Prognostic Significance of CHEK2 Mutation in Progression of Breast Cancer

Narges Ansari, MD; Saeid Shahrabi, PhD; Abbas Khosravi, PhD; Reza Shirzad, Msc; Hadi Rezaeean, Msc


Lab Med. 2019;50(3):e36-e41. 

In This Article

Abstract and Introduction


Breast cancer (BC) is one of the most common cancers among women; genetic mutations reflect the development of this disease. Mutations in cell signaling factors can be the main cause of BC development. In this study, we focused on mutations in checkpoint kinase 2 (CHEK2) and their impact as a prognostic factor in the pathogenesis of BC.

CHEK2 is controlled in cell signaling pathways through the influence of upstream genes. Also, several downstream genes are regulated by CHEK2. In addition, mutations in CHEK2 lead to resistance of BC cells to chemotherapy and metastasis of cancer cells to other parts of the body.

Finally, detection of mutations in CHEK2 can be used as a prognostic factor for patient response to treatment and for targeting downstream molecules of CHEK2 that are involved in the proliferation of breast tumor cells. Mutations such as c.1100delC and I157T can distinguish which patients are susceptible to metastasis.


Breast cancer (BC) is the most common type of cancer among women; changing habits and lifestyles have resulted in an increase in the incidence of this cancer during the past 50 years.[1] Several factors are involved in the incidence of BC, including genetic and epigenetic changes. However, epidemiologic evidence[2] suggests that family history is one of the main factors that predispose patients to BC. Most cases of BC are sporadic; however, the inheritance of certain mutated genes plays a role in this disease. Although the main genes implicated in family incidence of BC have not been identified, dysfunction of tumor suppressors is one of the main factors of genetic disorder in BC incidence.[4] BRAC1, BRCA2, TP53, and checkpoint kinase 2 (CHEK2) are among the genes involved in this disease. DNA-repair genes exhibit high levels of genomic instability in BC and are associated with deletion/insertion of chromosome segments, chromosomal abnormalities, and induction of proliferation.[5,6] These DNA changes are a function of alterations in molecular pathways regulating the proliferation of cells, differentiation, apoptosis, and DNA repair.

Following the process of replication, cell DNA is subject to breaks that are corrected by a series of factors such as ataxia telangiectasia mutated (ATM)/ataxia-telangiectasia and Rad3 related (ATR), TP53, CHEK2, nibrin (NBS1), breast cancer gene 1 (BRCA1), and breast cancer gene 2 (BRCA2) through pausing of the cell cycle; impaired function of these factors is associated with the incidence of BC.[7] However, DNA changes are known as risk factors in only 30% of BC cases; the risk factors are unknown in most cases.[8] Screening tests for 2 genes that predispose patients to BC, namely, BRCA1 and BRCA2, have become available since the discovery of those genes.[9] However, these genes were not responsible for all cases of BC, and it was expected that scientists would discover new genes that were also responsible for BC.[10] Therefore, CHEK2, ATM, PALB2, BRIP, and NCOA3 also were identified as genes that predispose patients to BC.[11,12] However, it has been shown[10] that mutations in CHEK2can lead to the development of cancer in susceptible individuals, due to the activation or inactivation of factors involved in the signaling pathway. Hence, we evaluate the mutations in domains of CHEK2 and their impact on progression of BC.