RT Journal Article
SR Electronic
T1 Clinical applicability of the Polygenic Risk Score for breast cancer risk prediction in familial cases
JF Journal of Medical Genetics
JO J Med Genet
FD BMJ Publishing Group Ltd
SP 327
OP 336
DO 10.1136/jmg-2022-108502
VO 60
IS 4
A1 Inge M M Lakeman
A1 Mar D M Rodríguez-Girondo
A1 Andrew Lee
A1 Nandi Celosse
A1 Merel E Braspenning
A1 Klaartje van Engelen
A1 Irma van de Beek
A1 Annemiek H van der Hout
A1 Encarna B Gómez García
A1 Arjen R Mensenkamp
A1 Margreet G E M Ausems
A1 Maartje J Hooning
A1 Muriel A Adank
A1 Antoinette Hollestelle
A1 Marjanka K Schmidt
A1 Christi J van Asperen
A1 Peter Devilee
YR 2023
UL http://jmg.bmj.com/content/60/4/327.abstract
AB Background Common low-risk variants are presently not used to guide clinical management of familial breast cancer (BC). We explored the additive impact of a 313-variant-based Polygenic Risk Score (PRS313) relative to standard gene testing in non-BRCA1/2 Dutch BC families.Methods We included 3918 BC cases from 3492 Dutch non-BRCA1/2 BC families and 3474 Dutch population controls. The association of the standardised PRS313 with BC was estimated using a logistic regression model, adjusted for pedigree-based family history. Family history of the controls was imputed for this analysis. SEs were corrected to account for relatedness of individuals. Using the BOADICEA (Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm) V.5 model, lifetime risks were retrospectively calculated with and without individual PRS313. For 2586 cases and 2584 controls, the carrier status of pathogenic variants (PVs) in ATM, CHEK2 and PALB2 was known.Results The family history-adjusted PRS313 was significantly associated with BC (per SD OR=1.97, 95% CI 1.84 to 2.11). Including the PRS313 in BOADICEA family-based risk prediction would have changed screening recommendations in up to 27%, 36% and 34% of cases according to BC screening guidelines from the USA, UK and the Netherlands (National Comprehensive Cancer Network, National Institute for Health and Care Excellence, and Netherlands Comprehensive Cancer Organisation), respectively. For the population controls, without information on family history, this was up to 39%, 44% and 58%, respectively. Among carriers of PVs in known moderate BC susceptibility genes, the PRS313 had the largest impact for CHEK2 and ATM.Conclusions Our results support the application of the PRS313 in risk prediction for genetically uninformative BC families and families with a PV in moderate BC risk genes.Data are available upon reasonable request. The gene sequencing and SNP array genotyping results, and digitalised family histories of this study are part of the BCAC database. Access to the BCAC data is governed by a data access coordinating committee. If you are interested in gaining access to the BCAC data, please contact the BCAC coordinator by email (BCAC@medschl.cam.ac.uk). Summary results from the iCOGS and OncoArray projects are now publicly available and can be accessed via the links on the BCAC website (https://bcac.ccge.medschl.cam.ac.uk/bcacdata/).