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Mutations in ATM , NBN and BRCA2 predispose to aggressive prostate cancer in Poland
Author(s) -
Wokołorczyk Dominika,
Kluźniak Wojciech,
Huzarski Tomasz,
Gronwald Jacek,
Szymiczek Agata,
Rusak Bogna,
Stempa Klaudia,
Gliniewicz Katarzyna,
Kashyap Aniruddh,
Morawska Sylwia,
Dębniak Tadeusz,
Jakubowska Anna,
Szwiec Marek,
Domagała Paweł,
Lubiński Jan,
Narod Steven A.,
Akbari Mohammad R.,
Cybulski Cezary
Publication year - 2020
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.33272
Subject(s) - chek2 , prostate cancer , msh6 , mlh1 , msh2 , pten , cancer research , cancer , mutation , genetics , pms2 , biology , germline mutation , gene , medicine , oncology , dna mismatch repair , pi3k/akt/mtor pathway , apoptosis , colorectal cancer
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 and 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 noncarriers. 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 = .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.