Evaluation of polygenic risk scores for breast and ovarian cancer risk prediction in BRCA1 and BRCA2 mutation carriers

Forskningsoutput: TidskriftsbidragArtikel i vetenskaplig tidskrift

Abstract

Background: Genome-wide association studies (GWAS) have identified 94 common single-nucleotide polymorphisms (SNPs) associated with breast cancer (BC) risk and 18 associated with ovarian cancer (OC) risk. Several of these are also associated with risk of BC or OC for women who carry a pathogenic mutation in the high-risk BC and OC genes BRCA1 or BRCA2. The combined effects of these variants on BC or OC risk for BRCA1 and BRCA2 mutation carriers have not yet been assessed while their clinical management could benefit from improved personalized risk estimates. Methods: We constructed polygenic risk scores (PRS) using BC and OC susceptibility SNPs identified through population-based GWAS: for BC (overall, estrogen receptor [ER]-positive, and ER-negative) and for OC. Using data from 15 252 female BRCA1 and 8211 BRCA2 carriers, the association of each PRS with BC or OC risk was evaluated using a weighted cohort approach, with time to diagnosis as the outcome and estimation of the hazard ratios (HRs) per standard deviation increase in the PRS. Results: The PRS for ER-negative BC displayed the strongest association with BC risk in BRCA1 carriers (HR = 1.27, 95% confidence interval [CI] = 1.23 to 1.31, P = 8.2 × 10-53). InBRCA2 carriers, the strongest association with BC risk was seen for the overall BCPRS (HR = 1.22, 95% CI = 1.17 to 1.28, P = 7.2 × 10-20). The OC PRS was strongly associated with OC risk for both BRCA1 and BRCA2 carriers. These translate to differences in absolute risks (more than 10% in each case) between the top and bottom deciles of the PRS distribution; for example, the OC risk was 6% by age 80 years for BRCA2 carriers at the 10th percentile of the OC PRS compared with 19% risk for those at the 90th percentile of PRS. Conclusions: BC and OC PRS are predictive of cancer risk in BRCA1 and BRCA2 carriers. Incorporation of the PRS into risk prediction models has promise to better inform decisions on cancer risk management.

Detaljer

Författare
  • Karoline B. Kuchenbaecker
  • Lesley McGuffog
  • Daniel Barrowdale
  • Andrew Lee
  • Penny Soucy
  • Joe Dennis
  • Susan M. Domchek
  • Mark Robson
  • Amanda B. Spurdle
  • Susan J. Ramus
  • Nasim Mavaddat
  • Mary Beth Terry
  • Susan L. Neuhausen
  • Rita Katharina Schmutzler
  • Jacques Simard
  • Paul D.P. Pharoah
  • Kenneth Offit
  • Fergus J. Couch
  • Georgia Chenevix-Trench
  • Douglas F. Easton
  • Antonis C. Antoniou
  • Sue Healey
  • Michael Lush
  • Ute Hamann
  • Melissa Southey
  • Esther M. John
  • Wendy K. Chung
  • Mary B. Daly
  • Saundra S. Buys
  • David E. Goldgar
  • Cecilia M. Dorfling
  • Elizabeth J. van Rensburg
  • Yuan Chun Ding
  • Bent Ejlertsen
  • Anne Marie Gerdes
  • Thomas V.O. Hansen
  • Susan Slager
  • Emily Hallberg
  • Javier Benitez
  • Ana Osorio
  • Nancy Cohen
  • William Lawler
  • Jeffrey N. Weitzel
  • Paolo Peterlongo
  • Valeria Pensotti
  • Riccardo Dolcetti
  • Monica Barile
  • Bernardo Bonanni
Enheter & grupper
Externa organisationer
  • Wellcome Trust Genome Campus
  • University of Cambridge
  • Centre hospitalier universitaire de Québec
  • Cochin Hospital
  • Memorial Sloan-Kettering Cancer Center
  • QIMR Berghofer Medical Research Institute
  • University of New South Wales
  • Garvan Institute of Medical Research
  • Columbia University
  • City of Hope National Medical Center
  • University Hospital of Cologne
  • Mayo Clinic Minnesota
  • German Cancer Research Centre
  • University of Melbourne
  • Cancer Prevention Institute of California
  • Fox Chase Cancer Center
  • Huntsman Cancer Institute
  • University of Utah
  • University of Pretoria
  • Copenhagen University Hospital
  • Spanish National Cancer Research Center (CNIO)
  • CIBER de Enfermedades Raras (CIBERER)
  • IFOM - The FIRC Institute of Molecular Oncology
  • Cogentech
  • CRO (Centro di Riferimento Oncologico) Aviano National Cancer Institute
  • University of Queensland
  • European Institute of Oncology
  • Skåne University Hospital
Forskningsområden

Ämnesklassifikation (UKÄ) – OBLIGATORISK

  • Cancer och onkologi
Originalspråkengelska
TidskriftJournal of the National Cancer Institute
Volym109
Utgivningsnummer7
StatusPublished - 2017 jul 1
PublikationskategoriForskning
Peer review utfördJa