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

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

DOI

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

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.

OriginalsprogEngelsk
TidsskriftJournal of clinical oncology : official journal of the American Society of Clinical Oncology
Vol/bind38
Udgave nummer7
Sider (fra-til)674-685
Antal sider12
ISSN0732-183X
DOI
StatusUdgivet - 1 mar. 2020

ID: 59118331