Germline CHEK2 Gene Mutations in Hereditary Breast Cancer Predisposition – Mutation Types and their Biological and Clinical Relevance
Authors:
Petra Kleiblová 1,2; Lenka Stolařová 1; Křížová Křížová 3; Filip Lhota 1; Jan Hojný 1; Petra Zemánková 1; Ondřej Havránek 4,5; Michal Vočka 6; Marta Černá 1; Klára Lhotová 1; Marianna Borecká 1; Markéta Janatová 1; Jana Soukupová 1; Jan Ševčík 1; Martina Zimovjanová 6; Jaroslav Kotlas 2; Aleš Panczak 2,7; Kamila Veselá 2; Jana Červenková 8; Michaela Schneiderová 9; Monika Burócziová 3; Kamila Burdová 3; Viktor Stránecký 10; Lenka Foretová 1; Eva Macháčková 11; Spiros Tavandzis 12; Stanislav Kmoch 10; Libor Macůrek 3; Zdeněk Kleibl 1
Authors‘ workplace:
Laboratoř onkogenetiky, Ústav biochemie a experimentální onkologie, 1. LF UK v Praze
1; Ústav biologie a lékařské genetiky, 1. LF UK a VFN v Praze
2; Laboratoř biologie nádorové buňky, Ústav molekulární genetiky AV ČR v. v. i., Praha
3; BIOCEV, 1. LF UK v Praze 5 I. interní klinika 1. LF UK a VFN v Praze
4; Onkologická klinika 1. LF UK a VFN v Praze
6; Radiologická klinika 1. LF UK a VFN v Praze
7; Radioterapeutická a onkologická klinika FN Královské Vinohrady, Praha
8; I. chirurgická klinika 1. LF UK a VFN v Praze
9; Laboratoř pro studium vzácných nemocí, Klinika dětského a dorostového lékařství 1. LF UK a VFN v Praze
10; Oddělení nádorové epidemiologie, Masarykův onkologický ústav, Brno
11; Oddělení lékařské genetiky, Laboratoře AGEL, Praha
12
Published in:
Klin Onkol 2019; 32(Supplementum2): 36-50
Category:
Original Articles
doi:
https://doi.org/10.14735/amko2019S36
Overview
Background: Hereditary mutations in the CHEK2 gene (which encodes CHK2 kinase) contribute to a moderately increased risk of breast cancer (BC) and other cancers. Large variations in the frequency of CHEK2 mutations and the occurrence of variants of unknown clinical significance (VUS) complicate estimation of cancer risk in carriers of germline CHEK2 mutations.
Patients and methods: We performed mutation analysis of 1,526 high-risk Czech BC patients and 3,360 Czech controls. Functional analysis was performed for identified VUS using a model system based on a human RPE1-CHEK2-KO cell line harboring biallelic inactivation of endogenous CHEK2.
Results: The frequency of ten truncating CHEK2 variants differed markedly between BC patients (2.26%) and controls (0.11%; p = 4.1 × 10−12). We also found 23 different missense variants in 4.5% patients and in 4.0% of controls. The most common was p.I157T, which was found in patients and controls with the same frequency. Functional analysis identified nine functionally deleterious VUS, another nine functionally neutral VUS, and four intermediate VUS (including p.I157T). We found that carriers of truncating CHEK2 mutations had a high BC risk (OR 8.19; 95% CI 4.11–17.75), and that carriers of functionally deleterious missense variants had a moderate risk (OR 4.06; 95% CI, 1.37–13.39). Carriers of these mutations developed BC at 44.4 and 50.7 years, respectively. Functionally neutral and functionally intermediate missense variants did not increase the BC risk. BC in CHEK2 mutation carriers was frequently ER-positive and of higher grade. Notably, carriers of CHEK2 mutations developed second cancers more frequently than BRCA1/BRCA2/PALB2/p53 or mutation non-carriers.
Conclusion: Hereditary CHEK2 mutations contribute to the development of hereditary BC. The associated cancer risk in mutation carriers increases with the number of affected individuals in a family. Annual follow-up with breast ultrasound, mammography, or magnetic resonance imaging is recommended for asymptomatic mutation carriers from the age of 40. Surgical prevention and specific follow-up of other tumors should be considered based on family cancer history.
The work was supported by grants from the Czech Health Research Council of the Ministry of Health of the Czech Republic NR 15-28830A, 16-29959A, NV19-03-00279, projects of the PROGRES Q28/LF1, GAUK 762216, SVV2019 / 260367, PRIMUS/17/MED/9, UNCE/MED/016, Progress Q26, LQ1604 NPU II and project AVČR Qualitas. The analysis of a set of unselected controls was made possible by the existence and support of the scientific infrastructure of the National Center for Medical Genomics (LM2015091) and its project aimed at creating a reference database of genetic variants of the Czech Republic (CZ.02.1.01/0.0/0.0/16_013/0001634).
The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study.
The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers.
Submitted: 2. 4. 2019
Accepted: 14. 5. 2019
Keywords:
breast cancer – CHEK2 – hereditary mutations – variants of unknown significance – functional analysis
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