Genomic Ascertainment of CHEK2-Related Cancer Predisposition

Disease areas:

• cancer and other tissue growths
• clinical signs and symptoms

Last updated:

5 April 2026

Author(s):

Sun Young Kim, Jung Kim, Mark Ramos, Jeremy Haley, Diane Smelser, H. Shanker Rao, Uyenlinh L. Mirshahi, Katherine L. Nathanson, Barry I. Graubard, Hormuzd A. Katki, David Carey, Douglas R. Stewart, Aris Baras, Gonçalo Abecasis, Adolfo Ferrando, Giovanni Coppola, Andrew Deubler, Luca A Lotta, John D Overton, Jeffrey G Reid, Alan Shuldiner, Katherine Siminovitch, Jason Portnoy, Marcus B Jones, Lyndon Mitnaul, Alison Fenney, Jonathan Marchini, Manuel Allen Revez Ferreira, Maya Ghoussaini, Mona Nafde, William Salerno, Cristen 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, Adrian Campos, Liron Ganel, Sheila Gaynor, Benjamin Geraghty, Arkopravo Ghosh, Salvador Romero Martinez, Christopher Gillies, Lauren Gurski, Eric Jorgenson, Tyler Joseph, Michael Kessler, Jack Kosmicki, Adam 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 Wendt, Suganthi Balasubramanian, Suying Bao, Kathie Sun, Chuanyi Zhang, Sean Yu, Aaron Zhang, David Corrigan, Dhruv Shidhaye, Chen Wang, Keyrun Adhikari, Alexander Lachmann, Brian Hobbs, Jon Silver, William Palmer, Rita Guerreiro, Amit Joshi, Antoine Baldassari, Sarah Graham, Ernst Mayerhofer, Erola Pairo Castineira, Mary 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 Rajagopal, Sahar Gelfman, Vijay Kumar, Jacqueline Otto, Jose Bras, Silvia Alvarez, Jessie Brown, Hossein Khiabanian, Joana Revez, Kimberly Skead, Valentina 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, Larizbeth Romero, Ashley Paynter, Randi Schwartz, Jody Hankins, Anna Han, Samuel Hart, Ryan 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 Damrauer, Yuki Bradford, Scott Dudek, Theodore Drivas

Publish date:

1 December 2025

Journal:

JAMA Network Open

PubMed ID:

41396600

DOI:

10.1001/jamanetworkopen.2025.49730

Abstract

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] age, 60.5 [17.8] years; 3123 [98.8%] White; 1935 [61.5%] women). In case participants in both MyCode and UKBB, there was a significant excess risk of all cancers (odds ratio [OR], 1.33 [95% CI, 1.18-1.49]; OR, 1.41 [95% CI, 1.26-1.59], respectively), breast (OR, 1.54 [95% CI, 1.18-2.00]; OR, 1.84 [95% CI, 1.49-2.27], respectively), prostate (OR, 1.62 [95% CI, 1.27-2.07]; OR, 1.78 [95% CI, 1.48-2.16], respectively), kidney (OR, 1.58 [95% CI, 1.03-2.41]; OR, 1.84 [95% CI, 1.22-2.77], respectively), and bladder (OR, 1.50 [95% CI, 1.01-2.23]; OR, 1.64 [95% CI, 1.17-2.31], respectively) cancers as well as lymphoid leukemia (OR, 2.08 [95% CI, 1.17-3.69]; OR, 2.21 [95% CI, 1.19-4.08], respectively). Compared with control participants, time to cancer in case participants was significantly shorter in both cohorts; no significant difference was observed between the age-dependent penetrance of truncating and missense variants for cancer in either cohort. Overall survival was significantly decreased in case participants in UK Biobank; however, the primary consequence was seen after 75 years. There was no statistical difference in survival in MyCode. There were no differences in survival between case participants with cancer and control participants with cancer.

Conclusions and Relevance: In this case-control study of genomic ascertainment of individuals with heterozygous CHEK2 pathogenic or likely pathogenic variants in 2 population-scale cohorts, there was a significant excess risk of breast, prostate, kidney, bladder, and lymphoid leukemia cancer. The conferred excess mortality and cancer risk was low (ORs <2). This has clinical implications for individuals ascertained this way (vs with a family history of cancer).