ENIGMA CHEK2gether Project: A Comprehensive Study Identifies Functionally Impaired CHEK2 Germline Missense Variants Associated with Increased Breast Cancer Risk.
Journal
Clinical cancer research : an official journal of the American Association for Cancer Research
ISSN: 1557-3265
Titre abrégé: Clin Cancer Res
Pays: United States
ID NLM: 9502500
Informations de publication
Date de publication:
15 08 2023
15 08 2023
Historique:
received:
28
01
2023
revised:
06
04
2023
accepted:
14
06
2023
medline:
16
8
2023
pubmed:
14
7
2023
entrez:
14
7
2023
Statut:
ppublish
Résumé
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). 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. 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. 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.
Identifiants
pubmed: 37449874
pii: 727794
doi: 10.1158/1078-0432.CCR-23-0212
pmc: PMC10425727
doi:
Substances chimiques
Checkpoint Kinase 2
EC 2.7.1.11
CHEK2 protein, human
EC 2.7.11.1
Types de publication
Meta-Analysis
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
3037-3050Subventions
Organisme : NCI NIH HHS
ID : P50 CA116201
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA192393
Pays : United States
Organisme : NCI NIH HHS
ID : R35 CA253187
Pays : United States
Investigateurs
Koichi Matsuda
(K)
Yoichiro Kamatani
(Y)
Takayuki Morisaki
(T)
Akiko Nagai
(A)
Kaori Muto
(K)
Yoshinori Murakami
(Y)
Yoichi Furukawa
(Y)
Yuji Yamanashi
(Y)
Yusuke Nakamura
(Y)
Taisei Mushiroda
(T)
Yukihide Momozawa
(Y)
Toshihiro Tanaka
(T)
Yozo Ohnishi
(Y)
Michiaki Kubo
(M)
Shinichi Higashiue
(S)
Shuzo Kobayashi
(S)
Shiro Minami
(S)
Hiroki Yamaguhci
(H)
Hajime Arai
(H)
Ken Yamaji
(K)
Yasushi Okazaki
(Y)
Satoshi Asai
(S)
Yasuo Takahashi
(Y)
Tomoaki Fujioka
(T)
Wataru Obara
(W)
Seijiro Mori
(S)
Shigeo Murayama
(S)
Satoshi Nagayama
(S)
Yoshio Miki
(Y)
Akihide Masumoto
(A)
Akira Yamada
(A)
Yasuko Nishizawa
(Y)
Masahiko Higashiyama
(M)
Hiromu Kutsumi
(H)
Yukihiro Koretsune
(Y)
Takashi Yoshiyama
(T)
Marianna Borecka
(M)
Marta Cerna
(M)
Milena Hovhannisyan
(M)
Sandra Jelinkova
(S)
Petr Nehasil
(P)
Lenka Foretova
(L)
Eva Machackova
(E)
Vera Krutilkova
(V)
Spiros Tavandzis
(S)
Leona Cerna
(L)
Stepan Chvojka
(S)
Monika Koudova
(M)
Alena Puchmajerova
(A)
Ondrej Havranek
(O)
Jan Novotny
(J)
Kamila Vesela
(K)
Michal Vocka
(M)
Lucie Hruskova
(L)
Renata Michalovska
(R)
Denisa Schwetzova
(D)
Zdenka Vlckova
(Z)
Monika Cerna
(M)
Marketa Hejnalova
(M)
Nikol Jedlickova
(N)
Ivan Subrt
(I)
Tomas Zavoral
(T)
Marcela Kosarova
(M)
Gabriela Vacinova
(G)
Maria Janikova
(M)
Romana Kratochvilova
(R)
Vaclava Curtisova
(V)
Radek Vrtel
(R)
Ondrej Scheinost
(O)
Petra Duskova
(P)
Viktor Stranecky
(V)
Informations de copyright
©2023 The Authors; Published by the American Association for Cancer Research.
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