Association of BRCA1 and BRCA2 Pathogenic Variants with Increased Risk of Cancer

Besides female breast and ovarian cancers, BRCA1/2 pathogenic variants are associated with increased risks of breast cancer in men, and pancreatic and stomach cancers in both sexes, and BRCA2 carriers are at elevated prostate cancer risk. No associations were found with risks of other cancers. The study performed by the Consortium of Investigators of Modifiers of BRCA1/2 investigated the associations between the risks of 22 cancers and BRCA1/2 pathogenic variants using data from 5,341 families segregating BRCA1 or BRCA2 pathogenic variants. The findings provide age-specific cancer risk estimates and allow for improved cancer risk assessment of male and female carriers. The results are published by Prof. Antonis C. Antoniou of the Center for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge in Cambridge, UK and colleagues on 25 January 2022 in the Journal of Clinical Oncology.

It is well established that pathogenic variants in BRCA1 and BRCA2 are associated with increased risks of breast and ovarian cancers in women. Accumulated evidence indicates that BRCA1/2 pathogenic variants are also associated with pancreatic cancer and male breast cancer risks and that BRCA2 pathogenic variants are associated with prostate cancer risk, particularly aggressive prostate cancer. Associations with risks for other cancers have also been suggested, but these associations are based on studies with relatively small sample sizes, resulting in imprecise cancer risk estimates.

To inform clinical management strategies and optimise guidelines for cancer risk management in female and male BRCA1/2 carriers, the Consortium of Investigators of Modifiers of BRCA1/2 comprehensively assessed the associations of BRCA1/2 pathogenic variants with risks of 22 cancers, other than female breast and ovarian cancers. They used data from 3,184 BRCA1 and 2,157 BRCA2 families to estimate age-specific relative and absolute risks for 22 first primary cancer types adjusting for family ascertainment.

BRCA1 pathogenic variants were associated with risks of male breast cancer with relative risk (RR) of 4.30 (95% confidence interval [CI] 1.09 to 16.96), pancreatic cancer RR 2.36 (95% CI 1.51 to 3.68), and stomach cancer RR 2.17 (95% CI 1.25 to 3.77). Associations with colorectal and gallbladder cancers were also suggested.

BRCA2 pathogenic variants were associated with risks of male breast cancer with RR 44.0 (95% CI 21.3 to 90.9), stomach cancer RR 3.69 (95% CI 2.40 to 5.67), pancreatic cancer RR 3.34 (95% CI 2.21 to 5.06), and prostate cancer RR 2.22 (95% CI 1.63 to 3.03). The stomach cancer RR was higher for females than males (6.89 versus 2.76; p = 0.04).

The absolute risks to age 80 years ranged from 0.4% for male breast cancer to approximately 2.5% for pancreatic cancer for BRCA1 carriers and from approximately 2.5% for pancreatic cancer to 27% for prostate cancer for BRCA2 carriers.

This study has several limitations. It is a retrospective family-based study, with self-reported cancer family history, which may be inaccurate. Between 7% and 40% of reported cancer cases had missing age at diagnosis, with stomach cancer having the largest proportion. However, the study team performed sensitivity analyses excluding any study groups in which under-reporting was likely and any cases with missing age at diagnosis, and conclusions remained similar for most cancers. Furthermore, the results are presented without any multiple testing adjustment. The ethnicity of the family proband was not systematically collected. The investigators did not have data on other genetic and environmental factors and were unable to investigate the modification effects of these factors.

The authors concluded that their study further clarified the cancer spectrum associated with BRCA1/2 pathogenic variants. The associations of BRCA1/2 pathogenic variants with the risks of male breast and pancreatic cancers were confirmed and refined, as well as the association of prostate cancer with BRCA2 pathogenic variants, regardless of age and aggressiveness.

The study was previously presented at the Familial Aspects of Cancers: Research and Practice conference in Kingscliff, New South Wales, Australia on 1 September 2021.

It was supported by multiple grants from non-profit organisations.

Reference

Li S, Silvestri V, Leslie G, et al. Cancer Risks Associated With BRCA1 and BRCA2 Pathogenic Variants. JCO; Published online 25 January 2022. DOI: 10.1200/JCO.21.02112

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