Functional analysis identifies damaging CHEK2 missense variants associated with increased cancer risk.

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Date
2021-12-13ICR Author
Author
Boonen, RA
Wiegant, WW
Celosse, N
Vroling, B
Heijl, S
Kote-Jarai, Z
Mijuskovic, M
Cristea, S
Solleveld-Westerink, N
van Wezel, T
Beerenwinkel, N
Eeles, R
Devilee, P
Vreeswijk, MP
Marra, G
van Attikum, H
Type
Journal Article
Metadata
Show full item recordAbstract
Heterozygous carriers of germline loss-of-function variants in the tumor suppressor gene checkpoint kinase 2 (CHEK2) are at an increased risk for developing breast and other cancers. While truncating variants in CHEK2 are known to be pathogenic, the interpretation of missense variants of uncertain significance (VUS) is challenging. Consequently, many VUS remain unclassified both functionally and clinically. Here we describe a mouse embryonic stem (mES) cell-based system to quantitatively determine the functional impact of 50 missense VUS in human CHEK2. By assessing the activity of human CHK2 to phosphorylate one of its main targets, Kap1, in Chek2 knockout mES cells, 31 missense VUS in CHEK2 impaired protein function to a similar extent as truncating variants, and 9 CHEK2 missense VUS resulted in intermediate functional defects. Mechanistically, most VUS impaired CHK2 kinase function by causing protein instability or by impairing activation through (auto)phosphorylation. Quantitative results showed that the degree of CHK2 kinase dysfunction correlates with an increased risk for breast cancer. Both damaging CHEK2 variants as a group (OR 2,23; 95% CI 1,62-3,07; p<0,0001) and intermediate variants (OR 1,63; 95% CI 1,21-2,20; p=0,0014) were associated with an increased breast cancer risk, while functional variants did not show this association (OR 1,13; 95% CI 0,87-1,46; p=0,378). Finally, a damaging VUS in CHEK2, c.486A>G/p.D162G, was also identified, which co-segregated with familial prostate cancer. Altogether, these functional assays efficiently and reliably identified VUS in CHEK2 that associate with cancer.
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Research team
Oncogenetics
Language
eng
Date accepted
2021-12-06
License start date
2021-12-13
Citation
Cancer research, 2021