Citations 2
Evaluation of European-based polygenic risk score for breast cancer in Ashkenazi Jewish women in Israel
Yerushalmi, Rinat , Yablonski‐Peretz, Tamar, Wang, Qin , Bolla, Manjeet K. , Michailidou, Kyriaki , Ahearn, Thomas U. , Andrulis, Irene L. , Antoniou, Antonis C. , Auvinen, Päivi , Freeman, Laura Beane, Beckmann, Matthias W. , Bermisheva, Marina , Bodelón, Clara , Bogdanova, Natalia , Bojesen, Stig E. , Byers, Helen, Camp, Nicola J. , Chang‐Claude, Jenny , Chirlaque, María‐Dolores , Collaborators, NBCS, Collée, Margriet J., Dörk, Thilo , Eccles, Diana , Evans, D. Gareth , Fasching, Peter A. , Flyger, Henrik, García‐Closas, Montserrat , Goldberg, Mark S. , Guénel, Pascal , Hamann, Ute, He, Wei , Hillemanns, Peter , Hoppe, Reiner , Hopper, John L. , Investigators, ABCTB, Jakovchevska, Simona, John, Esther M. , Johnson, Nichola , Jones, Michael E. , Kristensen, Vessela N. , Kurian, Allison W. , Lambrechts, Diether , Lejbkowicz, Flavio, Lindblom, Annika , Loibl, Sibylle , Lori, Adriana , Mannermaa, Arto, Manoochehri, Mehdi, Mavroudis, Dimitrios, Menon, Usha , Nevelsteen, Ines, Obi, Nadia , Offit, Ken, Plaseska‐Karanfilska, Dijana , Park‐Simon, Tjoung‐Won , Patel, Alpa V. , Rack, Brigitte , Rhenius, Valerie , Romero, Atocha , Schwentner, Lukas , Shah, Mitul , Stone, Jennifer , Taylor, Jack A. , Kolk, Lizet E. van der, Wendt, Camilla, Yang, Xiaohong R. , Zheng, Wei , Pharoah, Paul D.P. , Easton, Douglas F. , Ben-Sachar, Shay, Elefant, Naama , Shamir, Ron , Elkon, Ran , Lambrechts, Diether , Michailidou, Kyriaki , Antoniou, Antonis C , Devilee, Peter , Eccles, Diana , Newman, William G , Radice, Paolo , Elkon, Ran , Dörk, Thilo , Lambrechts, Diether , Hillemanns, Peter , Pharoah, Paul D P , Menon, Usha , Evans, D Gareth , John, Esther M , Jones, Michael E , Lambrechts, Diether , Guénel, Pascal , Romero, Atocha , García-Closas, Montserrat , Bogdanova, Natalia V , Taylor, Jack A , Zheng, Wei , Kurian, Allison W , Stone, Jennifer , Bojesen, Stig E , Lindblom, Annika , Plaseska-Karanfilska, Dijana , Levi, Hagai , Carmi, Shai , Rosset, Saharon , Zick, Aviad , Dennis, Joe , Lush, Michael J. , Anton‐Culver, Hoda , Arndt, Volker , Augustinsson, Annelie , Behrens, Sabine , Brenner, Hermann , Castelao, Jose E. , Chung, Wendy K. , Clarke, Christine L. , Collaborators, NBCS, Collée, Margriet , Colonna, Sarah V. , Couch, Fergus J. , Cox, Angela , Cross, Simon S. , Czene, Kamila , Daly, Mary Beryl , Devilee, Peter , Dossus, Laure , Eliassen, A. Heather , Eriksson, Mikael , Fletcher, Olivia , Fritschi, Lin , Gabrielson, Marike , Gago-Domínguez, Manuela , García-Sáenz, José Á. , Genkinger, Jeanine M. , Giles, Graham G. , Hall, Per N , Hollestelle, Antoinette , Investigators, ABCTB, Jakubowska, Anna , Jernström, Helena , Vijai, Joseph , Kaaks, Rudolf , Хуснутдинова, Э. К. , Kitahara, Cari M. , Koutros, Stella , Lacey, James V. , Marchand, Loı̈c Le , Lubiński, Jan , Mannermaa, Arto, Mulligan, Anna Marie , Murphy, Rachel A. , Newman, William G. , O’Brien, Katie M. , Olshan, Andrew F. , Olson, Janet E. , Panico, Salvatore , Peterlongo, Paolo , Radice, Paolo , Rennert, Gad , Saloustros, Emmanouil , Sandler, Dale P. , Schmidt, Marjanka K. , Sharma, Priyanka , Simard, Jacques , Southey, Melissa C. , Tapper, William , Teras, Lauren R. , Toland, Amanda Ewart , Troester, Melissa A. , Truong, Thérèse , Weinberg, Clarice R. , Ziogas, Argyrios , Dunning, Alison M.
