Identification of deleterious germline CHEK2 mutations and their association with breast and ovarian cancer
The result's identifiers
Result code in IS VaVaI
<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F68378050%3A_____%2F19%3A00508568" target="_blank" >RIV/68378050:_____/19:00508568 - isvavai.cz</a>
Alternative codes found
RIV/00216208:11110/19:10400312 RIV/00209805:_____/19:00078192 RIV/00064165:_____/19:10400312
Result on the web
<a href="https://onlinelibrary.wiley.com/doi/abs/10.1002/ijc.32385" target="_blank" >https://onlinelibrary.wiley.com/doi/abs/10.1002/ijc.32385</a>
DOI - Digital Object Identifier
<a href="http://dx.doi.org/10.1002/ijc.32385" target="_blank" >10.1002/ijc.32385</a>
Alternative languages
Result language
angličtina
Original language name
Identification of deleterious germline CHEK2 mutations and their association with breast and ovarian cancer
Original language description
Germline mutations in checkpoint kinase 2 (CHEK2), a multiple cancer-predisposing gene, increase breast cancer (BC) risk, however, risk estimates differ substantially in published studies. We analyzed germline CHEK2 variants in 1,928 high-risk Czech breast/ovarian cancer (BC/OC) patients and 3,360 population-matched controls (PMCs). For a functional classification of VUS, we developed a complementation assay in human nontransformed RPE1-CHEK2-knockout cells quantifying CHK2-specific phosphorylation of endogenous protein KAP1. We identified 10 truncations in 46 (2.39%) patients and in 11 (0.33%) PMC (p = 1.1 x 10(-14)). Two types of large intragenic rearrangements (LGR) were found in 20/46 mutation carriers. Truncations significantly increased unilateral BC risk (OR = 7.94,95%CI 3.90-17.47, p = 1.1 x 10(-14)) and were more frequent in patients with bilateral BC (4/149, 2.68%, p = 0.003), double primary BC/OC (3/79, 3.80%, p = 0.004), male BC (3/48, 6.25%, p = 8.6 x 10(-4)), but not with OC (3/354, 0.85%, p = 0.14). Additionally, we found 26 missense VUS in 88 (4.56%) patients and 131 (3.90%) PMC (p = 0.22). Using our functional assay, 11 variants identified in 15 (0.78%) patients and 6 (0.18%) PMC were scored deleterious (p = 0.002). Frequencies of functionally intermediate and neutral variants did not differ between patients and PMC. Functionally deleterious CHEK2 missense variants significantly increased BC risk (OR = 3.90, 95%CI 1.24-13.35, p = 0.009) and marginally OC risk (OR = 4.77, 95%CI 0.77-22.47, p = 0.047), however, carriers low frequency will require evaluation in larger studies. Our study highlights importance of LGR detection for CHEK2 analysis, careful consideration of ethnicity in both cases and controls for risk estimates, and demonstrates promising potential of newly developed human nontransformed cell line assay for functional CHEK2 VUS classification.
Czech name
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Czech description
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Classification
Type
J<sub>imp</sub> - Article in a specialist periodical, which is included in the Web of Science database
CEP classification
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OECD FORD branch
30101 - Human genetics
Result continuities
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)
Others
Publication year
2019
Confidentiality
S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů
Data specific for result type
Name of the periodical
International Journal of Cancer
ISSN
0020-7136
e-ISSN
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Volume of the periodical
145
Issue of the periodical within the volume
7
Country of publishing house
US - UNITED STATES
Number of pages
16
Pages from-to
1782-1797
UT code for WoS article
000479320800008
EID of the result in the Scopus database
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