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. (Cancer Epidemiol

Prostate cancer susceptibility has previously been associated with truncating germline variants in the gene TP53AIP1 (tumor protein p53 regulated apoptosis inducing protein 1). For two apparently recurrent mutations (p.Q22fs and p.S32X) a remarkable OR of 5.1 was reported for prostate cancer risk. Since these findings have not been validated so far, we genotyped p.Q22fs and p.S32X in two German series with a total of 1,207 prostate cancer cases and 1,495 controls. The truncating variants were not significantly associated with prostate cancer in none of the two cohorts, nor in the combined analysis [odds ratio (OR) = 1.16; 95% confidence interval (CI 95%) = 0.62–2.15; p = 0.66]. Carriers showed no significant differences in family history of prostate cancer, age at diagnosis, Gleason score or PSA at diagnosis when compared to non-carrier prostate cancer cases. The large sample size of the combined cohort rejects a high-risk effect greater than 2.2 and indicates a limited role of TP53AIP1 in prostate cancer predisposition.