Germline CHEK2 mutations in Jewish Ashkenazi women at high risk for breast cancer.

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 CHEK21100delC truncating mutation was reported in a subset of mostly North European breast cancer families. The rate of the CHEK21100delC 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 CHK21157T mutation, as did two of three families with the CHK2S428F mutation.

CONCLUSIONS

CHEK2 missense mutations may contribute to breast cancer susceptibility in Ashkenazi Jews.