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 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%.


OBJECTIVE
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.
Laitman
Yael
Y
Oncogenetics Unit, Gertner Institute of Human Genetics, Sheba Medical Center, Tel Hashomer, Israel.
Kaufman
Bella
B
Lahad
Ephrat Levy
EL
Papa
Moshe Z
MZ
Friedman
Eitan
E
D000328:Adult; D000368:Aged; D001943:Breast Neoplasms / Q000453:epidemiology / Q000235:genetics*; D064447:Checkpoint Kinase 2; D016521:Electrophoresis, Gel, Pulsed-Field; D005260:Female; D020022:Genetic Predisposition to Disease / Q000208:ethnology* / Q000235:genetics; D018095:Germ-Line Mutation / Q000235:genetics*; D006801:Humans; D007557:Israel; D007585:Jews / Q000235:genetics*; D008875:Middle Aged; D020125:Mutation, Missense / Q000235:genetics*; D009691:Nucleic Acid Denaturation; D010051:Ovarian Neoplasms / Q000453:epidemiology; D010375:Pedigree; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D017422:Sequence Analysis, DNA
D064447:Checkpoint Kinase 2; C578634:CHEK2 protein, human; D017346:Protein Serine-Threonine Kinases