Risks of non-breast, non-ovarian cancers for BRCA1 and BRCA2 pathogenic variant carriers: a prospective cohort study

Ruotong Yang^{1

2}, Robert J MacInnis^{1

3}, Roger L Milne^{1

3

4}, Tu Nguyen-Dumont^{5

6}, Whitney F Maxwell⁷, Jeanine M Genkinger^{8

9}, Gord Glendon¹⁰; Kathleen Cuningham Foundation Consortium for Research Into Familial Breast Cancer (kConFab); Eric A Ross¹¹, Irene L Andrulis^{10

12}, Sarah V Colonna⁷, Mary Daly¹³, Esther M John^{14

15}, Allison W Kurian^{14

15}, Mary Beth Terry^{8

9

16}, John L Hopper¹, Melissa C Southey^{1

3

4}, Kelly-Anne Phillips^{1

17

18}, Shuai Li^{19

20}

Affiliations

¹ Center for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Carlton, VIC, Australia.
² Department of Epidemiology and Biostatistics, School of Public Health, Peking University Health Science Center, Beijing, China.
³ Cancer Epidemiology Division, Cancer Council Victoria, East Melbourne, VIC, Australia.
⁴ Precision Medicine, School of Clinical Sciences at Monash Health, Monash University, Clayton, VIC, Australia.
⁵ Clinical Genomics, School of Translational Medicine, Monash University, Melbourne, VIC, Australia.
⁶ Department of Clinical Pathology, The University of Melbourne, Melbourne, VIC, Australia.
⁷ Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA.
⁸ Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, USA.
⁹ Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, USA.
¹⁰ Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, ON, Canada.
¹¹ Biostatistics and Bioinformatics Facility, Fox Chase Cancer Center-Temple Health, Philadelphia, PA, USA.
¹² Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada.
¹³ Fox Chase Cancer Center, Philadelphia, PA, USA.
¹⁴ Department of Epidemiology & Population Health, Stanford University School of Medicine, Stanford, CA, USA.
¹⁵ Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA.
¹⁶ Silent Spring Institute, Newton, MA, USA.
¹⁷ Department of Medical Oncology, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia.
¹⁸ Department of Oncology, Sir Peter MacCallum, University of Melbourne, Parkville, VIC, Australia.
¹⁹ Center for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Carlton, VIC, Australia. shuai.li@unimelb.edu.au.
²⁰ Precision Medicine, School of Clinical Sciences at Monash Health, Monash University, Clayton, VIC, Australia. shuai.li@unimelb.edu.au.

PMID: 41776557
DOI: 10.1186/s12916-026-04753-8

Free article

Risks of non-breast, non-ovarian cancers for BRCA1 and BRCA2 pathogenic variant carriers: a prospective cohort study

Ruotong Yang et al. BMC Med. 2026.

Free article

. 2026 Mar 4.

doi: 10.1186/s12916-026-04753-8. Online ahead of print.

Authors

Affiliations

¹ Center for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Carlton, VIC, Australia.
² Department of Epidemiology and Biostatistics, School of Public Health, Peking University Health Science Center, Beijing, China.
³ Cancer Epidemiology Division, Cancer Council Victoria, East Melbourne, VIC, Australia.
⁴ Precision Medicine, School of Clinical Sciences at Monash Health, Monash University, Clayton, VIC, Australia.
⁵ Clinical Genomics, School of Translational Medicine, Monash University, Melbourne, VIC, Australia.
⁶ Department of Clinical Pathology, The University of Melbourne, Melbourne, VIC, Australia.
⁷ Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA.
⁸ Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, USA.
⁹ Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, USA.
¹⁰ Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, ON, Canada.
¹¹ Biostatistics and Bioinformatics Facility, Fox Chase Cancer Center-Temple Health, Philadelphia, PA, USA.
¹² Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada.
¹³ Fox Chase Cancer Center, Philadelphia, PA, USA.
¹⁴ Department of Epidemiology & Population Health, Stanford University School of Medicine, Stanford, CA, USA.
¹⁵ Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA.
¹⁶ Silent Spring Institute, Newton, MA, USA.
¹⁷ Department of Medical Oncology, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia.
¹⁸ Department of Oncology, Sir Peter MacCallum, University of Melbourne, Parkville, VIC, Australia.
¹⁹ Center for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Carlton, VIC, Australia. shuai.li@unimelb.edu.au.
²⁰ Precision Medicine, School of Clinical Sciences at Monash Health, Monash University, Clayton, VIC, Australia. shuai.li@unimelb.edu.au.

