Breast cancer is the most frequently diagnosed cancer and the second leading cause of cancer death in females worldwide. In China, breast cancers are diagnosed almost 10 years younger than in US and Europe, and higher percentage of patients are diagnosed before age 40 in China than in Caucasians. However, the prevalence of Breast cancer type 1/2 susceptibility protein (BRCA1/2) mutations and reported Checkpoint kinase 2 (CHEK2) germline mutations is low or absent in Chinese population, suggesting that Chinese early onset breast cancer may have other hereditary factors.
In Search for novel genetic alleles associated with early onset breast cancer in China, DING Hongyu and his colleagues from a research group led by Prof. JIANG Hai at the Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences collaborated with Changhai Hospital and identified a novel CHEK2 Y390C mutation in young, high risk breast cancer patients in China. This mutation exists in 12 of 150 patients (8.0%) and only 2 in 250 healthy controls (0.8%). 4 of the Y390C carriers also have family history of breast and/or ovarian cancers, and Y390C carriers tend to develop breast cancer early, before 35 years of age. These facts indicate that the CHEK2 Y390C mutation is probably a novel hereditary factor in Chinese breast cancer patients.
CHEK2 is a central effector of cell’s response to DNA damage. Upon DNA damage, CHEK2 phosphorylates BRCA2, p53 and CDC25 to orchestrate DNA repair and cell cycle arrest, as well as cell death when the damage is beyond repair. 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 mutant also showed impaired p21 and Puma expression after DNA damage. Such deregulated cell cycle checkpoint and apoptotic response may help conserve mutations and therefore contribute to tumourigeneisis. Moreover, cancer cells expressing the CHEK2 Y390C mutant showed resistance to important chemotherapy drugs, such as cisplatin and doxorubicin. This study offers a new subject for breast cancer prevention, suggesting the need for early monitoring of breast cancer in the 0.8% Y390C carriers in Chinese population. It also suggests that novel therapeutic regimens should be considered for such breast cancer patients in clinics.
This study entitled “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” was published online in Oncogene on Jan 26, 2015.
This work was done in collaboration with Prof. WANG Yajie of Changhai Hospital, and supported by grants from the major scientific research project, Natural Science Foundation of the People’s Republic of China, and Shanghai Science and Technology Committee.
CONTACT:
JIANG Hai, Principal Investigator
Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences
Shanghai 200031, China.
Email: hai@sibcb.ac.cn
Phone: +86-21-54921190
Fig. This picture illustrated that CHEK2 Y390C mutation leads to DNA repair dysfunction, deregulated cell cycle checkpoint and apoptotic response may help conserve mutations and therefore contribute to tumourigeneisis.(Image provided by Prof. JIANG Hai’s group)
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