Assessment of Cancer Risk Profile for Germline BRCA1 and BRCA2 Pathogenic Variants in Patients With Common Cancers

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In a Japanese case-control study reported in JAMA Oncology, Momozawa et al found that germline BRCA1/2 pathogenic variants were associated with an increased risk of biliary tract, esophageal, and gastric cancers, in addition to an increased risk of cancers that have well-established associations with such variants.

As stated by the investigators, “The clinical importance of genetic testing of BRCA1 and BRCA2 in breast, ovarian, prostate, and pancreatic cancers is widely recognized. However, there is insufficient evidence to include other cancer types that are potentially associated with BRCA1 and BRCA2 in clinical management guidelines.”

The study involved data on 63,828 patients with 14 common cancer types and 37,086 controls sourced from BioBank Japan, a multi-institutional hospital-based registry, between April 2003 and March 2018.

Key Findings

Pathogenic variants were associated with a significantly increased risk of cancers with an established association: odds ratios (ORs) were 16.1 for BRCA1 and 10.9 for BRCA2 for female breast cancer; 75.6 and 11.3, respectively, for ovarian cancer; 12.6 and 10.7, respectively, for pancreatic cancer; and 4.0 for BRCA2 for prostate cancer.

Significant associations for pathogenic variants at P < 1 × 10−4 with odds ratios > 4.0 were found for biliary tract cancer (OR = 17.4, 95% confidence interval [CI] = 5.8–51.9) for BRCA1; esophageal cancer (OR = 5.6, 95% CI = 2.9–11.0) for BRCA2; and gastric cancer (OR = 5.2, 95% CI = 2.6–10.5) for BRCA1 and (OR = 4.7, 95% CI = 3.1–7.1) for BRCA2.

Additional associations were found for lung cancer and lymphoma for BRCA1 pathogenic variants, and for male breast cancer, cervical cancer, endometrial cancer, liver cancer, and kidney cancer for BRCA2 pathogenic variants.  

The investigators concluded, “The results of this large-scale registry-based case-control study suggest that pathogenic variants in BRCA1 and BRCA2 were associated with the risk of seven cancer types. These results indicate broader clinical relevance of BRCA1 and BRCA2 genetic testing.”

Yukihide Momozawa, DVM, PhD, of the RIKEN Center for Integrative Medical Sciences, Yokohama, is the corresponding author for the JAMA Oncology article.

Disclosure: The study was supported by the Japan Agency for Medical Research and Development. For full disclosures of the study authors, visit


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