Heterozygous Germ Line hCHK2 Mutations in Li-Fraumeni Syndrome

Abstract

The hCHK2 gene encodes the human homolog of the yeast Cds1 and Rad53 G2 checkpoint kinases, whose activation in response to DNA damage prevents cellular entry into mitosis. Here, it is shown that heterozygous germ line mutations in hCHK2 occur in Li-Fraumeni syndrome, a highly penetrant familial cancer phenotype usually associated with inherited mutations in the TP53 gene. These observations suggest that hCHK2 is a tumor suppressor gene conferring predisposition to sarcoma, breast cancer, and brain tumors, and they also provide a link between the central role of p53 inactivation in human cancer and the well-defined G2 checkpoint in yeast.

CHEK2 variants associate with hereditary prostate cancer

“…Two of the variants, a missense variant 470T4C (I157T) in exon 3 and a frameshift mutation 1100delC in exon 10, were the same as previously reported in patients with Li -Fraumeni syndrome (Bell et al, 1999), breast (Allinen et al, 2001;Vahteristo et al, 2002), and prostate cancer (Dong et al, 2003). The frameshift 1100delC mutation has been proven to result in the loss of kinase activity (Wu et al, 2001), and I157T variant has been shown to be defective in its ability to bind and phosphorylate Cdc25A, one of its normal substrates (Falck et al, 2001).…”

“…These variants were further studied in a set of 1137 samples. In addition, a silent exonic change also reported by Bell et al (1999), an intronic change (not affecting splice site), and a novel missense mutation 1312G4T (D438Y) were observed. D438Y mutation was found only in one proband.…”

“…CHEK2 has been suggested to be a candidate tumour suppressor gene on the basis of the findings that normal function of CHEK2 is involved in DNA-damage respond and some of the mutations identified in Li -Fraumeni families were expected to result in a truncated protein (Bell et al, 1999). Subsequently, these findings were supported by the reports concerning identical and additional mutations in patients with Li -Fraumeni syndrome (Lee et al, 2001) and breast cancer (Meijers-Heijboer et al, 2002;Vahteristo et al, 2002).…”

“…The CHEK2 gene localises to chromosome 22q12.1 and contains 14 exons. 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).…”

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).…”