Journal of Medical Genetics | July 14, 2023 | Volume: 60 | Issue: 12 | Pages: 1186-1197
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.
A Recurrent ERCC3 Truncating Mutation Confers Moderate Risk for Breast Cancer
Vijai, Joseph , Topka, Sabine , Villano, Danylo , Ravichandran, Vignesh , Maria, Ann, Gaddam, Pragna, Lincoln, Anne , Kazzaz, Sarah A. , Wenz, Brandon M., Carmi, Shai , Schrader, Kasmintan A. , Hart, Steven N. , Lipkin, Steve M., Walsh, Michael F. , Zhang, Liying , Lejbkowicz, Flavio, Rennert, Hedy S., Weitzel, Jeffrey N. , Daly, Mark J., Nathanson, Katherine L. , Rennert, Gad , Offit, Kenneth , Maxwell, Kara N. , Thomas, Tinu , Neuhausen, Susan L. , Stadler, Zsofia , Robson, Mark E. , Domchek, Susan M. , Couch, Fergus J. , Norton, Larry , Schrader, Intan , Rennert, Gad , Weitzel, Jeffrey N , Joseph, Vijai , Hart, Steven N , Nathanson, Katherine L , Ravichandran, Vignesh , Topka, Sabine
Cancer Discovery | September 21, 2016 | Volume: 6 | Issue: 11 | Pages: 1267-1275
Abstract Known gene mutations account for approximately 50% of the hereditary risk for breast cancer. Moderate and low penetrance variants, discovered by genomic approaches, account for an as-yet-unknown proportion of the remaining heritability. A truncating mutation c.325C>T:p.Arg109* (R109X) in the ATP-dependent helicase ERCC3 was observed recurrently among exomes sequenced in BRCA wild-type, breast cancer–affected individuals of Ashkenazi Jewish ancestry. Modeling of the mutation in ERCC3-deficient or CRISPR/Cas9-edited cell lines showed a consistent pattern of reduced expression of the protein and concomitant hypomorphic functionality when challenged with UVC exposure or treatment with the DNA alkylating agent IlludinS. Overexpressing the mutant protein in ERCC3-deficient cells only partially rescued their DNA repair–deficient phenotype. Comparison of frequency of this recurrent mutation in over 6,500 chromosomes of breast cancer cases and 6,800 Ashkenazi controls showed significant association with breast cancer risk (ORBC = 1.53, ORER+ = 1.73), particularly for the estrogen receptor–positive subset (P < 0.007). Significance: A functionally significant recurrent ERCC3 mutation increased the risk for breast cancer in a genetic isolate. Mutated cell lines showed lower survival after in vitro exposure to DNA-damaging agents. Thus, similar to tumors arising in the background of homologous repair defects, mutations in nucleotide excision repair genes such as ERCC3 could constitute potential therapeutic targets in a subset of hereditary breast cancers. Cancer Discov; 6(11); 1267–75. ©2016 AACR. This article is highlighted in the In This Issue feature, p. 1197