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The CHEK2 gene and inherited breast cancer susceptibility
1Department of Obstetrics and Gynecology, Helsinki University Central Hospital, Helsinki, Finland. heli.nevanlinna@hus.fi
Abstract:
Checkpoint kinase 2 (CHEK2, Chk2) emerges as an important signal transducer of cellular responses to DNA damage and a candidate tumor suppressor whose defects contribute to molecular pathogenesis of diverse types of human malignancies, both sporadic and hereditary. Here, we briefly outline the molecular properties, regulation and physiological role of CHEK2, and review in more detail its defects that predispose to tumors, with particular emphasis on familial breast cancer. The frequency, penetrance and epidemiological as well as clinical significance of the two most studied breast cancer-predisposing variants of the CHEK2 gene, 1100delC and I157T, are highlighted in more depth, and additional CHEK2 mutations and their cancer relevance are discussed as well. These recent findings are considered also from a broader perspective of CHEK2 as the integral component of the ataxia telangiectasia-mutated-CHEK2-p53 pathway within the genome integrity maintenance system and a barrier against tumor progression. Finally, the potential value of information about the CHEK2 status in family counseling and optimizition of individualized cancer treatment is discussed.
Insights
Defects in Checkpoint kinase 2 (CHEK2) are linked to various cancers, particularly familial breast cancer. Understanding CHEK2 variants aids in cancer risk assessment and personalized treatment strategies.
Area of Science:
- Molecular Biology
- Genetics
- Oncology
Background:
- Checkpoint kinase 2 (CHEK2) is a key signal transducer in DNA damage response.
- CHEK2 acts as a tumor suppressor, with defects contributing to human malignancies.
- CHEK2 is part of the critical ATM-CHEK2-p53 pathway for genome integrity.
Purpose of the Study:
- To review the molecular properties, regulation, and physiological role of CHEK2.
- To detail CHEK2 defects predisposing to tumors, focusing on familial breast cancer.
- To discuss the clinical significance of CHEK2 variants and their role in cancer development.
Main Methods:
- Literature review of CHEK2 gene function and mutations.
- Analysis of epidemiological and clinical data for CHEK2 variants (1100delC, I157T).
- Discussion of CHEK2's role in the DNA damage response pathway.
Main Results:
- CHEK2 defects are implicated in both sporadic and hereditary cancers.
- Specific CHEK2 variants (1100delC, I157T) are associated with increased breast cancer risk.
- CHEK2 mutations impact the genome integrity maintenance system and tumor progression.
Conclusions:
- CHEK2 is a crucial barrier against tumor progression.
- Information on CHEK2 status has potential value in family cancer counseling.
- CHEK2 status can aid in optimizing individualized cancer treatment strategies.
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