BACKGROUND: Germline mutations in BRCA1 and BRCA2 genes account for only 20-40% of familial breast cancer cases. The CHEK2 gene encodes a checkpoint kinase, involved in response to DNA damage, and hence is a candidate gene for breast cancer susceptibility. Indeed, the CHEK2*1100delC truncating mutation was reported in a subset of mostly North European breast cancer families. The rate of the CHEK2*1100delC variant in the Ashkenazi Jewish population was reported to be 0.3%. OBJECTIVES: To evaluate whether CHEK2 germline mutations contribute to a breast cancer predisposition in Ashkenazi** Jewish high risk families. METHODS: High risk Ashkenazi Jewish women, none of whom was a carrier of the predominant Jewish mutations in BRCA1/BRCA2, were genotyped for germline mutations in the CHEK2 gene by exon-specific polymerase chain reaction followed by denaturing gradient gel electrophoresis and sequencing of abnormally migrating fragments. RESULTS: Overall, 172 high risk women were genotyped: 75 (43.6%) with breast cancer (average age at diagnosis 49.6 +/- 9.6 years, mean +/- SD) and 97 asymptomatic individuals (age at counseling 48.3 +/- 8.2 years). No truncating mutations were noted and four previously described missense mutations were detected (R3W 1.2%, 1157T 1.2%, R180C 0.6% and S428F 5%), one silent polymorphism (E84E 20.5%) and one novel missense mutation (Y424H 1.2%). Segregation analysis of the 1157T and S428F mutations (shown to affect protein function) with the cancer phenotype showed concordance for the CHK2*1157T mutation, as did two of three families with the CHK2*S428F mutation. CONCLUSIONS: CHEK2 missense mutations may contribute to breast cancer susceptibility in Ashkenazi Jews.
BACKGROUND: Germline mutations in BRCA1 and BRCA2 genes account for only 20-40% of familial breast cancer cases. The CHEK2 gene encodes a checkpoint kinase, involved in response to DNA damage, and hence is a candidate gene for breast cancer susceptibility. Indeed, the CHEK2*1100delC truncating mutation was reported in a subset of mostly North European breast cancer families. The rate of the CHEK2*1100delC variant in the Ashkenazi Jewish population was reported to be 0.3%. OBJECTIVES: To evaluate whether CHEK2 germline mutations contribute to a breast cancer predisposition in Ashkenazi** Jewish high risk families. METHODS: High risk Ashkenazi Jewish women, none of whom was a carrier of the predominant Jewish mutations in BRCA1/BRCA2, were genotyped for germline mutations in the CHEK2 gene by exon-specific polymerase chain reaction followed by denaturing gradient gel electrophoresis and sequencing of abnormally migrating fragments. RESULTS: Overall, 172 high risk women were genotyped: 75 (43.6%) with breast cancer (average age at diagnosis 49.6 +/- 9.6 years, mean +/- SD) and 97 asymptomatic individuals (age at counseling 48.3 +/- 8.2 years). No truncating mutations were noted and four previously described missense mutations were detected (R3W 1.2%, 1157T 1.2%, R180C 0.6% and S428F 5%), one silent polymorphism (E84E 20.5%) and one novel missense mutation (Y424H 1.2%). Segregation analysis of the 1157T and S428F mutations (shown to affect protein function) with the cancer phenotype showed concordance for the CHK2*1157T mutation, as did two of three families with the CHK2*S428F mutation. CONCLUSIONS:CHEK2 missense mutations may contribute to breast cancer susceptibility in Ashkenazi Jews.
Authors: Florence Le Calvez-Kelm; Fabienne Lesueur; Francesca Damiola; Maxime Vallée; Catherine Voegele; Davit Babikyan; Geoffroy Durand; Nathalie Forey; Sandrine McKay-Chopin; Nivonirina Robinot; Tù Nguyen-Dumont; Alun Thomas; Graham B Byrnes; John L Hopper; Melissa C Southey; Irene L Andrulis; Esther M John; Sean V Tavtigian Journal: Breast Cancer Res Date: 2011-01-18 Impact factor: 6.466
Authors: Suriati Mohamad; Nurismah Md Isa; Rohaizak Muhammad; Nor Aina Emran; Nor Mayah Kitan; Peter Kang; In Nee Kang; Nur Aishah Mohd Taib; Soo Hwang Teo; Sharifah Noor Akmal Journal: PLoS One Date: 2015-01-28 Impact factor: 3.240