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Int J Cancer. 2019 May 3. doi: 10.1002/ijc.32385. [Epub ahead of print]

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

Author information

1
Institute of Biochemistry and Experimental Oncology, First Faculty of Medicine, Charles University, Prague, Czech Republic.
2
Institute of Biology and Medical Genetics, First Faculty of Medicine, Charles University and General University Hospital, Prague, Czech Republic.
3
Laboratory of Cancer Cell Biology, Institute of Molecular Genetics of the ASCR, Prague, Czech Republic.
4
BIOCEV, First Faculty of Medicine, Charles University, Prague, Czech Republic.
5
Department of Hematology, First Faculty of Medicine, Charles University and General University Hospital, Prague, Czech Republic.
6
Department of Oncology, First Faculty of Medicine, Charles University and General University Hospital, Prague, Czech Republic.
7
Department of Radiology, First Faculty of Medicine, Charles University and General University Hospital, Prague, Czech Republic.
8
First Department of Surgery, First Faculty of Medicine, Charles University and General University Hospital, Prague, Czech Republic.
9
Research Unit for Rare Diseases, Department of Pediatrics and Adolescent Medicine, First Faculty of Medicine, Charles University and General University Hospital, Prague, Czech Republic.
10
Department of Cancer Epidemiology and Genetics, Masaryk Memorial Cancer Institute, Brno, Czech Republic.
11
Department of Medical Genetics, AGEL Laboratories, AGEL Research and Training Institute, Novy Jicin, Czech Republic.

Abstract

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 × 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 × 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 × 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.

KEYWORDS:

CHEK2; KAP1; VUS; breast cancer; functional assay; germline mutations; ovarian cancer

PMID:
31050813
DOI:
10.1002/ijc.32385

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