CHEK2, also known as checkpoint kinase 2, is a key gene in the DNA damage response (DDR) pathway. The ATM-CHEK2-p53 axis serves as a backbone for DDR, and although CHK2 kinase, coded by the CHEK2 gene, expedites the DDR signal, its function in activating p53-dependent cell cycle arrest is dispensable [2].

Germline alterations in CHEK2 are recognized as pathogenic factors in hereditary cancer predisposition. Protein-truncating variants in CHEK2 are associated with a moderately increased risk of breast cancer. For missense variants of uncertain significance (VUS), functional assays have been used to classify them, and there is an association between impaired protein function and increased breast cancer risk. Functional analyses suggest that damaging CHEK2 missense VUS may carry a similar breast cancer risk to protein-truncating variants [1]. CHEK2 mutations are also among the most frequent germline alterations in various hereditary cancer predispositions, including breast, prostate, kidney, thyroid, and colon cancers [2]. In hematopoietic malignancies, germline CHEK2 variants predispose to a range of myeloid malignancies, such as myeloproliferative neoplasms, myelodysplastic syndromes, and chronic lymphocytic leukemia [3].

In conclusion, CHEK2 plays a crucial role in the DNA damage response and is significantly associated with an increased risk of multiple cancers, including breast, colorectal, prostate, and hematopoietic malignancies. Functional studies of CHEK2 variants, especially through in vivo models, are essential for understanding the associated cancer risks and guiding personalized cancer prevention and management strategies.

References:

1. Boonen, Rick A C M, Vreeswijk, Maaike P G, van Attikum, Haico. 2022. CHEK2 variants: linking functional impact to cancer risk. In Trends in cancer, 8, 759-770. doi:10.1016/j.trecan.2022.04.009. https://pubmed.ncbi.nlm.nih.gov/35643632/

2. Stolarova, Lenka, Kleiblova, Petra, Janatova, Marketa, Macurek, Libor, Kleibl, Zdenek. 2020. CHEK2 Germline Variants in Cancer Predisposition: Stalemate Rather than Checkmate. In Cells, 9, . doi:10.3390/cells9122675. https://pubmed.ncbi.nlm.nih.gov/33322746/

3. Stubbins, Ryan J, Korotev, Sophia, Godley, Lucy A. 2022. Germline CHEK2 and ATM Variants in Myeloid and Other Hematopoietic Malignancies. In Current hematologic malignancy reports, 17, 94-104. doi:10.1007/s11899-022-00663-7. https://pubmed.ncbi.nlm.nih.gov/35674998/