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

Checkpoint genes, activated in response to DNA damage and other stresses, a re frequently targeted for alteration in cancer. Checkpoint kinase 2 (CHK2, CDS1, RAD53) is activated by ataxia telangiectasia mutated (ATM) in respon se to gamma irradiation. Activated CHK2 stabilizes TP53, and acts on other cell cycle and stress regulators. These findings place CHK2 in the middle o f a pathway frequently targeted in cancer. Because of this, and the observa tion that CHK2 mutations are inherited in some Li-Fraumeni cancer syndrome families, we decided to examine the role of CHK2 mutations in sporadic canc ers. Exploiting the genomic sequence of chromosome 22, we looked for mutati ons 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, 2 0 ovarian, and 33 breast cancers). Missense mutations affecting the forkhea d 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 occur rence of CHK2 mutations in sporadic cancers emphasizes the importance of th e stress pathway which includes TP53. (C) 2002 Wiley-Liss, Inc.