Citations 2
Threshold-Based Overlap of Breast Cancer High-Risk Classification Using Family History, Polygenic Risk Scores, and Traditional Risk Models in 180,398 Women
Ho, Peh Joo , Loo, Christine Kim Yan , Lim, Ryan Jak Yang, Goh, Mui Heng, Abubakar, Mustapha , Ahearn, Thomas U. , Andrulis, Irene L. , Antonenkova, Natalia, Aronson, Kristan J. , Augustinsson, Annelie , Behrens, Sabine , Bodelón, Clara , Bogdanova, Natalia , Bolla, Manjeet K. , Brantley, Kristen D. , Brenner, Hermann , Byers, Helen L., Camp, Nicola J. , Cessna, Melissa H., Chang-Claude, Jenny, Choi, Ji-Yeob , Czene, Kamila , Dörk, Thilo , Eliassen, A. Heather , Engel, Christoph , Eriksson, Mikael , Evans, D. Gareth , Fritschi, Lin , Genkinger, Jeanine M. , Geurts-Giele, Willemina R.R. , Glendon, Gord, Hall, Per , Hamann, U. , Ho, Cecilia Y.S., Hooning, Maartje J. , Hoppe, Reiner , Humphreys, Keith , Ito, Hidemi , Jakubowska, Anna , Jernström, Helena , John, Esther M. , Johnson, Nichola , Kang, Daehee , Kim, Sung‐Won , Kitahara, Cari M. , Ko, Yon-Dschun, Kraft, Peter, Kwong, Ava , Lambrechts, Diether, Larsson, Susanna C. , Li, Shuai , Lindblom, Annika , Linet, Martha, Lissowska, Jolanta , Lophatananon, Artitaya , MacInnis, Robert J. , Mannermaa, Arto, Manoukian, Siranoush, Margolin, Sara, Matsuo, Keitaro , Michailidou, Kyriaki , Taib, Nur Aishah Mohd , Murphy, Rachel A. , Newman, William G. , Obi, Nadia , Olopade, Olufunmilayo I., Panayiotidis, Mihalis I. , Park, Sue K. , Park‐Simon, Tjoung‐Won , Patel, Alpa V , Peterlongo, Paolo , Plaseska‐Karanfilska, Dijana , Pylkäs, Katri , Rashid, Muhammad Usman , Rodríguez, Juan , Sandler, Dale P. , Sawyer, Elinor J. , Scott, Christopher G. , Shahi, Shamim , Shu, Xiao‐Ou , Shulman, Katerina, Simard, Jacques , Southey, Melissa C., Stone, Jennifer , Taylor, Jack A. , Teo, Soo‐Hwang , Teras, Lauren R. , Vachon, Celine M., Houdt, Maxime Van , Verhoeven, Jelle , Weinberg, Clarice R. , Wolk, Alicja , Yamaji, Taiki , Yip, Cheng Har , Zheng, Wei , Hartman, Mikael , Li, Jingmei , Investigators, on behalf of the ABCTB, Investigators, kConFab, Investigators, MyBrCa, Investigators, SGBCC, Olopade, Olufunmilayo I. , Lambrechts, Diether , Lambrechts, Diether , Hamann, Ute , Hooning, Maartje J. , Bogdanova, Natalia V , Czene, Kamila , Dörk, Thilo , Eliassen, A Heather , Engel, Christoph , Eriksson, Mikael , Evans, D Gareth , Fletcher, Olivia , Fritschi, Lin , Genkinger, Jeanine , Hall, Per N , Ho, Cecilia Y S , Humphreys, Keith , Ito, Hidemi , Jakubowska, Anna , Jernström, Helena , Johnson, Nichola , Kim, Sung-Won , Kitahara, Cari M , Kwong, Ava , Larsson, Susanna C , Li, Shuai , Lindblom, Annika , Lissowska, Jolanta , Lophatananon, Artitaya , Maclnnis, Robert , Matsuo, Keitaro , Michailidou, Kyriaki , Mohd Taib, Nur Aishah , Murphy, Rachel A , Newman, William G , Obi, Nadia , Panayiotidis, Mihalis I , Park, Sue K , Park-Simon, Tjoung-Won , Peterlongo, Paolo , Plaseska-Karanfilska, Dijana , Pylkäs, Katri , Rashid, Muhammad U , Rennert, Gad , Rodriguez, Juan , Sandler, Dale P , Sawyer, Elinor J , Scott, Christopher , Shu, Xiao-Ou , Simard, Jacques , Stone, Jennifer , Taylor, Jack A , Teo, Soo H , Teras, Lauren R , Houdt, Maxime Van , Verhoeven, Jelle , Weinberg, Clarice R , Wolk, Alicja , Zheng, Wei , Hartman, Mikael , Li, Jingmei , Lambrechts, Diether , Behrens, Sabine , John, Esther M , Olopade, Olufunmilayo I , Lambrechts, Diether , Augustinsson, Annelie , Brenner, Hermann , Camp, Nicola J , Brantley, Kristen D , Lim, Ryan Jak Yang, Byers, Helen, Castelao, Jose E. , Chang‐Claude, Jenny , Chanock, Stephen Jacob , Chenevix‐Trench, Georgia , Colonna, Sarah V. , Daly, Mary Beryl , Derouane, Françoise , Fletcher, Olivia , Gago-Domínguez, Manuela , Ho, Weang-Kee , Howell, Anthony , Iwasaki, Motoki , Ko, Yon‐Dschun, Mannermaa, Arto , Manoukian, Siranoush , Margolin, Sara , Milne, Roger L. , Muir, Kenneth , O’Brien, Katie M. , Rennert, Gad , Saloustros, Emmanouil , Southey, Melissa C. , Terry, Mary Beth , Torres, Diana , Investigators, on behalf of the ABCTB, Investigators, kConFab, Investigators, MyBrCa, Investigators, SGBCC
Cancers | November 3, 2025 | Volume: 17 | Issue: 21 | Pages: 3561
Background: Breast cancer polygenic risk scores (PRS) and traditional risk models (e.g., the Gail model [Gail]) are known to contribute largely independent information, but it is unclear how the overlap varies by ancestry, age, disease type (invasive breast cancer, DCIS), and risk threshold. Methods: In a retrospective case–control study, we evaluated risk prediction performance in 180,398 women (161,849 of European ancestry; 18,549 of Asian ancestry). Odds ratios (ORs) from logistic regression models and the area under the receiver operating characteristic curve (AUC) were estimated. Results: PRS for invasive disease showed a stronger association in younger (<50 years) women (OR = 2.51, AUC = 0.622) than in women ≥ 50 years (OR = 2.06, AUC = 0.653) of European ancestry. PRS performance in Asians was lower (OR range = 1.62–1.64, AUC = 0.551–0.600). Gail performance was modest across groups and poor in younger Asian women (OR = 0.94–0.99, AUC = 0.523–0.533). Age interactions were observed for both PRS (p < 0.001) and Gail (p < 0.001) in Europeans, whereas in Asians, age interaction was observed only for Gail (invasive: p < 0.001; DCIS: p = 0.002). PRS identified more high-risk individuals than Gail in Asian populations, especially ≥50 years, while Gail identified more in Europeans. Overlap between PRS, Gail, and family history was limited at higher thresholds. Calibration analysis, comparing empirical and model-based ROC curves, showed divergence for both PRS and Gail (p < 0.001), which indicates miscalibration. In Europeans, family history and prior biopsies drove Gail discrimination. In younger Asians, age at first live birth was influential. Conclusions: PRS adds value to risk stratification beyond traditional tools, especially in younger women and Asian ancestry populations.
