Literature DB >> 31841383

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

Xin Yang1, Goska Leslie1, Alicja Doroszuk2, Sandra Schneider2, Jamie Allen1, Brennan Decker1,3,4, Alison M Dunning5, James Redman2, James Scarth2, Inga Plaskocinska2, Craig Luccarini5, Mitul Shah5, Karen Pooley1, Leila Dorling1, Andrew Lee1, Muriel A Adank6, Julian Adlard7, Kristiina Aittomäki8, Irene L Andrulis9, Peter Ang10, Julian Barwell11, Jonine L Bernstein12, Kristie Bobolis13, Åke Borg14, Carl Blomqvist15, Kathleen B M Claes16, Patrick Concannon17, Adeline Cuggia18,19, Julie O Culver20, Francesca Damiola21, Antoine de Pauw22, Orland Diez23, Jill S Dolinsky24, Susan M Domchek25,26, Christoph Engel27, D Gareth Evans28, Florentia Fostira29, Judy Garber26,30, Lisa Golmard22, Ellen L Goode31, Stephen B Gruber32, Eric Hahnen33,34, Christopher Hake13, Tuomas Heikkinen35, Judith E Hurley36, Ramunas Janavicius37,38, Zdenek Kleibl39, Petra Kleiblova39,40, Irene Konstantopoulou29, Anders Kvist14, Holly Laduca24, Ann S G Lee11,41,42, Fabienne Lesueur43, Eamonn R Maher2, Arto Mannermaa44, Siranoush Manoukian45, Rachel McFarland24,46, Wendy McKinnon47, Alfons Meindl48, Kelly Metcalfe49, Nur Aishah Mohd Taib50, Jukka Moilanen51, Katherine L Nathanson25, Susan Neuhausen52, Pei Sze Ng50,53, Tu Nguyen-Dumont54,55, Sarah M Nielsen56, Florian Obermair57, Kenneth Offit26,58, Olufunmilayo I Olopade56, Laura Ottini59, Judith Penkert60, Katri Pylkäs61, Paolo Radice62, Susan J Ramus63,64, Vilius Rudaitis37, Lucy Side65, Rachel Silva-Smith66, Valentina Silvestri59, Anne-Bine Skytte67, Thomas Slavin13,68, Jana Soukupova39, Carlo Tondini69, Alison H Trainer70,71, Gary Unzeitig13, Lydia Usha13, Thomas van Overeem Hansen72,73, James Whitworth2, Marie Wood47, Cheng Har Yip53, Sook-Yee Yoon53, Amal Yussuf24, George Zogopoulos18,19, David Goldgar74, John L Hopper75, Georgia Chenevix-Trench76, Paul Pharoah1, Sophia H L George77, Judith Balmaña23,26, Claude Houdayer22,78, Paul James70,71, Zaki El-Haffaf79, Hans Ehrencrona80,81, Marketa Janatova39, Paolo Peterlongo82, Heli Nevanlinna35, Rita Schmutzler33,34, Soo-Hwang Teo50,53, Mark Robson26,83, Tuya Pal84, Fergus Couch26,85, Jeffrey N Weitzel13,68, Aaron Elliott24, Melissa Southey54,55, Robert Winqvist61, Douglas F Easton1, William D Foulkes18,86, Antonis C Antoniou1, Marc Tischkowitz2.   

Abstract

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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Year:  2019        PMID: 31841383      PMCID: PMC7049229          DOI: 10.1200/JCO.19.01907

Source DB:  PubMed          Journal:  J Clin Oncol        ISSN: 0732-183X            Impact factor:   44.544


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