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Li−Fraumeni Syndrome
Published in Dongyou Liu, Handbook of Tumor Syndromes, 2020
The CHEK2 (checkpoint kinase 2) gene on chromosome 22q12.1 is 54 kb in length with 14 exons and encodes a 543 aa, 60.9 kDa serine/threonine-protein kinase involved in checkpoint-mediated cell cycle arrest, activation of DNA repair (through phosphorylation of BRCA2, enhancing the association of RAD51 with chromatin) and apoptosis (through phosphorylation of p53/TP53, MDM4, and PML) in response to DNA double-strand breaks, as well as negative regulation of cell cycle progression. Mutations in CHEK2 are implicated in LFL, and also confer susceptibility to sarcoma, breast cancer, and brain tumor. However, carriers of CHEK2 mutations have lower incidence of cancer in their families than those of TP53 mutations [12–14].
Malignant Neoplasms of the Colon
Published in Philip H. Gordon, Santhat Nivatvongs, Lee E. Smith, Scott Thorn Barrows, Carla Gunn, Gregory Blew, David Ehlert, Craig Kiefer, Kim Martens, Neoplasms of the Colon, Rectum, and Anus, 2007
Evidence demonstrates that patients in families with breast and colon carcinoma (hereditary breast and colon carcinoma) may have a carcinoma family syndrome caused by CHEK2 1100delC mutations that are present in a subset of the families (79). The CHECK2 mutation is incompletely penetrant.
Genetic Susceptibility to Colorectal Cancer
Published in Jim Cassidy, Patrick Johnston, Eric Van Cutsem, Colorectal Cancer, 2006
Rebecca A. Barnetson, Malcolm G. Dunlop
Cell cycle checkpoint kinase 2 (CHEK2) is involved in cellular responses to DNA damage that culminate in cell cycle arrest, apoptosis, and/or DNA repair. A variant in CHEK2, 1100delC, has been shown to be causally involved in a small proportion of breast cancer families and acts as a lowpenetrance susceptibility allele for breast cancer, with a twofold increased breast cancer risk for carriers. In some breast cancer families there is an excess of colorectal cancer and so by inference, CHEK2 has been proposed as a colorectal cancer susceptibility gene (160). However, although descriptive studies in breast and colorectal cancer families seem to indicate a common genetic etiology, namely, the CHEK2 1100delC allele, the largest association study to date has failed to show any convincing effect (161). A recent study has suggested an effect in certain risk subgroups (162), but again large studies are clearly required to determine definitively whether CHEK2 variants confer any excess risk of colorectal cancer, the level of any associated risk, and the overall contribution of such alleles to colorectal cancer disease burden. In short, the role of CHEK2 in colorectal cancer susceptibility remains unresolved.
Poly (ADP-ribose) polymerase inhibitors (PARPi) for advanced malignancies with multiple DNA-repair genetic aberrations
Published in Expert Review of Anticancer Therapy, 2022
Jian Hu, Peihe Liang, Dachun Jin, Runze Fan, Xiaodu Xie, Chuan Liu, Qing Jiang, Liang Gao
In a single-arm, open label, phase 1 trial, the effect of DNA-repair gene mutation on the response to the combination of PARPi and chemoradiotherapy was assessed [11]. In this trial, one patient harboring alterations in CHEK2 and MLH1 had a significant response to the combination therapy, with a PFS and overall survival (OS) of 20 and 24 months, respectively. Furthermore, this patient was sufficiently downstaged during therapy and subsequently experienced a margin-negative resection. Notably, the impairment of DNA repair caused by deleterious mutations resulted in a higher risk of pathogenic changes in the genomic structure, as well as genomic instability, leading to an increase in the tumor mutational burden (TMB) [18,19]. This patient had a higher TMB of 23.4 compared with a mean of 5.6 in the DNA-repair genetic mutations subgroup.
Cell cycle kinase CHEK2 in macrophages alleviates the inflammatory response to Staphylococcus aureus-induced pneumonia
Published in Experimental Lung Research, 2022
Fei Xie, Ruidong Chen, Jie Zhao, Chunyan Xu, Chunxiang Zan, Bin Yue, Wenqiu Tian, Wenxia Yi
As a checkpoint kinase and tumor suppressor, Chek2 can regulate cell arrest and have the ability to prevent cells from dividing too rapidly or in an uncontrolled manner.24,25 While to our surprise, Chek2 inhibition does not significantly affect the survival or proliferation of macrophages. At the same time, Chek2 inhibition enhances the sensitivity of S. aureus-mediated pneumonia in mice with the up-regulated NF-κB pathway and inflammatory response. Scientists have also found that some people with a Chek2 mutation will develop Li-Fraumeni syndrome, a rare, autosomal dominant, hereditary disorder, which predisposes carriers to breast cancer and ovarian cancer.26 Whether Chek2 mutation is associated with the prevalence of S. aureus-mediated pneumonia in clinics needs further investigation.
Ras-Mediated Activation of NF-κB and DNA Damage Response in Carcinogenesis
Published in Cancer Investigation, 2020
Few other honorable mentions of the vital DNA damage and repair pathways include Bloom syndrome protein (BLM), that in humans is regulated by BLM gene and possess both DNA-stimulated ATPase and ATP-dependent DNA helicase activities. Mutations may delete or modify the helicase motifs and may incapacitate its helicase function and is somatically altered which becomes the hallmark of a number of cancer types including colorectal cancer (195–198). Similarly Checkpoint kinase 2 (CHEK2) is another tumor suppressor gene that gives the protein CHK2 and regulates genome instability. It is needed in homology directed repair by regulating cell cycle checkpoints in such a way that DNA double strand breaks get correctly repaired. The erroneous activity of CHEK2 is linked with cell cycle checkpoint errors and incorrect DNA repair and tumor development (199–201) (Figure 8).