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

CHECK2:c.1100delC Mutation

Similar to Y390C mutation, CHECK2:c.1100delC occurs in the serine/threonine KD.[26] CHEK2 regulates the cell cycle in the cell-signaling pathway and phosphorylates several downstream factors, including BRCA1 and BRCA2.[46] BRCA is involved in the regulation of a number of processes, including apoptosis and the cell cycle, in normal conditions. For this purpose, the transcription of genes such as FADD, CKS1B, and MEIS2 is regulated by BRCA; those genes are involved in the cell cycle, apoptosis, and transcriptional regulation, respectively.[47] In BC, CHECK2:c.1100delC mutation prevents the phosphorylation of BRCA, and thus, the absence of damaged DNA repair in cells leads to the formation of breast tumor cells, and apoptosis inhibition of these cells (having damaged genomes) leads to sustained cell growth that spreads in the body.[48,49] It has been shown[50] that BRCA1 has an inhibitory effect on estrogen receptor (ER), which is involved in the proliferation of breast tumor cells due to growth factors and expression regulation of some genes. Therefore, the inactivation of BRCA1 because of mutation in CHEK2 can result in the proliferation of breast tumor cells by ER. Also, it has been determined[51] that the mutation in CHEK2 and the inactivation of BRCA1 lead to the proliferation of breast tumor cells and their resistance to chemotherapy due to increased expression of CDK4/-6.

In contrast, poly (adenosine diphosphate–ribose) polymerase (PARP) and BRCAare involved in DNA repair in normal cells. However, in breast tumor cells, given the inactivation of BRCA due to c.1100delC mutation in CHEK2 to prevent the survival and proliferation of breast tumor cells by PARP, anti-PARP antibody is used to cause apoptosis of these cells.[52,53] Therefore, we state that c.1100delC mutation in CHEK2 is able to disrupt the apoptosis of BC cells, which causes their unchecked proliferation. Hence, the occurrence of this mutation can be accompanied with poor prognosis.