ENIGMA CHEK2gether Project: A Comprehensive Study Identifies Functionally Impaired CHEK2 Germline Missense Variants Associated with Increased Breast Cancer Risk

Lenka Stolarova, Petra Kleiblova, Petra Zemankova, Barbora Stastna, Marketa Janatova, Jana Soukupova, Maria Isabel Achatz, Christine Ambrosone, Paraskevi Apostolou, Banu K. Arun, Paul Auer, Mollie Barnard, Birgitte Bertelsen, Biobank Japan, Marinus J. Blok, Nicholas Boddicker, Joan Brunet, Elizabeth S. Burnside, Mariarosaria Calvello, Ian CampbellSock Hoai Chan, Fei Chen, Jian Bang Chiang, Anna Coppa, Laura Cortesi, Ana Crujeiras-González, Consortium Czecanca, Kim De Leeneer, Robin De Putter, Allison DePersia, Lisa Devereux, Susan Domchek, Anna Efremidis, Christoph Engel, Corinna Ernst, Gareth D.R. Evans, Lidia Feliubadaló, Florentia Fostira, Olivia Fuentes-Ríos, Encarna B. Gómez-García, Sara González, Christopher Haiman, Thomas van Overeem Hansen, Jan Hauke, James Hodge, Chunling Hu, Hongyan Huang, Nur Diana Binte Ishak, Yusuke Iwasaki, Irene Konstantopoulou, Peter Kraft, James Lacey, Conxi Lázaro, Na Li, Weng Khong Lim, Sara Lindstrom, Adriana Lori, Elana Martinez, Alexandra Martins, Koichi Matsuda, Giuseppe Matullo, Simone McInerny, Kyriaki Michailidou, Marco Montagna, Alvaro N.A. Monteiro, Luigi Mori, Katherine Nathanson, Susan L. Neuhausen, Heli Nevanlinna, Janet E. Olson, Julie Palmer, Barbara Pasini, Alpa Patel, Maria Piane, Bruce Poppe, Paolo Radice, Alessandra Renieri, Nicoletta Resta, Marcy E. Richardson, Toon Rosseel, Kathryn J. Ruddy, Marta Santamariña, Elizabeth Santana Dos Santos, Lauren Teras, Amanda E. Toland, Amy Trentham-Dietz, Celine M. Vachon, Alexander E. Volk, Nana Weber-Lassalle, Jeffrey N. Weitzel, Lisa Wiesmuller, Stacey Winham, Siddhartha Yadav, Drakoulis Yannoukakos, Song Yao, Valentina Zampiga, Magnus Zethoven, Ze Wen Zhang, Tomas Zima, Amanda B. Spurdle, Ana Vega, Maria Rossing, Jesús Del Valle, Arcangela De Nicolo, Eric Hahnen, Kathleen B.M. Claes, Joanne Ngeow, Yukihide Momozawa, Paul A. James, Fergus J. Couch, Libor Macurek, Zdenek Kleibl

Research output: Contribution to journalArticlepeer-review

15 Scopus citations

Abstract

Purpose: Germline pathogenic variants in CHEK2 confer moderately elevated breast cancer risk (odds ratio, OR ~ 2.5), qualifying carriers for enhanced breast cancer screening. Besides pathogenic variants, dozens of missense CHEK2 variants of uncertain significance (VUS) have been identified, hampering the clinical utility of germline genetic testing (GGT). Experimental Design: We collected 460 CHEK2 missense VUS identified by the ENIGMA consortium in 15 countries. Their functional characterization was performed using CHEK2-complementation assays quantifying KAP1 phosphorylation and CHK2 autophosphorylation in human RPE1–CHEK2-knockout cells. Concordant results in both functional assays were used to categorize CHEK2 VUS from 12 ENIGMA case–control datasets, including 73,048 female patients with breast cancer and 88,658 ethnicity-matched controls. Results: A total of 430/460 VUS were successfully analyzed, of which 340 (79.1%) were concordant in both functional assays and categorized as functionally impaired (N ¼ 102), functionally intermediate (N ¼ 12), or functionally wild-type (WT)–like (N ¼ 226). We then examined their association with breast cancer risk in the case–control analysis. The OR and 95% CI (confidence intervals) for carriers of functionally impaired, intermediate, and WT-like variants were 2.83 (95% CI, 2.35–3.41), 1.57 (95% CI, 1.41–1.75), and 1.19 (95% CI, 1.08–1.31), respectively. The meta-analysis of population-specific datasets showed similar results. Conclusions: We determined the functional consequences for the majority of CHEK2 missense VUS found in patients with breast cancer (3,660/4,436; 82.5%). Carriers of functionally impaired missense variants accounted for 0.5% of patients with breast cancer and were associated with a moderate risk similar to that of truncating CHEK2 variants. In contrast, 2.2% of all patients with breast cancer carried functionally wild-type/intermediate missense variants with no clinically relevant breast cancer risk in heterozygous carriers.

Original languageEnglish (US)
Pages (from-to)3037-3050
Number of pages14
JournalClinical Cancer Research
Volume29
Issue number16
DOIs
StatePublished - Aug 15 2023

ASJC Scopus subject areas

  • General Medicine

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