Mutations in ATM, NBN and BRCA2 predispose to aggressive prostate cancer in Poland - PubMed

Mutations in ATM, NBN and BRCA2 predispose to aggressive prostate cancer in Poland - PubMed

Mutations in ATM, NBN and BRCA2 predispose to aggressive prostate cancer in Poland

Dominika Wokołorczyk 1, Wojciech Kluźniak 1, Tomasz Huzarski 1 2, Jacek Gronwald 1, Agata Szymiczek 3, Bogna Rusak 1, Klaudia Stempa 1, Katarzyna Gliniewicz 1, Aniruddh Kashyap 1, Sylwia Morawska 1, Tadeusz Dębniak 1, Anna Jakubowska 1 4, Marek Szwiec 5, Paweł Domagała 6, Jan Lubiński 1, Steven A Narod 3 7, Mohammad R Akbari 3 7, Cezary Cybulski 1, Polish Hereditary Prostate Cancer Consortium

Collaborators, Affiliations 

• PMID: 32875559
 
• DOI: 10.1002/ijc.33272

Abstract

In designing national strategies for genetic testing, it is important to define the full spectrum of pathogenic mutations in prostate cancer (PCa) susceptibility genes. To investigate the frequency of mutations in PCa susceptibility genes in Polish familial PCa cases, to estimate gene-related PCa risks and probability of aggressive disease, we analyzed the coding regions of 14 genes by exome sequencing in 390 men with familial prostate cancer and 308 cancer-free controls. We compared the mutation frequencies between PCa cases and controls. We also compared clinical characteristics of prostate cancers between mutation carriers and non-carriers. Of the 390 PCa cases, 76 men (19.5%) carried a mutation in BRCA1, BRCA2, NBN, ATM, CHEK2, HOXB13, MSH2 or MSH6 genes. No mutations were found in BRIP1, PTEN, TP53, MLH1, PMS2 and SPOP. Significant associations with familial PCa risk were observed for CHEK2, NBN, ATM, and HOXB13. High grade (Gleason 8-10) tumors were seen in 56% of BRCA2, NBN or ATM carriers, compared to 21% of patients who tested negative for mutations in these genes (OR = 4.7, 95%CI 2.0-10.7, P = 0.0003). In summary, approximately 20% of familial prostate cancer cases in Poland can be attributed to mutations in eight susceptibility genes. Carriers of mutations in BRCA2, NBN and ATM develop aggressive disease and may benefit from intensified screening and/or chemotherapy.

Keywords: ATM; BRCA1; BRCA2; CHEK2; HOXB13; NBN; aggressive phenotype; hereditary; mutation; prostate cancer; sequencing.

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