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


ABSTRACT:

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?=?3×10-72). For BRCA2, the strongest association was with overall BC PRS (HR?=?1.31 [95% CI 1.27-1.36], P?=?7×10-50). 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?=?3×10-22) and BRCA2 (HR?=?1.44 [95% CI 1.30-1.60], P?=?4×10-12) 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.

SUBMITTER: Barnes DR 

PROVIDER: S-EPMC7521995 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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Publications

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

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

Genetics in medicine : official journal of the American College of Medical Genetics 20200715 10


<h4>Purpose</h4>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.<h4>Methods</h4>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 recepto  ...[more]

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