Genome-Wide Linkage Analysis of <i>TMPRSS2-ERG</i> Fusion in Familial Prostate Cancer

Hofer, Matthias; Kuefer, Rainer; Maier, Christiane; Herkommer, Kathleen; Perner, Sven; Demichelis, Francesca; Paiss, Thomas; Vogel, Walter; Rubin, Mark A.; Hoegel, Josef

doi:10.1158/0008-5472.can-08-2008

Cited by 30 publications

(28 citation statements)

References 38 publications

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“…In our pilot study, no significant association was identified between ERG status and tumour stage in a limited cohort of patients (16). However, ERG rearrangement was found to be positively correlated with advanced tumour stage in a larger cohort of samples in this study, which is consistent with previous reports (28)(29)(30)(31). Overall, ERG rearrangement tends to be positively associated with advanced pathological stage, which has been further verified in a meta-analysis of 34 series (32).…”

Section: Discussionsupporting

confidence: 91%

ERG rearrangement as a novel marker for predicting the extra-prostatic extension of clinically localised prostate cancer

Zhang

Pang

et al. 2016

Oncology Letters

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Abstract. Currently, there are no well-established preoperative clinicopathological parameters for predicting extra-prostatic extension (EPE) in patients with clinically localised prostate cancer (PCa). The transmembrane protease serine 2 (TMPRSS2)-ETS-related gene (ERG) fusion gene is a specific biomarker of PCa and is considered a prognostic predictor. The aim of the present study was to assess the value of this marker for predicting EPE in patients with clinically localised PCa. In total, 306 PCa patients with clinically localised disease, including 220 patients (71.9%) with organ-confined disease and 86 EPE cases (28.1%), were included in the study. Receiver operating characteristic curves and logistic regression were employed to establish the optimal cut-off value and to investigate whether ERG rearrangement was an independent predictor for the EPE of clinically localised PCa. A leave-one-out cross-validation (LOOCV) model was implemented to validate the predictive power of ERG rearrangement. An increase in ERG rearrangements was identified to be associate`d with EPE, and the optimal cut-off for predicting EPE was determined to be 2.25%, with a sensitivity of 70.24% [95% confidence interval (CI), 62.6-78.9%], a specificity of 80. 43% (95% CI,, and an area under the curve (AUC) of 0.781 (95% CI,. In the LOOCV model, ERG rearrangement also demonstrated good performance for predicting EPE (sensitivity, 76.923%; specificity, 71.429%; 95% CI for AUC, 0.724-0.958). In addition, a high Gleason score (≥7) and a cT2c classification upon biopsy were independent factors for EPE.

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Section: Discussionsupporting

confidence: 91%

ERG rearrangement as a novel marker for predicting the extra-prostatic extension of clinically localised prostate cancer

Zhang

Pang

et al. 2016

Oncology Letters

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“…Both TMPRSS2 and ERG are located on chromosome 21q22 with about 2.8 Mb of distance and about 40% to 60% of all PCas harbor their fusion. In our previous study, we found evidence for an inherited susceptibility for TMPRSS2-ERG fusion-positive PCa and obtained several candidate loci at 5q14, 9q21, 10q26, 11q26, 12q21, 13q12, 18q, and Xq27 by linkage analysis (8). We hypothesize that susceptibility for the oncogenic fusion could be explained by a generally elevated chromosomal instability with subsequent selection for growth advancing rearrangements.…”

Section: Introductionmentioning

confidence: 84%

“…The index patients' mean age at diagnosis was 62.9 y (range, 40-80 y). For the sequencing of candidate genes, index probands were chosen from 10 independent families with at least two TMPRSS2-ERG fusion-positive PCa cases that were used for a genomewide linkage analysis (8). Two additional fusion-positive index probands were screened, of which the fusion status of affected relatives was unknown.…”

Section: Methodsmentioning

confidence: 99%

Predisposition for TMPRSS2-ERG Fusion in Prostate Cancer by Variants in DNA Repair Genes

Luedeke

Linnert

Hofer

et al. 2009

Cancer Epidemiology, Biomarkers &Amp; Prevention

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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

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“…Although TMPRSS2 -ERG fusion has typically been reported as prevalent in 40 -50% of prostate tumours, the range has varied by as much as 25 -60% (Nam et al, 2007;Setlur et al, 2008;Sun et al, 2008;Yoshimoto et al, 2008;Hofer et al, 2009;Mosquera et al, 2009). The techniques used for TMPRSS2 -ERG detection, novel potential fusion products and genetic differences in population cohorts may account for these discrepancies.…”

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confidence: 99%

Prostate cancer genes associated with TMPRSS2–ERG gene fusion and prognostic of biochemical recurrence in multiple cohorts

et al. 2010

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BACKGROUND: Recent studies have indicated that prostate cancer patients with the TMPRSS2 -ERG gene fusion have a higher risk of recurrence. To identify markers associated with TMPRSS2 -ERG fusion and prognostic of biochemical recurrence, we analysed a cohort of 139 men with prostate cancer for 502 molecular markers. METHODS: RNA from radical prostatectomy tumour specimens was analysed using cDNA-mediated, annealing, selection, extension and ligation (DASL) to determine mRNAs associated with TMPRSS2 -ERG T1/E4 fusion and prognostic of biochemical recurrence. Differentially expressed mRNAs in T1/E4-positive tumours were determined using significance analysis of microarrays (false discovery rate (FDR) o5%). Univariate and multivariate Cox regression determined genes, gene signatures and clinical factors prognostic of recurrence (P-value o0.05, log -rank test). Analysis of two prostate microarray studies (GSE1065 and GSE8402) validated the findings. RESULTS: In the 139 patients from this study and from a 455-patient Swedish cohort, 15 genes in common were differentially regulated in T1/E4 fusion-positive tumours (FDR o0.05). The most significant mRNAs in both cohorts coded ERG. Nine genes were found prognostic of recurrence in this study and in a 596-patient Minnesota cohort. A molecular recurrence score was significant in prognosticating recurrence (P-value 0.000167) and remained significant in multivariate analysis of a mixed clinical model considering Gleason score and TMPRSS2 -ERG fusion status. CONCLUSIONS: TMPRSS2 -ERG T1/E4 fusion-positive tumours had differentially regulated mRNAs observed in multiple studies, the most significant one coded for ERG. Several mRNAs were consistently associated with biochemical recurrence and have potential clinical utility but will require further validation for successful translation.

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Genome-Wide Linkage Analysis of TMPRSS2-ERG Fusion in Familial Prostate Cancer

Cited by 30 publications

References 38 publications

ERG rearrangement as a novel marker for predicting the extra-prostatic extension of clinically localised prostate cancer

ERG rearrangement as a novel marker for predicting the extra-prostatic extension of clinically localised prostate cancer

Predisposition for TMPRSS2-ERG Fusion in Prostate Cancer by Variants in DNA Repair Genes

Prostate cancer genes associated with TMPRSS2–ERG gene fusion and prognostic of biochemical recurrence in multiple cohorts

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