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The predictive ability of the 313 variant-based polygenic risk score for contralateral breast cancer risk prediction in women of European ancestry with a heterozygous BRCA1 or BRCA2 pathogenic variant

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  • Inge M M Lakeman
  • Alexandra J van den Broek
  • Juliën A M Vos
  • Daniel R Barnes
  • Julian Adlard
  • Irene L Andrulis
  • Adalgeir Arason
  • Norbert Arnold
  • Banu K Arun
  • Judith Balmaña
  • Daniel Barrowdale
  • Javier Benitez
  • Ake Borg
  • Trinidad Caldés
  • Maria A Caligo
  • Wendy K Chung
  • Kathleen B M Claes
  • J Margriet Collée
  • Fergus J Couch
  • Mary B Daly
  • Joe Dennis
  • Mallika Dhawan
  • Susan M Domchek
  • Ros Eeles
  • Christoph Engel
  • D Gareth Evans
  • Lidia Feliubadaló
  • Lenka Foretova
  • Eitan Friedman
  • Debra Frost
  • Patricia A Ganz
  • Judy Garber
  • Simon A Gayther
  • Anne-Marie Gerdes
  • Andrew K Godwin
  • David E Goldgar
  • Eric Hahnen
  • Christopher R Hake
  • Ute Hamann
  • Frans B L Hogervorst
  • Maartje J Hooning
  • John L Hopper
  • Peter J Hulick
  • Evgeny N Imyanitov
  • Claudine Isaacs
  • Louise Izatt
  • Anna Jakubowska
  • Paul A James
  • Ramunas Janavicius
  • Uffe Birk Jensen
  • GEMO Study Collaborators
Vis graf over relationer

PURPOSE: To evaluate the association between a previously published 313 variant-based breast cancer (BC) polygenic risk score (PRS313) and contralateral breast cancer (CBC) risk, in BRCA1 and BRCA2 pathogenic variant heterozygotes.

METHODS: We included women of European ancestry with a prevalent first primary invasive BC (BRCA1 = 6,591 with 1,402 prevalent CBC cases; BRCA2 = 4,208 with 647 prevalent CBC cases) from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), a large international retrospective series. Cox regression analysis was performed to assess the association between overall and ER-specific PRS313 and CBC risk.

RESULTS: For BRCA1 heterozygotes the estrogen receptor (ER)-negative PRS313 showed the largest association with CBC risk, hazard ratio (HR) per SD = 1.12, 95% confidence interval (CI) (1.06-1.18), C-index = 0.53; for BRCA2 heterozygotes, this was the ER-positive PRS313, HR = 1.15, 95% CI (1.07-1.25), C-index = 0.57. Adjusting for family history, age at diagnosis, treatment, or pathological characteristics for the first BC did not change association effect sizes. For women developing first BC < age 40 years, the cumulative PRS313 5th and 95th percentile 10-year CBC risks were 22% and 32% for BRCA1 and 13% and 23% for BRCA2 heterozygotes, respectively.

CONCLUSION: The PRS313 can be used to refine individual CBC risks for BRCA1/2 heterozygotes of European ancestry, however the PRS313 needs to be considered in the context of a multifactorial risk model to evaluate whether it might influence clinical decision-making.

OriginalsprogEngelsk
TidsskriftGenetics in medicine : official journal of the American College of Medical Genetics
Vol/bind23
Udgave nummer9
Sider (fra-til)1726-1737
Antal sider12
ISSN1098-3600
DOI
StatusUdgivet - sep. 2021

ID: 66476570