PMID: 41776557
DOI: 10.1186/s12916-026-04753-8

Abstract

Background: The non-breast non-ovarian cancers associated with BRCA1 and BRCA2 pathogenic variants (PVs) are controversial. We aimed to examine this using a prospective cohort design.

Methods: This study included 1260 BRCA1 and 1058 BRCA2 PV carriers (91% were females) from two consortia: the Breast Cancer Family Registry (BCFR) and the Kathleen Cuningham Foundation Consortium for Research into Familial Breast Cancer Follow-Up Study (kConFab-FUS). The carriers were free of cancer other than breast or ovarian cancer at baseline and had a median baseline age of 45.5 years. For 16 types of non-breast, non-ovarian cancers, standardized incidence ratios (SIRs) relative to population incidence, the probabilities of relative risk effect size > 2 (i.e., moderate risk) and cumulative risks to age 80 years were estimated.

Results: During a median follow-up time of 11.4 years, 161 non-breast, non-ovarian cancers were observed. For BRCA1 PV carriers, little evidence of increased risk was observed. The prostate, pancreatic, and all non-pancreatic cancer SIRs were 1.7 (95% CI 0.7-4.2), 1.1 (95% CI 0.3-4.6) and 0.85 (95% CI 0.68-1.06), respectively; the probabilities of relative risk > 2 were 0 and 67% for prostate and pancreatic cancers, respectively. For BRCA2 PV carriers, increased risks of pancreatic (SIR = 6.6, 95% CI 3.8-11.6), prostate (SIR = 3.6, 95% CI 1.9-6.8) and stomach (SIR = 3.1, 95% CI 1.01-9.8) cancer were observed, with a cumulative risk to age 80 years of 8.3, 82.0, and 1.6%, respectively. For all the other non-breast, non-ovarian cancers combined, the SIR was 0.85 (95% CI 0.66-1.10).

Conclusions: Apart from pancreatic, prostate, and possibly stomach cancers for BRCA2 PV carriers, and possibly pancreatic cancer for BRCA1 PV carriers, there is no evidence that BRCA1 and BRCA2 PV carriers have substantially increased risks of other non-breast, non-ovarian cancers. Our prospective risk estimates are informative for cancer risk assessment for people with BRCA1 and BRCA2 PVs.

Keywords: BRCA1; BRCA2; Cancer risk; Penetrance; Prospective study.

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Conflict of interest statement

Declarations. Ethics approval and consent to participate: All participants provided written informed consent, and all centers in the consortia obtained local ethics approvals. Consent for publication: Not applicable. Competing interests: The authors declare no competing interests.

References

1. Kuchenbaecker KB, Hopper JL, Barnes DR, Phillips KA, Mooij TM, Roos-Blom MJ, et al. Risks of breast, ovarian, and contralateral breast cancer for BRCA1 and BRCA2 mutation carriers. JAMA. 2017;317(23):2402–16.
1. Li S, Silvestri V, Leslie G, Rebbeck TR, Neuhausen SL, Hopper JL, et al. Cancer risks associated with BRCA1 and BRCA2 pathogenic variants. J Clin Oncol. 2022;40(14):1529–41.
1. Momozawa Y, Sasai R, Usui Y, Shiraishi K, Iwasaki Y, Taniyama Y, et al. Expansion of cancer risk profile for BRCA1 and BRCA2 pathogenic variants. JAMA Oncol. 2022;8(6):871–8.
1. Nyberg T, Frost D, Barrowdale D, Evans DG, Bancroft E, Adlard J, et al. Prostate cancer risks for male BRCA1 and BRCA2 mutation carriers: a prospective cohort study. Eur Urol. 2020;77(1):24–35.
1. National Comprehensive Cancer Network. Genetic/Familial High-Risk Assessment: Breast, Ovarian, Pancreatic, and Prostate (Version 3.2025).

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Risks of non-breast, non-ovarian cancers for BRCA1 and BRCA2 pathogenic variant carriers: a prospective cohort study

Affiliations

Risks of non-breast, non-ovarian cancers for BRCA1 and BRCA2 pathogenic variant carriers: a prospective cohort study

Authors

Affiliations

Abstract

Conflict of interest statement

References

Grants and funding

LinkOut - more resources

Full Text Sources

Research Materials

Miscellaneous