Cancer Risks Associated With GermlinePALB2Pathogenic Variants: An International Study of 524 Families
Authors: Yang Xin , Leslie Goska , Doroszuk Alicja , Schneider Sandra , Allen Jamie , Decker Brennan , Dunning Alison M. , Redman James , Scarth James , Plaskocinska Inga , Luccarini Craig , Shah Mitul , Pooley Karen , Dorling Leila , Lee Andrew , Adank Muriel A. , Adlard Julian , Aittomäki Kristiina , Andrulis Irene L. , Ang Peter , Barwell Julian , Bernstein Jonine L. , Bobolis Kristie , Borg Åke , Blomqvist Carl , Claes Kathleen B.M. , Concannon Patrick , Cuggia Adeline , Culver Julie O. , Damiola Francesca , de Pauw Antoine , Diez Orland , Dolinsky Jill S. , Domchek Susan M. , Engel Christoph , Evans D. Gareth , Fostira Florentia , Garber Judy , Golmard Lisa , Goode Ellen L. , Gruber Stephen B. , Hahnen Eric , Hake Christopher , Heikkinen Tuomas , Hurley Judith E. , Janavicius Ramunas , Kleibl Zdenek , Kleiblova Petra , Konstantopoulou Irene , Kvist Anders , Laduca Holly , Lee Ann S.G. , Lesueur Fabienne , Maher Eamonn R. , Mannermaa Arto , Manoukian Siranoush , McFarland Rachel , McKinnon Wendy , Meindl Alfons , Metcalfe Kelly , Mohd Taib Nur Aishah , Moilanen Jukka , Nathanson Katherine L. , Neuhausen Susan , Ng Pei Sze , Nguyen-Dumont Tu , Nielsen Sarah M. , Obermair Florian , Offit Kenneth , Olopade Olufunmilayo I. , Ottini Laura , Penkert Judith , Pylkäs Katri , Radice Paolo , Ramus Susan J. , Rudaitis Vilius , Side Lucy , Silva-Smith Rachel , Silvestri Valentina , Skytte Anne-Bine , Slavin Thomas , Soukupova Jana , Tondini Carlo , Trainer Alison H. , Unzeitig Gary , Usha Lydia , van Overeem Hansen Thomas , Whitworth James , Wood Marie , Yip Cheng Har , Yoon Sook-Yee , Yussuf Amal , Zogopoulos George , Goldgar David , Hopper John L. , Chenevix-Trench Georgia , Pharoah Paul , George Sophia H.L. , Balmaña Judith , Houdayer Claude , James Paul , El-Haffaf Zaki , Ehrencrona Hans , Janatova Marketa , Peterlongo Paolo , Nevanlinna Heli , Schmutzler Rita , Teo Soo-Hwang , Robson Mark , Pal Tuya , Couch Fergus , Weitzel Jeffrey N. , Elliott Aaron , Southey Melissa , Winqvist Robert , Easton Douglas F. , Foulkes William D. , Antoniou Antonis C. , Tischkowitz Marc 
Published: December 2019

PURPOSETo 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.METHODSWe 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.RESULTSWe 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.CONCLUSIONThese 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.