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Prognostic significance of pathogenic variants in BRCA1, BRCA2, ATM and PALB2 genes in men undergoing hormonal therapy for advanced prostate cancer

by Mizuno, Kei , Fujimoto, Naohiro , Ogura, Keiji , Iwasaki, Yusuke , Hakozaki, Nozomi , Ishitoya, Satoshi , Nakagawa, Hidewaki , Sumiyoshi, Takayuki , Narita, Shintaro , Hatano, Shotaro , Kobayashi, Takashi , Kamoto, Toshiyuki , Kimura, Hiroko , Akamatsu, Shusuke , Shiota, Masaki , Goto, Takayuki , Eto, Masatoshi , Ogawa, Osamu , Terada, Naoki , Momozawa, Yukihide , Habuchi, Tomonori

in Biopsy / BRCA1 protein / BRCA2 protein / Castration / Homologous recombination / Homologous recombination repair / Medical prognosis / Metastases / Metastasis / Mutation / p53 Protein / Patients / Prostate cancer

2022

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Prognostic significance of pathogenic variants in BRCA1, BRCA2, ATM and PALB2 genes in men undergoing hormonal therapy for advanced prostate cancer

2022

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Prognostic significance of pathogenic variants in BRCA1, BRCA2, ATM and PALB2 genes in men undergoing hormonal therapy for advanced prostate cancer

2022

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Journal Article

Prognostic significance of pathogenic variants in BRCA1, BRCA2, ATM and PALB2 genes in men undergoing hormonal therapy for advanced prostate cancer

Mizuno, Kei,

Fujimoto, Naohiro,

Ogura, Keiji,

Iwasaki, Yusuke,

Hakozaki, Nozomi,

Ishitoya, Satoshi,

Nakagawa, Hidewaki,

Sumiyoshi, Takayuki,

Narita, Shintaro,

Hatano, Shotaro,

Kobayashi, Takashi,

Kamoto, Toshiyuki,

Kimura, Hiroko,

Akamatsu, Shusuke,

Shiota, Masaki,

Goto, Takayuki,

Eto, Masatoshi,

Ogawa, Osamu,

Terada, Naoki,

Momozawa, Yukihide,

Habuchi, Tomonori

2022

Overview

BackgroundThe prognostic significance of germline variants in homologous recombination repair genes in advanced prostate cancer (PCa), especially with regard to hormonal therapy, remains controversial.MethodsGermline DNA from 549 Japanese men with metastatic and/or castration-resistant PCa was sequenced for 27 cancer-predisposing genes. The associations between pathogenic variants and clinical outcomes were examined. Further, for comparison, DNA from prostate biopsy tissue samples from 80 independent patients with metastatic PCa were analysed.ResultsForty-four (8%) patients carried germline pathogenic variants in one of the analysed genes. BRCA2 was most frequently altered (n = 19), followed by HOXB13 (n = 9), PALB2 (n = 5) and ATM (n = 5). Further, the BRCA1, BRCA2, PALB2 and ATM variants showed significant association with a short time to castration resistance and overall survival (hazard ratio = 1.99 and 2.36; 95% CI, 1.15–3.44 and 1.23–4.51, respectively), independent of other clinical variables. Based on log-rank tests, the time to castration resistance was also significantly short in patients with BRCA1, BRCA2, PALB2 or ATM somatic mutations and TP53 mutations.ConclusionsGermline variants in BRCA1, BRCA2, PALB2 or ATM are independent prognostic factors of the short duration of response to hormonal therapy in advanced PCa.

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Publisher

Nature Publishing Group

Subject

/ Homologous recombination

/ Homologous recombination repair

/ Medical prognosis