PT - JOURNAL ARTICLE AU - Aleksandra Omari AU - Paulina Nastały AU - Aneta Bałabas AU - Michalina Dąbrowska AU - Beata Bielińska AU - Sebastian Huss AU - Klaus Pantel AU - Axel Semjonow AU - Elke Eltze AU - Burkhard Brandt AU - Natalia Bednarz-Knoll TI - Somatic aberrations of BRCA1 gene are associated with progressive and stem cell-like phenotype of prostate cancer AID - 10.1101/271312 DP - 2018 Jan 01 TA - bioRxiv PG - 271312 4099 - http://biorxiv.org/content/early/2018/02/26/271312.short 4100 - http://biorxiv.org/content/early/2018/02/26/271312.full AB - Background BRCA1 is a pivotal tumor suppressor. Its dysfunction is known to play a role in different tumor entities. Among others, BRCA1 germline mutations account for higher risk and more aggressive course of prostate cancer (PCa). In addition, somatic BRCA1 gene loss was demonstrated to be a signature of PCa dissemination to regional lymph nodes and peripheral blood, and indicate worse clinical outcome. In order to substantiate the data for BRCA1 gene loss in PCa and to reveal its phenotypical background, BRCA1 gene status was assessed in a large cohort of PCa patients and compared to different molecular factors.Methods BRCA1 gene dosage was assessed in 2398 tumor samples from 1199 PCa patients using fluorescent in situ hybridization. It was compared to clinic-pathological parameters, patients’ outcome as well as selected proteins (Ki-67, apoptosis marker, cytokeratins, vimentin, E- and N-cadherin, ALDH1 and EGFR) examined by immunohistcohemistry.Results BRCA1 losses were found in 10%, whereas gains appeared in 7% of 603 informative PCa patients. BRCA1 losses correlated to higher T status (p=0.027), Gleason score (p=0.039), shorter time to biochemical recurrence in patients with Gleason score >7 independently of other factors (multivariate analysis, p=0.005) as well as expression of proteins regulating stemness and epithelial-mesenchymal transition i.e. ALDH1 (p=0.021) and EGFR (p=0.011), respectively. BRCA1 gains correlated to shorter time to metastasis (p=0.012) and expression of ALDH1 (p=0.014).Conclusions The presented results support the assumption that BRCA1 gene losses contribute to a progressive and stem cell-like phenotype of PCa. Furthermore, they reveal that also BRCA1 gain might mark more invasive tumors.AbbreviationsALDH1aldehyde dehydrogenaseCKcytokeratinCTCscirculating tumor cellsDFSdisease-free survivalEGFRepidermal growth factor receptorEMTepithelial-mesenchymal transitionFISHfluorescent in situ hybridizationIHCimmunohistochemistryLNMlymph node metastasisPARPpoly(ADP-ribose) polymerasePCaprostate cancerPSAprostate specific antigenPTprimary tumorREMARKREporting recommendations for tumour MARKer prognostic studiesTMAtissue microarray