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.

Genomic analysis reveals frequent TRAF7 mutations in intraneural perineuriomas

“…18,19 Of note, 1 of our cases with macro chromosomal deletion/duplication (Case 10) also has CHEK2 p.Y390C, a variant associated with lung cancer. 20 That patient is without malignancy and is the oldest onset in our cohort. No patients had malignant transformation.…”

Molecular Biology In Young Women With Breast Cancer: From Tumor Gene Expression To Dna Mutations

“…The most studied germline mutation, c.1100delC, significantly augments the risk of early-onset and familial BC 91 . Other mutations have been reported in very young Pakistani women (p.P92R, p.R406C, p.H371Y, and p.D438Y) 92,93 , and in Chinese very young women (1169A > G) 94 .…”

Study on the Mechanism of Cell Cycle Checkpoint Kinase 2 (CHEK2) Gene Dysfunction in Chemotherapeutic Drug Resistance of Triple Negative Breast Cancer Cells

“…Our previous studies [ 7 – 9 ] have been carried out on multiple related genes of the DNA damage pathway, and we found that CHEK2 Y390C mutation inhibited the efficacy of CHEK2 in response to DNA damage agents, indicating Y390C mutation significantly impaired CHEK2 function during DNA damage response. Based on the previous studies, we propose the following hypothesis: CHEK2 is involved in the regulation of the effect of chemotherapeutic drugs on human breast cancer cells, and CHEK2 mutations may cause drug resistance to chemotherapy agents in breast cancer cells.…”

“…Subsequently, CHEK2 WT (wild-type CHEK2) or CHEK2 Y390C (CHEK2 Y390C mutation) was re-expressed in the CHEK2 knockdown MDA-MB-231 cells as previously described [ 7 ]. Cells transfected with vector control were used as the control group.…”