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

Result code in IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F68378050%3A_____%2F23%3A00576835" target="_blank" >RIV/68378050:_____/23:00576835 - isvavai.cz</a>

Alternative codes found

RIV/00216208:11110/23:10468343 RIV/00064165:_____/23:10468343

Result on the web

<a href="https://aacrjournals.org/clincancerres/article/29/16/3037/728222/ENIGMA-CHEK2gether-Project-A-Comprehensive-Study" target="_blank" >https://aacrjournals.org/clincancerres/article/29/16/3037/728222/ENIGMA-CHEK2gether-Project-A-Comprehensive-Study</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1158/1078-0432.CCR-23-0212" target="_blank" >10.1158/1078-0432.CCR-23-0212</a>

Result language

angličtina

Original language name

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

Original language description

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 inhumanRPE1–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. TheORand 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.

Czech name

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Czech description

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Type

J_imp - Article in a specialist periodical, which is included in the Web of Science database

CEP classification

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OECD FORD branch

10601 - Cell biology

Project

Result was created during the realization of more than one project. More information in the Projects tab.

Continuities

P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)

Publication year

2023

Confidentiality

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Name of the periodical

Clinical Cancer Research

ISSN

1078-0432

e-ISSN

1557-3265

Volume of the periodical

29

Issue of the periodical within the volume

16

Country of publishing house

US - UNITED STATES

Number of pages

14

Pages from-to

3037-3050

UT code for WoS article

001053492300001

EID of the result in the Scopus database

2-s2.0-85168222787