TY - JOUR
T1 - ENIGMA CHEK2gether Project
T2 - A Comprehensive Study Identifies Functionally Impaired CHEK2 Germline Missense Variants Associated with Increased Breast Cancer Risk
AU - Stolarova, Lenka
AU - Kleiblova, Petra
AU - Zemankova, Petra
AU - Stastna, Barbora
AU - Janatova, Marketa
AU - Soukupova, Jana
AU - Achatz, Maria Isabel
AU - Ambrosone, Christine
AU - Apostolou, Paraskevi
AU - Arun, Banu K
AU - Auer, Paul
AU - Barnard, Mollie
AU - Bertelsen, Birgitte
AU - Blok, Marinus J
AU - Boddicker, Nicholas
AU - Brunet, Joan
AU - Burnside, Elizabeth S
AU - Calvello, Mariarosaria
AU - Campbell, Ian
AU - Chan, Sock Hoai
AU - Chen, Fei
AU - Chiang, Jian Bang
AU - Coppa, Anna
AU - Cortesi, Laura
AU - Crujeiras-González, Ana
AU - De Leeneer, Kim
AU - De Putter, Robin
AU - DePersia, Allison
AU - Devereux, Lisa
AU - Domchek, Susan
AU - Efremidis, Anna
AU - Engel, Christoph
AU - Ernst, Corinna
AU - Evans, D Gareth R
AU - Feliubadaló, Lidia
AU - Fostira, Florentia
AU - Fuentes-Ríos, Olivia
AU - Gómez-García, Encarna B
AU - González, Sara
AU - Haiman, Christopher
AU - Hansen, Thomas van Overeem
AU - Hauke, Jan
AU - Hodge, James
AU - Hu, Chunling
AU - Huang, Hongyan
AU - Ishak, Nur Diana Binte
AU - Iwasaki, Yusuke
AU - Konstantopoulou, Irene
AU - Kraft, Peter
AU - Rossing, Maria
AU - Biobank Japan
N1 - ©2023 The Authors; Published by the American Association for Cancer Research.
PY - 2023/8/15
Y1 - 2023/8/15
N2 - 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 = 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.
AB - 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 = 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.
KW - Humans
KW - Female
KW - Breast Neoplasms/epidemiology
KW - Genetic Predisposition to Disease
KW - Checkpoint Kinase 2/genetics
KW - Mutation, Missense
KW - Germ-Line Mutation
KW - Germ Cells
UR - http://www.scopus.com/inward/record.url?scp=85168222787&partnerID=8YFLogxK
U2 - 10.1158/1078-0432.CCR-23-0212
DO - 10.1158/1078-0432.CCR-23-0212
M3 - Journal article
C2 - 37449874
VL - 29
SP - 3037
EP - 3050
JO - Clinical Cancer Research
JF - Clinical Cancer Research
SN - 1078-0432
IS - 16
ER -