Evaluation of European-based polygenic risk score for breast cancer in Ashkenazi Jewish women in Israel
Authors: Levi Hagai , Carmi Shai , Rosset Saharon , Yerushalmi Rinat , Zick Aviad , Yablonski-Peretz Tamar ,   The BCAC Consortium, Wang Qin , Bolla Manjeet K , Dennis Joe , Michailidou Kyriaki , Lush Michael , Ahearn Thomas , Andrulis Irene L , Anton-Culver Hoda , Antoniou Antonis C , Arndt Volker , Augustinsson Annelie , Auvinen Päivi , Beane Freeman Laura , Beckmann Matthias , Behrens Sabine , Bermisheva Marina , Bodelon Clara , Bogdanova Natalia V , Bojesen Stig E , Brenner Hermann , Byers Helen , Camp Nicola , Castelao Jose , Chang-Claude Jenny , Chirlaque María-Dolores , Chung Wendy , Clarke Christine ,   NBCS Collaborators, Collee Margriet J , Colonna Sarah ,   CTS Consortium, Couch Fergus , Cox Angela , Cross Simon S , Czene Kamila , Daly Mary , Devilee Peter , Dork Thilo , Dossus Laure , Eccles Diana M , Eliassen A. Heather , Eriksson Mikael , Evans Gareth , Fasching Peter , Fletcher Olivia , Flyger Henrik , Fritschi Lin , Gabrielson Marike , Gago-Dominguez Manuela , García-Closas Montserrat , Garcia-Saenz Jose Angel , Genkinger Jeanine , Giles Graham G , Goldberg Mark , Guénel Pascal , Hall Per , Hamann Ute , He Wei , Hillemanns Peter , Hollestelle Antoinette , Hoppe Reiner , Hopper John ,   ABCTB Investigators, Jakovchevska Simona , Jakubowska Anna , Jernström Helena , John Esther , Johnson Nichola , Jones Michael , Vijai Joseph , Kaaks Rudolf , Khusnutdinova Elza , Kitahara Cari , Koutros Stella , Kristensen Vessela , Kurian Allison W , Lacey James , Lambrechts Diether , Le Marchand Loic , Lejbkowicz Flavio , Lindblom Annika , Loibl Sibylle , Lori Adriana , Lubinski Jan , Mannermaa Arto , Manoochehri Mehdi , Mavroudis Dimitrios , Menon Usha , Mulligan AnnaMarie , Murphy Rachel , Nevelsteen Ines , Newman William G , Obi Nadia , O'Brien Katie , Offit Ken , Olshan Andrew , Plaseska-Karanfilska Dijana , Olson Janet , Panico Salvatore , Park-Simon Tjoung-Won , Patel Alpa , Peterlongo Paolo , Rack Brigitte , Radice Paolo , Rennert Gad , Rhenius Valerie , Romero Atocha , Saloustros Emmanouil , Sandler Dale , Schmidt Marjanka K , Schwentner Lukas , Shah Mitul , Sharma Priyanka , Simard Jacques , Southey Melissa , Stone Jennifer , Tapper William J , Taylor Jack , Teras Lauren , Toland Amanda E , Troester Melissa , Truong Thérèse , van der Kolk Lizet E , Weinberg Clarice , Wendt Camilla , Yang Xiaohong Rose , Zheng Wei , Ziogas Argyrios , Dunning Alison M , Pharoah Paul , Easton Douglas F , Ben-Sachar Shay , Elefant Naama , Shamir Ron , Elkon Ran 
Published: July 2023

Background

Polygenic risk score (PRS), calculated based on genome-wide association studies (GWASs), can improve breast cancer (BC) risk assessment. To date, most BC GWASs have been performed in individuals of European (EUR) ancestry, and the generalisation of EUR-based PRS to other populations is a major challenge. In this study, we examined the performance of EUR-based BC PRS models in Ashkenazi Jewish (AJ) women.

Methods

We generated PRSs based on data on EUR women from the Breast Cancer Association Consortium (BCAC). We tested the performance of the PRSs in a cohort of 2161 AJ women from Israel (1437 cases and 724 controls) from BCAC (BCAC cohort from Israel (BCAC-IL)). In addition, we tested the performance of these EUR-based BC PRSs, as well as the established 313-SNP EUR BC PRS, in an independent cohort of 181 AJ women from Hadassah Medical Center (HMC) in Israel.

Results

In the BCAC-IL cohort, the highest OR per 1 SD was 1.56 (±0.09). The OR for AJ women at the top 10% of the PRS distribution compared with the middle quintile was 2.10 (±0.24). In the HMC cohort, the OR per 1 SD of the EUR-based PRS that performed best in the BCAC-IL cohort was 1.58±0.27. The OR per 1 SD of the commonly used 313-SNP BC PRS was 1.64 (±0.28).

Conclusions

Extant EUR GWAS data can be used for generating PRSs that identify AJ women with markedly elevated risk of BC and therefore hold promise for improving BC risk assessment in AJ women.