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INTRODUCTION: Deletion of 3p13 is one of the most common alterations in prostate cancer preferentially occurring in tumors with TMPRSS2:ERG fusion. The cause for the striking association between 3p13 loss and ERG fusion is unknown. METHODS: Here, we made use of a preexisting heterogeneity prostate cancer tissue microarray including ten tissue spots from ten different tumor areas of 317 cancers to examine the spatial distribution of 3p13 deletions (determined by fluorescence in situ hybridization) in prostate cancer areas with and without ERG overexpression (determined by immunohistochemistry). RESULTS: 3p13 deletions were found in 61 of 299 (20.4%) and ERG positivity in 174 of 317 (54.9%) interpretable cancers. The likelihood of 3p13 loss was twice as high in ERG-positive cancers (39/152, 25.7%) than in ERG-negative cancers (17/124, 13.7%, P=0.010). At least three tissue spots were interpretable for 3p13 deletion status in 279 cancers: only these were used for heterogeneity assessment. Among these tumors, 58 (20.8%) had a 3p13 deletion and 221 (79.2%) were undeleted. The majority of 3p13-deleted cancers showed marked intratumoral heterogeneity. Areas with and without 3p13 loss were found in 50 (18%) of 279 cancers with three or more interpretable tissue spots, while only eight (3%) tumors had a homogeneous 3p13 loss. Comparison with ERG data revealed that ERG fusion usually precede 3p13 deletions. In total, 26 (66.7%) of 39 cancers with ERG and 3p13 alteration had only focal 3p13 deletions in an otherwise ERG-positive background. In contrast, none of the cancers showed a pattern that would be consistent with 3p13 deletion preceding ERG fusion. CONCLUSION: Our study identifies 3p13 deletion as a highly heterogeneous alteration in prostate cancer preferentially developing at rather late stages of progression in TMPRSS2:ERG fusion-positive tumors.
RESUMEN
BACKGROUND: Animal model experiments have suggested a role of the DNA repair protein ERCC1 (Excision Repair Cross-Complementation Group 1) in prostate cancer progression. METHODS: To better understand the impact of ERCC1 protein expression in human prostate cancer, a preexisting tissue microarray (TMA) containing more than 12,000 prostate cancer specimens was analyzed by immunohistochemistry and data were compared with tumor phenotype, PSA recurrence and several of the most common genomic alterations (TMPRSS2:ERG fusions: deletions of PTEN, 6q, 5q, 3p). RESULTS: ERCC1 staining was seen in 64.7% of 10,436 interpretable tissues and was considered weak in 37.1%, moderate in 22.6% and strong in 5% of tumors. High-level ERCC1 staining was linked to advanced pT stage, high Gleason grade, positive lymph nodes, high pre-operative serum PSA, and positive surgical margin status (p < 0.0001 each). High ERCC1 expression was strongly associated with an elevated risk of PSA recurrence (p < 0.0001). This was independent of established prognostic features. A subgroup analysis of cancers defined by comparable quantitative Gleason grades revealed that the prognostic impact was mostly driven by low-grade tumors with a Gleason 3 + 3 or 3 + 4 (Gleason 4: ≤5%). High ERCC1 expression was strongly associated with the presence of genomic alterations and expression levels increased with the number of deletions present in the tumor. These latter data suggest a functional relationship of ERCC1 expression with genomic instability. CONCLUSION: The results of our study demonstrate that expression of ERCC1 - a potential surrogate for genomic instability - is an independent prognostic marker in prostate cancer with particular importance in low-grade tumors.
