title: A novel recurrent CHEK2 Y390C mutation identified in high-risk Chinese breast cancer patients impairs its activity and is associated with increased breast cancer risk.
abstract: Certain predisposition factors such as BRCA1/2 and CHEK2 mutations cause familial breast cancers that occur early. In China, breast cancers are diagnosed at relatively younger age, and higher percentage of patients are diagnosed before 40 years, than that in Caucasians. However, the prevalence for BRCA1/2 mutations and reported CHEK2 germline mutations is much lower or absent in Chinese population, arguing for the need to study other novel risk alleles among Chinese breast cancer patients. In this study, we searched for CHEK2 mutations in young, high-risk breast cancer patients in China and detected a missense variant Y390C (1169A > G) in 12 of 150 patients (8.0%) and 2 in 250 healthy controls (0.8%, P = 0.0002). Four of the Y390C carriers have family history of breast and/or ovarian cancer. In patients without family history, Y390C carriers tend to develop breast cancer early, before 35 years of age. The codon change at Y390, a highly conserved residue located in CHEK2's kinase domain, appeared to significantly impair CHEK2 activity. Functional analysis suggested that the CHEK2 Y390C mutation is deleterious as judged by the mutant protein's inability to inactivate CDC25A or to activate p53 after DNA damage. Cells expressing the CHEK2 Y390C variant showed impaired p21 and Puma expression after DNA damage, and the deregulated cell cycle checkpoint and apoptotic response may help conserve mutations and therefore contribute to tumorigeneisis. Taken together, our results not only identified a novel CHEK2 allele that is associated with cancer families and confers increased breast cancer risk, but also showed that this allele significantly impairs CHEK2 function during DNA damage response. Our results provide further insight on how the function of such an important cancer gene may be impaired by existing mutations to facilitate tumorigenesis. It also offers a new subject for breast cancer monitoring, prevention and management.
authors.affiliation: Department of Oncology, Changhai Hospital, the Second Military Medical University, Shanghai, China.
authors.forename: N
authors.initials: N
authors.lastname: Wang
authors.affiliation: Key Laboratory of Systems Biology, State Key Laboratory of Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
authors.forename: H
authors.initials: H
authors.lastname: Ding
authors.affiliation: Department of Oncology, Changhai Hospital, the Second Military Medical University, Shanghai, China.|Key Laboratory of Systems Biology, State Key Laboratory of Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
authors.forename: C
authors.initials: C
authors.lastname: Liu
authors.affiliation: Key Laboratory of Systems Biology, State Key Laboratory of Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
authors.forename: X
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Oncology, Changhai Hospital, the Second Military Medical University, Shanghai, China.|Department of Oncology, the 401 hospital of PLA, Qingdao, China.
authors.forename: L
authors.initials: L
authors.lastname: Wei
authors.affiliation: Key Laboratory of Systems Biology, State Key Laboratory of Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
authors.forename: J
authors.initials: J
authors.lastname: Yu
authors.affiliation: Key Laboratory of Systems Biology, State Key Laboratory of Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
authors.forename: M
authors.initials: M
authors.lastname: Liu
authors.affiliation: Department of Oncology, Changhai Hospital, the Second Military Medical University, Shanghai, China.
authors.forename: M
authors.initials: M
authors.lastname: Ying
authors.affiliation: Department of Oncology, Changhai Hospital, the Second Military Medical University, Shanghai, China.
authors.forename: W
authors.initials: W
authors.lastname: Gao
authors.affiliation: Key Laboratory of Systems Biology, State Key Laboratory of Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
authors.forename: H
authors.initials: H
authors.lastname: Jiang
authors.affiliation: Department of Oncology, Changhai Hospital, the Second Military Medical University, Shanghai, China.|Xinhua Cancer Center, Xinhua Hospital affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Wang
mesh_terms: D000328:Adult; D044466:Asian People / Q000235:genetics*; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000235:genetics; D064447:Checkpoint Kinase 2 / Q000235:genetics*; D004252:DNA Mutational Analysis; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D018095:Germ-Line Mutation; D006801:Humans; D016133:Polymerase Chain Reaction; D012307:Risk Factors
chemical_list: D064447:Checkpoint Kinase 2; C578634:CHEK2 protein, human