Polygenic risk scores and breast and epithelial ovarian cancer risks for carriers of BRCA1 and BRCA2 pathogenic variants.

Authors:
Daniel R Barnes Matti A Rookus Lesley McGuffog Goska Leslie Thea M Mooij Joe Dennis Nasim Mavaddat Julian Adlard Munaza Ahmed Kristiina Aittomäki Nadine Andrieu Irene L Andrulis Norbert Arnold Banu K Arun Jacopo Azzollini Judith Balmaña Rosa B Barkardottir Daniel Barrowdale Javier Benitez Pascaline Berthet Katarzyna Białkowska Amie M Blanco Marinus J Blok Bernardo Bonanni Susanne E Boonen Åke Borg Aniko Bozsik Angela R Bradbury Paul Brennan Carole Brewer Joan Brunet Saundra S Buys Trinidad Caldés Maria A Caligo Ian Campbell Lise Lotte Christensen Wendy K Chung Kathleen B M Claes Chrystelle Colas Marie-Agnès Collonge-Rame Jackie Cook Mary B Daly Rosemarie Davidson Miguel de la Hoya Robin de Putter Capucine Delnatte Peter Devilee Orland Diez Yuan Chun Ding Susan M Domchek Cecilia M Dorfling Martine Dumont Ros Eeles Bent Ejlertsen Christoph Engel D Gareth Evans Laurence Faivre Lenka Foretova Florentia Fostira Michael Friedlander Eitan Friedman Debra Frost Patricia A Ganz Judy Garber Andrea Gehrig Anne-Marie Gerdes Paul Gesta Sophie Giraud Gord Glendon Andrew K Godwin David E Goldgar Anna González-Neira Mark H Greene Daphne Gschwantler-Kaulich Eric Hahnen Ute Hamann Helen Hanson Julia Hentschel Frans B L Hogervorst Maartje J Hooning Judit Horvath Chunling Hu Peter J Hulick Evgeny N Imyanitov Claudine Isaacs Louise Izatt Angel Izquierdo Anna Jakubowska Paul A James Ramunas Janavicius Esther M John Vijai Joseph Beth Y Karlan Karin Kast Marco Koudijs Torben A Kruse Ava Kwong Yael Laitman Christine Lasset Conxi Lazaro Jenny Lester Fabienne Lesueur Annelie Liljegren Jennifer T Loud Jan Lubiński Phuong L Mai Siranoush Manoukian Véronique Mari Noura Mebirouk Hanne E J Meijers-Heijboer Alfons Meindl Arjen R Mensenkamp Austin Miller Marco Montagna Emmanuelle Mouret-Fourme Semanti Mukherjee Anna Marie Mulligan Katherine L Nathanson Susan L Neuhausen Heli Nevanlinna Dieter Niederacher Finn Cilius Nielsen Liene Nikitina-Zake Catherine Noguès Edith Olah Olufunmilayo I Olopade Kai-Ren Ong Aoife O'Shaughnessy-Kirwan Ana Osorio Claus-Eric Ott Laura Papi Sue K Park Michael T Parsons Inge Sokilde Pedersen Bernard Peissel Ana Peixoto Paolo Peterlongo Georg Pfeiler Kelly-Anne Phillips Karolina Prajzendanc Miquel Angel Pujana Paolo Radice Juliane Ramser Susan J Ramus Johanna Rantala Gad Rennert Harvey A Risch Mark Robson Karina Rønlund Ritu Salani Hélène Schuster Leigha Senter Payal D Shah Priyanka Sharma Lucy E Side Christian F Singer Thomas P Slavin Penny Soucy Melissa C Southey Amanda B Spurdle Doris Steinemann Zoe Steinsnyder Dominique Stoppa-Lyonnet Christian Sutter Yen Yen Tan Manuel R Teixeira Soo Hwang Teo Darcy L Thull Marc Tischkowitz Silvia Tognazzo Amanda E Toland Alison H Trainer Nadine Tung Klaartje van Engelen Elizabeth J van Rensburg Ana Vega Jeroen Vierstraete Gabriel Wagner Lisa Walker Shan Wang-Gohrke Barbara Wappenschmidt Jeffrey N Weitzel Siddhartha Yadav Xin Yang Drakoulis Yannoukakos Dario Zimbalatti Kenneth Offit Mads Thomassen Fergus J Couch Rita K Schmutzler Jacques Simard Douglas F Easton Georgia Chenevix-Trench Antonis C Antoniou

Genet Med 2020 Oct 15;22(10):1653-1666. Epub 2020 Jul 15.

Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.

Purpose: We assessed the associations between population-based polygenic risk scores (PRS) for breast (BC) or epithelial ovarian cancer (EOC) with cancer risks for BRCA1 and BRCA2 pathogenic variant carriers.

Methods: Retrospective cohort data on 18,935 BRCA1 and 12,339 BRCA2 female pathogenic variant carriers of European ancestry were available. Three versions of a 313 single-nucleotide polymorphism (SNP) BC PRS were evaluated based on whether they predict overall, estrogen receptor (ER)-negative, or ER-positive BC, and two PRS for overall or high-grade serous EOC. Associations were validated in a prospective cohort.

Results: The ER-negative PRS showed the strongest association with BC risk for BRCA1 carriers (hazard ratio [HR] per standard deviation = 1.29 [95% CI 1.25-1.33], P = 3×10). For BRCA2, the strongest association was with overall BC PRS (HR = 1.31 [95% CI 1.27-1.36], P = 7×10). HR estimates decreased significantly with age and there was evidence for differences in associations by predicted variant effects on protein expression. The HR estimates were smaller than general population estimates. The high-grade serous PRS yielded the strongest associations with EOC risk for BRCA1 (HR = 1.32 [95% CI 1.25-1.40], P = 3×10) and BRCA2 (HR = 1.44 [95% CI 1.30-1.60], P = 4×10) carriers. The associations in the prospective cohort were similar.

Conclusion: Population-based PRS are strongly associated with BC and EOC risks for BRCA1/2 carriers and predict substantial absolute risk differences for women at PRS distribution extremes.

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Source
http://dx.doi.org/10.1038/s41436-020-0862-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7521995PMC
October 2020
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