CHEK2 Germline Variants in Cancer Predisposition: Stalemate Rather than Checkmate

Abstract

Germline alterations in many genes coding for proteins regulating DNA repair and DNA damage response (DDR) to DNA double-strand breaks (DDSB) have been recognized as pathogenic factors in hereditary cancer predisposition. The ATM-CHEK2-p53 axis has been documented as a backbone for DDR and hypothesized as a barrier against cancer initiation. However, although CHK2 kinase coded by the CHEK2 gene expedites the DDR signal, its function in activation of p53-dependent cell cycle arrest is dispensable. CHEK2 mutations rank among the most frequent germline alterations revealed by germline genetic testing for various hereditary cancer predispositions, but their interpretation is not trivial. From the perspective of interpretation of germline CHEK2 variants, we review the current knowledge related to the structure of the CHEK2 gene, the function of CHK2 kinase, and the clinical significance of CHEK2 germline mutations in patients with hereditary breast, prostate, kidney, thyroid, and colon cancers.

Keywords: CHEK2; CHK2; KAP1; WIP1; breast cancer; checkpoint kinase 2; colorectal cancer; germline mutation; hereditary cancer; prostate cancer; renal cancer; thyroid cancer.

Figure 1

The structure of a CHK2 dimer (left; www.rscb.org/structure/3I6W) consists of intertwined monomers (one subunit is colored in gray, and the second subunit is colored in gradient from the N- to C-terminus; missing parts of 3D structures are colored in gray). The same color-coding of the bar (right) indicates the positions of conserved domains (boundaries reflect the crystallographic analysis by Cai et al. [35]). Lollipops depict known sites of covalent modifications, founder mutations, and variants.

Figure 2

In the presence of DNA damage, especially in the presence of DNA double-strand breaks, sensor protein complexes (not shown) activate the apical kinase ATM phosphorylating CHK2. As an effector kinase, CHK2 phosphorylates numerous substrates (described in the text) participating in critical pathways deregulated in the process of tumorigenesis.