Abstract
Abstract INTRODUCTION: Germline BRCA mutations are an independent prognostic factor for PrCa prognosis and treatment outcomes. BRCA tumours are associated with chromosomal instability due to underlying DNA repair deficiency; however, recurrent patterns of genomic aberrations in this context have not been explored. METHODS: We collected PrCa formalin-fixed paraffin-embedded samples from diagnostic biopsies and/or prostatectomies from 5 BRCA1 and 24 BRCA2 germline mutation carriers, which were matched with at least 1 sporadic PrCa (ie PrCa with no germline mutation) by stage and treatment. All samples were reviewed by an expert pathologist, and the tumour relevant areas were selected for further analyses. Recurrent chromosomal abnormalities in PrCa were also analyzed using previously described fluorescence in situ hybridization (FISH) “break-apart” and/or “fusion” assays, including a novel FISH “combined break-fusion” assay for TMPRSS2-ERG designed with probes flanking 3´and 5´of ERG and 5´of TMPRSS2. Genomic abnormalities were confirmed by a second method (qPCR or IHC) whenever possible. RESULTS: No differences in Gleason score between mutation carriers and non-carriers were seen (p = 0.134). Neuroendocrine phenotype was not identified in any sample. The “break-apart” assay identified interstitial deletion of genomic sequences between TMPRSS2 and ERG in all BRCA mutated tumours in at least one focus (100%), compared with 45% of non-carriers (P<0.001). The novel “break-fusion” assay allowed us to identify TMPRSS2 as the fusion partner in all cases, excluding other potential partners previously described. ETV1 rearrangements were identified in 3.5% of carriers and in 4% of non-carriers (P = 0.662). CONCLUSIONS: The presence of TMPRRSS2-ERG fusion gene in all BRCA mutated tumours in our series identifies a non-random androgen-driven event on the background of high chromosomal instability. Our findings suggests that BRCA mutated PrCa is androgen-dependent which may have important implications for the management of these patients. Citation Format: Elena Castro, Floortje Van de Poll, Elena Piñeiro, Paz Nombela, Elizabeth Bancroft, Koveela Govindasami, Michelle Guy, G Kovacs, Steve Ellis, Antonis Antoniu, Douglas Easton, Zsofia Kote-Jarai, Fatima Al-Sharour, David Olmos, Rosalind Eeles. High-Frequency of TMPRSS2-ERG fusion gene identifies a non-random androgen-driven event of chromosomal instability in BRCA mutated prostate cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4249. doi:10.1158/1538-7445.AM2015-4249
Published Version
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