title: 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.
authors.affiliation: Division of Hematology/Oncology, Department of Medicine, UCLA School of Medicine, Cedars-Sinai Research Institute, 8700 Beverly Blvd., Davis 5019, Los Angeles, CA 90048, USA. millerc@ucla.edu
authors.forename: Carl W
authors.initials: CW
authors.lastname: Miller
authors.forename: Takayuki
authors.initials: T
authors.lastname: Ikezoe
authors.forename: Utz
authors.initials: U
authors.lastname: Krug
authors.forename: Wolf-K
authors.initials: WK
authors.lastname: Hofmann
authors.forename: Sigal
authors.initials: S
authors.lastname: Tavor
authors.forename: Vijaya
authors.initials: V
authors.lastname: Vegesna
authors.forename: Kunihiro
authors.initials: K
authors.lastname: Tsukasaki
authors.forename: Seisho
authors.initials: S
authors.lastname: Takeuchi
authors.forename: H Phillip
authors.initials: HP
authors.lastname: Koeffler
mesh_terms: D019943:Amino Acid Substitution / Q000235:genetics; D001943:Breast Neoplasms / Q000201:enzymology / Q000235:genetics*; D002289:Carcinoma, Non-Small-Cell Lung / Q000201:enzymology / Q000235:genetics*; D064447:Checkpoint Kinase 2; D004261:DNA Replication / Q000235:genetics; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000201:enzymology / Q000235:genetics*; D009154:Mutation / Q000235:genetics*; D020125:Mutation, Missense / Q000235:genetics; D012516:Osteosarcoma / Q000201:enzymology / Q000235:genetics*; D010051:Ovarian Neoplasms / Q000201:enzymology / Q000235:genetics*; D017354:Point Mutation / Q000235:genetics; D011494:Protein Kinases / Q000235:genetics* / Q000502:physiology; D017346:Protein Serine-Threonine Kinases
chemical_list: D011494:Protein Kinases; D064447:Checkpoint Kinase 2; C578634:CHEK2 protein, human; D017346:Protein Serine-Threonine Kinases