Identification of deleterious germline CHEK2 mutations and their association with breast and ovarian cancer

Kód výsledku v 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>

Nalezeny alternativní kódy

RIV/00216208:11110/19:10400312 RIV/00209805:_____/19:00078192 RIV/00064165:_____/19:10400312

Výsledek na webu

<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>

Jazyk výsledku

angličtina

Název v původním jazyce

Identification of deleterious germline CHEK2 mutations and their association with breast and ovarian cancer

Popis výsledku v původním jazyce

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.

Název v anglickém jazyce

Identification of deleterious germline CHEK2 mutations and their association with breast and ovarian cancer

Popis výsledku anglicky

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.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

30101 - Human genetics

Projekt

Výsledek vznikl pri realizaci vícero projektů. Více informací v záložce Projekty.

Návaznosti

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

Rok uplatnění

2019

Kód důvěrnosti údajů

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

Název periodika

International Journal of Cancer

ISSN

0020-7136

e-ISSN

—

Svazek periodika

145

Číslo periodika v rámci svazku

7

Stát vydavatele periodika

US - Spojené státy americké

Počet stran výsledku

16

Strana od-do

1782-1797

Kód UT WoS článku

000479320800008

EID výsledku v databázi Scopus

—