Genetic risk factors modulate the association between physical activity and colorectal cancer
Kim, Andre E., Fu, Yubo, Morrison, John, Lin, Yi, Berndt, Sonja, Chang-Claude, Jenny, Conti, David V., Corley, Douglas A. , Gruber, Stephen B. , Harlid, Sophia , Huyghe, Jeroen R. , Kundaje, Anshul , Martín, Vicente , Newton, Christina C. , Hardikar, Sheetal , Pai, Rish K. , Papadimitriou, Nikos , Pinchev, Mila, Schoen, Robert , Tsilidis, Konstantinos K, Duijnhoven, Franzel J. B. van, Visvanathan, Kala , Wolk, Alicja, Woods, Michael O. , Wu, Anna H. , Ulrich, Cornelia M. , Peters, Ulrike, Gauderman, W. James, Moreno, Victor, Martín, Vicente , Drew, David A. , Martín, Vicente , Drew, David A , Visvanathan, Kala , Kundaje, Anshul , Papadimitriou, Nikos , Peoples, Anita R , Obón‐Santacana, Mireia , Kawaguchi, Eric , Qu, Conghui , Moratalla-Navarro, Ferrán , Morrison, John, Arndt, Volker , Bien, Stephanie A. , Bishop, D. Timothy , Bouras, Emmanouil , Brenner, Hermann , Buchanan, Daniel D. , Campbell, Peter T. , Chan, Andrew T. , Chang‐Claude, Jenny , Conti, David V. , Devall, Matthew A M , Dimou, Niki , Gunter, Marc J. , Harrison, Tabitha A. , Hoffmeister, Michael , Hsu, Li , Keku, Temitope O , Lewinger, Juan Pablo , Lynch, Brigid M , Marchand, Loı̈c Le , Murphy, Neil , Ogino, Shuji , Ose, Jennifer , Palmer, Julie R. , Pardamean, Bens , Pellatt, Andrew J. , Platz, Elizabeth A. , Potter, John D. , Rennert, Gad , Ruiz-Narvaez, Edward , Sakoda, Lori C. , Schoen, Robert E., Shcherbina, Anna, Stern, Mariana Carla , Su, Yu-Ru , Thomas, Claire E. , Tian, Yu , Tsilidis, Konstantinos K. , Um, Caroline Y. , Guelpen, Bethany Van , Wang, Jun, White, Emily , Wolk, Alicja , Peters, Ulrike, Gauderman, W. James
No container title available | September 2, 2025 | Volume: No volume available | Issue: No issue available | Pages: No page available
Abstract Background Physical activity (PA) is an established protective factor for colorectal cancer (CRC), but it is unclear if genetic variants modify this effect. To investigate this possibility, we conducted a genome-wide gene–PA interaction analysis. Methods Using logistic regression and two-step and joint tests, we analyzed interactions between common genetic variants across the genome and PA in relation to CRC risk. Self-reported PA levels were categorized as active (≥ 8.75 MET-h/wk) vs. inactive (< 8.75 MET-h/wk) and as study- and sex-specific quartiles of activity. Results PA had an overall protective effect on CRC (OR [active vs. inactive] = 0.85; 95%CI = 0.81–0.90). The two-step GxE method identified an interaction between rs4779584, an intergenic variant near the GREM1 and SCG5 genes, and PA for CRC risk (p-interaction = 2.6×10 − 8 ). Stratification by genotype at this locus showed a significant reduction in CRC risk by 20% in active vs. inactive participants with the CC genotype (OR = 0.80; 95%CI = 0.75–0.85), but no significant PA–CRC association among CT or TT carriers. When PA was modeled as quartiles, the 1-d.f. GxE test identified that rs56906466, an intergenic variant near the KCNG1 gene, modified the association between PA and CRC (p-interaction = 3.5×10 − 8 ). Stratification at this locus showed that increase in PA (highest vs. lowest quartile) was associated with a lower CRC risk solely among TT carriers (OR = 0.77; 95%CI = 0.72–0.82). Conclusions In summary, we identified two genetic variants that modified the association between PA and CRC risk. One of them, related to GREM1 and SCG5 , suggests that the bone morphogenetic protein (BMP)-related, inflammatory, and/or insulin signaling pathways may be associated with the protective influence of PA on colorectal carcinogenesis.