The CHEK2 gene and inherited breast cancer susceptibility

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 cancerpredisposing 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.

Risk for contralateral breast cancer among carriers of the CHEK2*1100delC mutation in the WECARE Study

“…Ionising radiation is of particular interest because it induces DNA damage, and the protein of the CHEK2 gene is a kinase that plays a role in response to such damage by delaying cell-cycle progression to facilitate DNA repair or even induce cell death (Nevanlinna and Bartek, 2006). The germline mutation 1100delC truncates the CHEK2 protein, thereby abolishing the kinase function (Wu et al, 2001).…”

“…Carriers of the CHEK2*1100delC mutation are hypothesised to have an increased sensitivity to exposures such as radiation therapy (RT) and chemotherapy that cause DNA double-strand breaks, as the CHEK2 regulates cellcycle checkpoint response pathways that respond to such damage (Nevanlinna and Bartek, 2006). We investigated the risk for contralateral breast cancer (CBC) associated with the CHEK2*1100delC germline mutation among approximately 2100 women with breast cancer who were cases and controls in the multicentre Women's Environment, Cancer and Radiation Epidemiology (WECARE) Study (Bernstein et al, 2004).…”

Chk2 is required for optimal mitotic delay in response to irradiation-induced DNA damage incurred in G2 phase

“…Specifically, germ-line mutations in Chk2 are thought to act as low-penetrance predisposition alleles in breast and possibly other cancer types (Nevanlinna and Bartek, 2006), and in a small subset of Li-Fraumeni or Li-Fraumeni-like syndrome kindreds (Bell et al, 1999). In addition, somatic mutations affecting Chk2 occur sporadically at low frequency in various human tumour types (Miller et al, 2002).…”

Breast cancer susceptibility: current knowledge and implications for genetic counselling

“…48 In contrast, CHEK2 1100delC in exon 10, leading to an abolished kinase function, displayed a twofold increased breast cancer risk in female heterozygous mutation carriers. 39 Most recently, the results of a meta-analysis for the assessment of breast cancer risk in CHEK2 1100delC carriers of more than 50 000 cases and controls reported on a 4.8 relative risk of developing breast cancer for heterozygous CHEK2 1100delC mutation carriers with a family history of breast cancer. This leads to an estimated cumulative breast cancer risk of 37% by the age of 70 years.…”