Somatic aberrations of BRCA1 gene are associated with ALDH1, EGFR, and tumor progression in prostate cancer

Aleksandra Omari , Paulina Nastały , Sara Stoupiec , Aneta Bałabas , Michalina Dąbrowska , Beata Bielińska , Sebastian Huss , Klaus Pantel , Axel Semjonow , Elke Eltze , Burkhard Brandt , Natalia Bednarz-Knoll

Abstract

BRCA1 is a pivotal tumor suppressor. Its dysfunction is known to play a role in different tumors. 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 lymph nodes and peripheral blood, and indicate worse clinical outcome. In order to substantiate the data for BRCA1 gene loss in PCa and reveal its phenotypical background, BRCA1 gene status was assessed in a large cohort of PCa patients and compared to different molecular factors. BRCA1 gene dosage was assessed in 2398 tumor samples from 1,199 PCa patients using fluorescent in situ hybridization. It was compared to clinico‐pathological parameters, patients’ outcome as well as selected proteins (Ki‐67, apoptosis marker, cytokeratins, vimentin, E‐ and N‐cadherin, ALDH1 and EGFR) examined immunohistochemically. BRCA1 losses were found in 10%, whereas gains appeared in 7% of 603 informative PCa patients. BRCA1 losses correlated to higher T stage (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, that is, 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). These 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 conceivably representing loss‐of‐function might mark more invasive tumors.
Author Aleksandra Omari
Aleksandra Omari,,
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, Paulina Nastały
Paulina Nastały,,
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, Sara Stoupiec
Sara Stoupiec,,
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, Aneta Bałabas
Aneta Bałabas,,
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, Michalina Dąbrowska
Michalina Dąbrowska,,
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, Beata Bielińska
Beata Bielińska,,
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, Sebastian Huss
Sebastian Huss,,
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, Klaus Pantel
Klaus Pantel,,
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, Axel Semjonow
Axel Semjonow,,
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, Elke Eltze
Elke Eltze,,
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et al.`
Journal seriesInternational Journal of Cancer, ISSN 0020-7136, (N/A 140 pkt)
Issue year2019
Vol144
No3
Pages607-614
Publication size in sheets0.5
Keywords in Englishprostate cancer, BRCA1, somatic gene loss, prognostic marker, aggressiveness
ASJC Classification1306 Cancer Research; 2730 Oncology
DOIDOI:10.1002/ijc.31905
URL https://doi.org/10.1002/ijc.31905
Languageen angielski
Score (nominal)140
ScoreMinisterial score = 140.0, 30-09-2019, ArticleFromJournal
Publication indicators Scopus SNIP (Source Normalised Impact per Paper): 2017 = 2.182; WoS Impact Factor: 2017 = 7.36 (2) - 2017=5.933 (5)
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