Predisposition for TMPRSS2-ERG fusion in prostate cancer by variants in DNA repair genes

Manuel Luedeke, Carmen M. Linnert, Matthias D. Hofer, Harald M. Surowy, Antje E. Rinckleb, Josef Hoegel, Rainer Kuefer, Mark A. Rubin, Walther Vogel, Christiane Maier*

*Corresponding author for this work

Research output: Contribution to journalArticle

39 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)3030-3035
Number of pages6
JournalCancer Epidemiology Biomarkers and Prevention
Volume18
Issue number11
DOIs
StatePublished - Nov 1 2009

ASJC Scopus subject areas

  • Epidemiology
  • Oncology

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    Luedeke, M., Linnert, C. M., Hofer, M. D., Surowy, H. M., Rinckleb, A. E., Hoegel, J., Kuefer, R., Rubin, M. A., Vogel, W., & Maier, C. (2009). Predisposition for TMPRSS2-ERG fusion in prostate cancer by variants in DNA repair genes. Cancer Epidemiology Biomarkers and Prevention, 18(11), 3030-3035. https://doi.org/10.1158/1055-9965.EPI-09-0772