ENIGMA CHEK2gether Project: A Comprehensive Study Identifies Functionally Impaired CHEK2 Germline Missense Variants Associated with Increased Breast Cancer Risk
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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 = 102), functionally intermediate (N = 12), or functionally wild-type (WT)–like (N = 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.
Originalsprog | Engelsk |
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Tidsskrift | Clinical Cancer Research |
Vol/bind | 29 |
Udgave nummer | 16 |
Sider (fra-til) | 3037-3050 |
Antal sider | 14 |
ISSN | 1078-0432 |
DOI | |
Status | Udgivet - 2023 |
Bibliografisk note
Funding Information:
This work was supported by the grant projects of the Czech Ministry of Health NV19–03–00279, DRO-VFN-64165; Charles University projects COOPERATIO and SVV260516; Ministry of Education, Youths and Sports of the Czech Republic grant EXCELES no. LX22NPO05102 funded by EU. L. Stolarova was partially supported by Czech Academy of Science (PPPLZ project L200522201). The CARRIERS study was supported by NIH grants R01 CA192393, R35 CA253187 and a specialized program of research excellence (SPORE) in breast cancer (P50 CA116201). Contract grant sponsor A. Vega: supported by Spanish Instituto de Salud Carlos III (ISCIII) funding, an initiative of the Spanish Ministry of Economy and Innovation partially supported by European Regional Development FEDER Funds (PI22/00589, PI19/01424; INT20/ 00071), the Autonomous Government of Galicia (Consolidation and structuring program: IN607B), by the Fundación Mutua Madrileña (call 2018), and by the AECC (PRYES211091VEGA). A.B. Spurdle was supported by an NHMRC Investigator Fellowship (APP177524).
Publisher Copyright:
©2023 The Authors; Published by the American Association for Cancer Research.
ID: 386597941