Study: JGAS00000000057




TitleHomozygous inactivation of CHEK2 is linked to a familial case of multiple primary lung cancer with accompanying cancers in other organs
AbstractIn clinical practice, there are a number of cancer patients with clear family histories, but not belonging to existing familial malignancies. 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 myoma uteri. The latter had initially developed prostate cancer at the age of 59, and had a history of colon cancer. SNP genotyping revealed that approximately 10% of the genomes were homozygous in both patients. Exome sequencing revealed non-synonymous mutations in four genes in the runs of homozygosity: CHEK2, FCGRT, INPP5J, and SFI1. Evolutionary conservation of primary protein structures suggested the functional importance of the CHEK2 mutation, R474C. This mutation altered the tertiary structure of CHK2 by disrupting the salt bridge between R474 and E394. No such structural changes were observed with the other three mutated genes. Subsequent cell-based transfection analysis revealed that CHK2 R474C was unstable and scarcely activated. We concluded that CHEK2 is a causative gene in this case of familial cancer. Although homozygous inactivation of CHEK2 in mice led to cancers in multiple organs, accumulation of additional human cases is needed to establish its pathogenic role in humans.
Study Type 1
Study TypeCase Set
Study Type 2
Study TypeExome Sequencing
Study Type 3
Study TypeOther
New Study TypeSNP genotyping


TitleGrant-in-Aid for Scientific Research (C)
AgencyJapan Society for The Promotion of Science (JSPS)
Grant ID25430180


PubMed ID27900359
Publication Statuspublished

Study Attribute

NBDC Numberhum0061
Registration date2016-05-25
Submitting organizationOsaka Medical Center for Cancer and Cardiovascular Diseases
Principal InvestigatorKikuya Kato
Molecular Data TypeWhole Exome Sequencing
PlatformHiSeq 2000
Molecular Data TypeSNP Array
Primary PhenotypeCancer
Accession Title Dataset type Data objects Policy
JGAD00000000057 SNP genotyping data of 2 siblings with multiple primary lung cancer Genotyping by array 2 JGAP00000000001