Cancer Risks Associated With Germline <i>PALB2</i> Pathogenic Variants: An International Study of 524 Families.

Abstract

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 <i>PALB2</i> pathogenic variants (PVs) because these risks have not been extensively characterized. We analyzed data from 524 families with <i>PALB2</i> 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. We found associations between <i>PALB2</i> PVs and risk of female breast cancer (RR, 7.18; 95% CI, 5.82 to 8.85; <i>P</i> = 6.5 × 10^-76), ovarian cancer (RR, 2.91; 95% CI, 1.40 to 6.04; <i>P</i> = 4.1 × 10^-3), pancreatic cancer (RR, 2.37; 95% CI, 1.24 to 4.50; <i>P</i> = 8.7 × 10^-3), and male breast cancer (RR, 7.34; 95% CI, 1.28 to 42.18; <i>P</i> = 2.6 × 10^-2). There was no evidence for increased risks of prostate or colorectal cancer. The breast cancer RRs declined with age (<i>P</i> 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 (<i>P</i> 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. These results confirm <i>PALB2</i> as a major breast cancer susceptibility gene and establish substantial associations between germline <i>PALB2</i> PVs and ovarian, pancreatic, and male breast cancers. These findings will facilitate incorporation of <i>PALB2</i> into risk prediction models and optimize the clinical cancer risk management of <i>PALB2</i> PV carriers.