Cancer Risks Associated With Germline PALB2 Pathogenic Variants: An International Study of 524 Families
AuthorYang, X; Leslie, G; Doroszuk, A; Schneider, S; Allen, J; Decker, B; Dunning, AM; Redman, J; Scarth, J; Plaskocinska, I; ...
Source TitleJournal of Clinical Oncology
PublisherAMER SOC CLINICAL ONCOLOGY
University of Melbourne Author/sHopper, John; Southey, Melissa; Nguyen, Binh Thieu Tu; James, Paul; Trainer, Alison
AffiliationMelbourne School of Population and Global Health
Document TypeJournal Article
CitationsYang, X., Leslie, G., Doroszuk, A., Schneider, S., Allen, J., Decker, B., Dunning, A. M., Redman, J., Scarth, J., Plaskocinska, I., Luccarini, C., Shah, M., Pooley, K., Dorling, L., Lee, A., Adank, M. A., Adlard, J., Aittomaki, K., Andrulis, I. L. ,... Tischkowitz, M. (2020). Cancer Risks Associated With Germline PALB2 Pathogenic Variants: An International Study of 524 Families. JOURNAL OF CLINICAL ONCOLOGY, 38 (7), pp.674-+. https://doi.org/10.1200/JCO.19.01907.
Access StatusAccess this item via the Open Access location
Open Access URLPublished version
NHMRC Grant codeNHMRC/1029974
PURPOSE: To estimate age-specific relative and absolute cancer risks of breast cancer and to estimate risks of ovarian, pancreatic, male breast, prostate, and colorectal cancers associated with germline PALB2 pathogenic variants (PVs) because these risks have not been extensively characterized. METHODS: We analyzed data from 524 families with PALB2 PVs from 21 countries. Complex segregation analysis was used to estimate relative risks (RRs; relative to country-specific population incidences) and absolute risks of cancers. The models allowed for residual familial aggregation of breast and ovarian cancer and were adjusted for the family-specific ascertainment schemes. RESULTS: We found associations between PALB2 PVs and risk of female breast cancer (RR, 7.18; 95% CI, 5.82 to 8.85; P = 6.5 × 10-76), ovarian cancer (RR, 2.91; 95% CI, 1.40 to 6.04; P = 4.1 × 10-3), pancreatic cancer (RR, 2.37; 95% CI, 1.24 to 4.50; P = 8.7 × 10-3), and male breast cancer (RR, 7.34; 95% CI, 1.28 to 42.18; P = 2.6 × 10-2). There was no evidence for increased risks of prostate or colorectal cancer. The breast cancer RRs declined with age (P for trend = 2.0 × 10-3). After adjusting for family ascertainment, breast cancer risk estimates on the basis of multiple case families were similar to the estimates from families ascertained through population-based studies (P for difference = .41). On the basis of the combined data, the estimated risks to age 80 years were 53% (95% CI, 44% to 63%) for female breast cancer, 5% (95% CI, 2% to 10%) for ovarian cancer, 2%-3% (95% CI females, 1% to 4%; 95% CI males, 2% to 5%) for pancreatic cancer, and 1% (95% CI, 0.2% to 5%) for male breast cancer. CONCLUSION: These results confirm PALB2 as a major breast cancer susceptibility gene and establish substantial associations between germline PALB2 PVs and ovarian, pancreatic, and male breast cancers. These findings will facilitate incorporation of PALB2 into risk prediction models and optimize the clinical cancer risk management of PALB2 PV carriers.
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