title: Homozygous inactivation ofCHEK2is linked to a familial case of multiple primary lung cancer with accompanying cancers in other organs.
abstract: In clinical practice, there are a number of cancer patients with clear family histories, but the patients lack mutations in known familial cancer syndrome genes. Recent advances in genomic technologies have enhanced the possibility of identifying causative genes in such cases. Two siblings, an elder sister and a younger brother, were found to have multiple primary lung cancers at the age of 60. The former subsequently developed breast cancer and had a history of uterine myoma. The latter had initially developed prostate cancer at the age of 59 and had a history of colon cancer. Single-nucleotide polymorphism (SNP) genotyping revealed that ∼10% of the genomes were homozygous in both patients. Exome sequencing revealed nonsynonymous mutations in five genes in the runs of homozygosity:CHEK2,FCGRT,INPP5J,MYO18B, andSFI1. Evolutionary conservation of primary protein structures suggested the functional importance of theCHEK2mutation, p.R474C. This mutation altered the tertiary structure of CHK2 by disrupting the salt bridge between p.R474 and p.E394. No such structural changes were observed with the other mutated genes. Subsequent cell-based transfection analysis revealed that CHK2 p.R474C was unstable and scarcely activated. We concluded that the homozygousCHEK2variant was contributory in this case of familial cancer. Although homozygous inactivation ofCHEK2in mice led to cancers in multiple organs, accumulation of additional human cases is needed to establish its pathogenic role in humans.
authors.affiliation: Department of Molecular and Medical Genetics, Research Institute, Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka 537-8511, Japan.
authors.forename: Yoji
authors.initials: Y
authors.lastname: Kukita
authors.affiliation: Department of General Thoracic Surgery, Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka 537-8511, Japan.
authors.forename: Jiro
authors.initials: J
authors.lastname: Okami
authors.affiliation: Department of Tumor Cell Biology, Graduate School of Biological Sciences, Nara Institute of Science and Technology, Ikoma, Nara 630-0101, Japan.
authors.forename: Noriko
authors.initials: N
authors.lastname: Yoneda-Kato
authors.affiliation: Department of Tumor Cell Biology, Graduate School of Biological Sciences, Nara Institute of Science and Technology, Ikoma, Nara 630-0101, Japan.
authors.forename: Ikuko
authors.initials: I
authors.lastname: Nakamae
authors.affiliation: Institute for Protein Research, Osaka University, Suita, Osaka 565-0871, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Kawabata
authors.affiliation: Department of General Thoracic Surgery, Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka 537-8511, Japan.
authors.forename: Masahiko
authors.initials: M
authors.lastname: Higashiyama
authors.affiliation: Department of Tumor Cell Biology, Graduate School of Biological Sciences, Nara Institute of Science and Technology, Ikoma, Nara 630-0101, Japan.
authors.forename: Junya
authors.initials: J
authors.lastname: Kato
authors.affiliation: Department of General Thoracic Surgery, Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka 537-8511, Japan.
authors.forename: Ken
authors.initials: K
authors.lastname: Kodama
authors.affiliation: Department of Molecular and Medical Genetics, Research Institute, Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka 537-8511, Japan.
authors.forename: Kikuya
authors.initials: K
authors.lastname: Kato
mesh_terms: D000328:Adult; D001943:Breast Neoplasms / Q000235:genetics; D064447:Checkpoint Kinase 2 / Q000235:genetics* / Q000378:metabolism; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics; D006720:Homozygote; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics*; D008297:Male; D009154:Mutation; D009386:Neoplastic Syndromes, Hereditary / Q000235:genetics; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D000073359:Exome Sequencing / Q000379:methods
chemical_list: D064447:Checkpoint Kinase 2; C578634:CHEK2 protein, human
keywords: neoplasm of the lung