Genomic Ascertainment of CHEK2 -Related Cancer Predisposition

作者：Sun Young Kim, Jung Kim, Mark Ramos, Jeremy S. Haley, Diane T. Smelser, H. Shanker Rao, Uyenlinh L. Mirshahi, Katherine L. Nathanson, Barry I. Graubard, Hormuzd A. Katki, David J. Carey, Douglas R. Stewart, Aris Baras, Gonçalo R. Abecasis, Adolfo A. Ferrando, Giovanni Coppola, Andrew Deubler, Luca A. Lotta, John D. Overton, Jeffrey G. Reid, Alan R. Shuldiner, Katherine Siminovitch, Jason Portnoy, Marcus B. Jones, Lyndon J. Mitnaul, Alison Fenney, Jonathan Marchini, Manuel Allen Revez Ferreira, Maya Ghoussaini, Mona Nafde, William Salerno, Cristen J. Willer, Lourdes Crane, Christina Beechert, Erin Fuller, Laura M. Cremona, Eugene Kalyuskin, Hang Du, Caitlin Forsythe, Zhenhua Gu, Kristy Guevara, Michael Lattari, Alexander Lopez, Kia Manoochehri, Prathyusha Challa, Manasi Pradhan, Raymond Reynoso, Ricardo Schiavo, Maria Sotiropoulos Padilla, Chenggu Wang, Sarah E Wold, Manan Goyal, George Mitra, Sanjay Sreeram, Rouel Lanche, Vrushali Mahajan, Sai Lakshmi Vasireddy, Gisu Eom, Krishna Pawan Punuru, Sujit Gokhale, Benjamin Sultan, Pooja Mule, Mudasar Sarwar, Muhammad Aqeel, Xiaodong Bai, Lance Zhang, Sean O’Keeffe, Razvan Panea, Evan Edelstein, Ayesha Rasool, Evan K. Maxwell, Boris Boutkov, Alexander Gorovits, Ju Guan, Lukas Habegger, Alicia Hawes, Olga Krasheninina, Samantha Zarate, Adam J. Mansfield, Joshua Backman, Kathy Burch, Adrián Campos, Liron Ganel, Sheila M. Gaynor, Benjamin Geraghty, Arkopravo Ghosh, Salvador Romero Martinez, Christopher E. Gillies, Lauren Gurski, Eric Jorgenson, Tyler Joseph, Michael D. Kessler, Jack A. Kosmicki, Adam E. Locke, Priyanka Nakka, Karl Landheer, Olivier Delaneau, Anthony Marcketta, Joelle Mbatchou, Arden Moscati, Anita Pandit, Jonathan Ross, Carlo Sidore, Eli Stahl, Timothy Thornton, Sailaja Vedantam, Rujin Wang, Kuan-Han Wu, Bin Ye, Blair Zhang, Andrey Ziyatdinov, Yuxin Zou, Jingning Zhang, Kyoko Watanabe, Mira Tang, Frank R. Wendt, Suganthi Balasubramanian, Suying Bao, Kathie Sun, Chuanyi Zhang, Sean Yu, Aaron Zhang, David Corrigan, Dhruv Shidhaye, Chen Wang, Keyrun Adhikari, Alexander Lachmann, Brian D. Hobbs, Jon Silver, William Palmer, Rita Guerreiro, Amit D. Joshi, Antoine Baldassari, Sarah E. Graham, Ernst Mayerhofer, Erola Pairó Castiñeira, Mary E. Haas, Niek Verweij, George Hindy, Jonas Bovijn, Tanima De, Luanluan Sun, Olukayode Sosina, Arthur Gilly, Peter Dornbos, Juan Rodriguez-Flores, Moeen Riaz, Manav Kapoor, Gannie Tzoneva, Momodou W. Jallow, Anna Alkelai, Ariane Ayer, Veera M. Rajagopal, Sahar Gelfman, Vijay Kumar, Jacqueline M. Otto, José Brás, Silvia Álvarez, Jessie Brown, Hossein Khiabanian, Joana Revez, Kimberly Skead, Valentina A. Zavala, Jae Soon Sul, Lei Chen, Sam Choi, Amy Damask, Nan Lin, Charles Paulding, Sameer Malhotra, Joseph Herman, Michelle G. LeBlanc, Nadia Rana, Jennifer Rico‐Varela, Jaimee Hernandez, Luis Alfredo Hernández Romero, A.N. Paynter, Randi Schwartz, Jody Hankins, Anna Han, Samuel F. M. Hart, Ryan P. Smith, Ann Perez-Beals, Gina Solari, Johannie Rivera-Picart, Michelle Pagan, Sunilbe Siceron, Daniel J. Rader, Marylyn D. Ritchie, Nawar Naseer, Giorgio Sirugo, Afiya Poindexter, Yi-An Ko, Kyle P. Nerz, JoEllen Weaver, Meghan Livingstone, Fred Vadivieso, Stephanie DerOhannessian, Teo Tran, Julia Stephanowski, Salma Santos, Ned Haubein, Joseph Dunn, Anurag Verma, Colleen Morse Kripke, Marjorie Risman, Renae Judy, Colin Wollack, Shefali S. Verma, Scott M. Damrauer, Yuki Bradford, Scott Dudek, Theodore G. Drivas · 发表于：JAMA Network Open · 年份：2025 · DOI：10.1001/jamanetworkopen.2025.49730 · 被引用次数：3 · 研究领域：BRCA gene mutations in cancer、Male Breast Health Studies、Genomics and Rare Diseases

Importance: There is clear evidence that deleterious germline variants in CHEK2 increase risk for breast and prostate cancers; there is limited or conflicting evidence for other cancers. Objective: To quantify the prevalence of as well as cancer risk and survival associated with CHEK2 germline pathogenic and likely pathogenic variants using genomic ascertainment. Design, Setting, and Participants: This case-control study used 2 electronic health record-linked and exome-sequenced biobanks: UK Biobank (n = 469 765) and Geisinger MyCode (adults only; n = 167 050). Variants were classified according to American College of Medical Genetics and Genomics and the Association for Molecular Pathology criteria. Cases were defined as individuals with heterozygous CHEK2, harboring pathogenic or likely pathogenic variants; controls as individuals with a benign or likely benign CHEK2 variation or wildtype CHEK2. Cancer registry (MyCode since approximately 1943; UK Biobank since approximately 1970) and demographic data were retrieved; to adjust for relatedness, association analysis was performed with SAIGE-GENE+ with Bonferroni correction. Main Outcomes and Measures: Prevalence of as well as cancer risk and survival in adults with CHEK2 germline variants. Results: Of 469 765 individuals in the UK Biobank, there were 3232 case participants (mean [SD] age, 70.8 [8.0] years; 3139 [97.1%] White; 1744 [54.0%] women); of 167 050 individuals with MyCode, there were 3153 case participants (mean [SD]...