Genetic Susceptibility to Colorectal Cancer
Jim Cassidy, Patrick Johnston, Eric Van Cutsem in Colorectal Cancer, 2006
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.
Cutaneous Malignant Melanoma
Dongyou Liu in Handbook of Tumor Syndromes, 2020
The CHK2 (checkpoint kinase 2) gene on chromosome 22q12.1 is 54.6 kb in length and encodes a 543 aa, 60.9 kDa protein (CHK2), which is a serine/threonine-protein kinase required for checkpoint-mediated cell cycle arrest, activation of DNA repair, and apoptosis in response to DNA double-strand breaks. Specifically, CHK2 regulates cell cycle checkpoint arrest through inhibition of CDC25 phosphatase activity and subsequent blockage of cell cycle progression; regulates DNA repair by homologous recombination through phosphorylation of BRCA2, and increased association of RAD51, and regulates apoptosis through the phosphorylation of p53/TP53, MDM4, and PML, leading to increased accumulation and reduced degradation of p53/TP53. Germline mutation in CHK2 exon 10 (1100delC) is observed in patients with malignant melanoma.
Irradiation-induced damage and the DNA damage response
Michael C. Joiner, Albert J. van der Kogel in Basic Clinical Radiobiology, 2018
Cells that are in S phase at the time of irradiation demonstrate a dose-dependent reduction in the rate of DNA synthesis and as a result, the overall length of time that cells need to replicate their DNA substantially increases. This S-phase checkpoint is controlled by two highly related proteins known as CHK1 and CHK2 (Figure 2.6) (1). CHK1 and CHK2 are direct targets of ATR and ATM, respectively, and are activated by phosphorylation. They in turn phosphorylate the proteins CDC25A and CDC25C, which leads to their destruction or inactivation. CDC25A and CDC25C are phosphatases that keep CDK2 in its active dephosphorylated form. As a result, CHK1 and CHK2 activation by ATR and ATM results in an increase in the amount of phosphorylated CDK2 and thus slows progression through the S phase.
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).
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.
Systemic investigations into the molecular features of bilateral breast cancer for diagnostic purposes
Published in Expert Review of Molecular Diagnostics, 2020
Evgeny N. Imyanitov, Ekatherina Sh. Kuligina
The diagnosis of biBC per se is a clear clinical sign of hereditary BC and has to be regarded as a strong call for comprehensive genetic testing. The depth of DNA testing may vary depending on some factors. Some hospitals located in Western countries already exercise next-generation sequencing (NGS) for virtually all BC patients, i.e. they do not require any specific selection criteria for germline DNA multigene testing. This approach is yet not applicable worldwide due to the high cost and some uncertainty regarding the composition of gene panels. It is important to keep in mind that the map of pathogenic alleles is ethnicity-specific. Indeed, the identity of ethnic groups is attributed to the fact that they have their own pool of ancestors; therefore, each possesses a unique spectrum of pathogenic alleles. For example, CHEK2 germline mutations are highly characteristic for Dutch, Finnish, and Slavic people, but they are relatively rare in some other countries [37]. It is unclear, to what extent clinical testing for well-known hereditary BC genes is applicable to ethnic groups which have never been studied with regard to breast-cancer genetics.
Related Knowledge Centers
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- Amino Acid
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- Serine/Threonine-Specific Protein Kinase
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