Hiroko Kimura1, Kei Mizuno1, Masaki Shiota2, Shintaro Narita3, Naoki Terada4, Naohiro Fujimoto5, Keiji Ogura6, Shotaro Hatano6, Yusuke Iwasaki7, Nozomi Hakozaki7, Satoshi Ishitoya6, Takayuki Sumiyoshi1, Takayuki Goto1, Takashi Kobayashi1, Hidewaki Nakagawa8, Toshiyuki Kamoto4, Masatoshi Eto2, Tomonori Habuchi3, Osamu Ogawa1, Yukihide Momozawa7, Shusuke Akamatsu9,10. 1. Department of Urology, Kyoto University Graduate School of Medicine, Kyoto, Japan. 2. Department of Urology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. 3. Department of Urology, Akita University Graduate School of Medicine, Akita, Japan. 4. Department of Urology, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan. 5. Department of Urology, School of Medicine, University of Occupational and Environmental Health, Kitakyusyu, Japan. 6. Department of Urology, Japanese Red Cross Otsu Hospital, Otsu, Japan. 7. Laboratory for Genotyping Development, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan. 8. Laboratory for Cancer Genomics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan. 9. Department of Urology, Kyoto University Graduate School of Medicine, Kyoto, Japan. akamats@kuhp.kyoto-u.ac.jp. 10. Laboratory for Cancer Genomics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan. akamats@kuhp.kyoto-u.ac.jp.
Abstract
BACKGROUND: The prognostic significance of germline variants in homologous recombination repair genes in advanced prostate cancer (PCa), especially with regard to hormonal therapy, remains controversial. METHODS: Germline 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. RESULTS: Forty-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. CONCLUSIONS: Germline variants in BRCA1, BRCA2, PALB2 or ATM are independent prognostic factors of the short duration of response to hormonal therapy in advanced PCa.
BACKGROUND: The prognostic significance of germline variants in homologous recombination repair genes in advanced prostate cancer (PCa), especially with regard to hormonal therapy, remains controversial. METHODS: Germline 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. RESULTS: Forty-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. CONCLUSIONS: Germline 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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