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.
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,
Yue Jiao,
Esther M John,
Vijai Joseph,
Beth Y Karlan,
Carolien M Kets,
Irene Konstantopoulou,
Ava Kwong,
Clémentine Legrand,
Goska Leslie,
Fabienne Lesueur,
Jennifer T Loud,
Jan Lubiński,
Siranoush Manoukian,
Lesley McGuffog,
Austin Miller,
Denise Molina Gomes,
Marco Montagna,
Emmanuelle Mouret-Fourme,
Katherine L Nathanson,
Susan L Neuhausen,
Heli Nevanlinna,
Joanne Ngeow Yuen Yie,
Edith Olah,
Olufunmilayo I Olopade,
Sue K Park,
Michael T Parsons,
Paolo Peterlongo,
Marion Piedmonte,
Paolo Radice,
Johanna Rantala,
Gad Rennert,
Harvey A Risch,
Rita K Schmutzler,
Priyanka Sharma,
Jacques Simard,
Christian F Singer,
Zsofia Stadler,
Dominique Stoppa-Lyonnet,
Christian Sutter,
Yen Yen Tan,
Manuel R Teixeira,
Soo Hwang Teo,
Alex Teulé,
Mads Thomassen,
Darcy L Thull,
Marc Tischkowitz,
Amanda E Toland,
Nadine Tung,
Elizabeth J van Rensburg,
Ana Vega,
Barbara Wappenschmidt,
Peter Devilee,
Christi J van Asperen,
Jonine L Bernstein,
Kenneth Offit,
Douglas F Easton,
Matti A Rookus,
Georgia Chenevix-Trench,
Antonis C Antoniou,
Mark Robson,
Marjanka K Schmidt
Abstract
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.
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.
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.
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.
More about this publication
Genetics in medicine : official journal of the American College of Medical Genetics