Hoegel, Josef
AU - Kuefer, Rainer
AU - Rubin, Mark A.
AU - Vogel, Walther
AU - Maier, Christiane
N1 - Copyright:
Copyright 2010 Elsevier B.V., All rights reserved.
PY - 2009/11
Y1 - 2009/11
N2 - The somatic fusion of TMPRSS2 to ETS oncogenes is a common event in prostate cancer (PCa). We hypothesized that defects in DNA repair may lead to an increase of chromosomal rearrangements and thus to the occurrence of ETS oncogene fusion. We have previously conducted a genome-wide linkage analysis in TMPRSS2-ERG fusion-positive PCa families, revealing potential susceptibility loci on chromosomes 5q14, 9q21, 10q26, 11q24, 12q15, 13q12, 18q, and Xq27. In the present study, nine candidate genes from these regions were selected from the context of DNA repair and screened for mutations in TMPRSS2-ERG fusion-positive families. Thirteen nonsynonymous variants, 5 of which had a minor allele frequency of <0.05, were genotyped in 210 familial cases, 47 of which with a known TMPRSS2-ERG status, 329 sporadic cases, and 512 controls. Significant association of TMPRSS2-ERG fusion-positive PCa was found with rare variants in the genes for POLI [variant F532S: P = 0.0011; odds ratios (OR), 4.62; 95% confidence interval (95% CI), 1.84-11.56] and ESCO1 (variant N191S: P = 0.0034; OR, 4.27; 95% CI, 1.62-11.28). Additional findings, regardless of TMPRSS2-ERG status, were the overrepresentation of a rare BRCA2 variant (V2728I: P = 0.03; OR, 6.16; 95% CI, 1.19-32.00) in familial PCa and of a common allele of RMI1 (variant N455S: P = 0.02; OR, 1.33; 95% CI, 1.04-1.70) in unselected PCa cases. The DNA repair genes POLI and ESCO1 are proposed as susceptibility genes for TMPRSS2-ERG fusion-positive PCa that warrant further investigation.
AB - The somatic fusion of TMPRSS2 to ETS oncogenes is a common event in prostate cancer (PCa). We hypothesized that defects in DNA repair may lead to an increase of chromosomal rearrangements and thus to the occurrence of ETS oncogene fusion. We have previously conducted a genome-wide linkage analysis in TMPRSS2-ERG fusion-positive PCa families, revealing potential susceptibility loci on chromosomes 5q14, 9q21, 10q26, 11q24, 12q15, 13q12, 18q, and Xq27. In the present study, nine candidate genes from these regions were selected from the context of DNA repair and screened for mutations in TMPRSS2-ERG fusion-positive families. Thirteen nonsynonymous variants, 5 of which had a minor allele frequency of <0.05, were genotyped in 210 familial cases, 47 of which with a known TMPRSS2-ERG status, 329 sporadic cases, and 512 controls. Significant association of TMPRSS2-ERG fusion-positive PCa was found with rare variants in the genes for POLI [variant F532S: P = 0.0011; odds ratios (OR), 4.62; 95% confidence interval (95% CI), 1.84-11.56] and ESCO1 (variant N191S: P = 0.0034; OR, 4.27; 95% CI, 1.62-11.28). Additional findings, regardless of TMPRSS2-ERG status, were the overrepresentation of a rare BRCA2 variant (V2728I: P = 0.03; OR, 6.16; 95% CI, 1.19-32.00) in familial PCa and of a common allele of RMI1 (variant N455S: P = 0.02; OR, 1.33; 95% CI, 1.04-1.70) in unselected PCa cases. The DNA repair genes POLI and ESCO1 are proposed as susceptibility genes for TMPRSS2-ERG fusion-positive PCa that warrant further investigation.
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U2 - 10.1158/1055-9965.EPI-09-0772
DO - 10.1158/1055-9965.EPI-09-0772
M3 - Article
C2 - 19861517
AN - SCOPUS:72749125600
VL - 18
SP - 3030
EP - 3035
JO - Cancer Epidemiology Biomarkers and Prevention
JF - Cancer Epidemiology Biomarkers and Prevention
SN - 1055-9965
IS - 11
ER -