Mutations of the CHK2 gene are found in some osteosarcomas, but are rare in breast, lung, and ovarian tumors

Abstract

Checkpoint genes, activated in response to DNA damage and other stresses, are frequently targeted for alteration in cancer. Checkpoint kinase 2 (CHK2, CDS1, RAD53) is activated by ataxia telangiectasia mutated (ATM) in response to gamma irradiation. Activated CHK2 stabilizes TP53, and acts on other cell cycle and stress regulators. These findings place CHK2 in the middle of a pathway frequently targeted in cancer. Because of this, and the observation that CHK2 mutations are inherited in some Li-Fraumeni cancer syndrome families, we decided to examine the role of CHK2 mutations in sporadic cancers. Exploiting the genomic sequence of chromosome 22, we looked for mutations in the exons and intron junctions of the CHK2 gene in DNA samples from 170 patients (57 osteosarcomas, 25 other sarcomas, 35 nonsmall-cell lung, 20 ovarian, and 33 breast cancers). Missense mutations affecting the forkhead and kinase domains were detected in four osteosarcomas and in one ovarian and one lung cancer. These findings of CHK2 gene mutations are consistent with osteosarcoma being a defining tumor of Li-Fraumeni syndrome. The occurrence of CHK2 mutations in sporadic cancers emphasizes the importance of the stress pathway which includes TP53.

CHEK2 variants associate with hereditary prostate cancer

“…Originally, germline mutations in CHEK2 gene were reported in Li -Fraumeni syndrome and breast cancer (Bell et al, 1999;Allinen et al, 2001). Rare somatic mutations in CHEK2 have also been identified in a number of cancer types, including lung and ovarian cancers and osteosarcomas (Miller et al, 2002). These results together with the normal function of CHEK2 in DNA damage checkpoints are consistent with the idea that CHEK2 might act as a tumour suppressor gene.…”

Frequent deletion of the CDKN2A locus in chordoma: analysis of chromosomal imbalances using array comparative genomic hybridisation

“…Moreover, the CHEK2 gene is located in a region on chromosome 22, which was lost in 13 of the cases. CHEK2 is considered a tumour suppressor and mutations of CHEK2 have been implicated in the pathogenesis of various types of familial as well as sporadic tumours, for example, the malignant bone tumour osteosarcoma (Miller et al, 2002). In the minimally deleted region on chromosome 11, which was lost in eight cases, ATM is located.…”

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). At present, the molecular basis for tumour suppression by Chk2 in humans is unclear.…”