title: Association of a missense single nucleotide polymorphism, Cys1367Arg of the WRN gene, with the risk of bone and soft tissue sarcomas in Japan.
abstract: Bone and soft tissue sarcomas (BSTSs) are rare malignant tumors of mesenchymal origin. Although BSTSs frequently occur in some hereditary cancer syndromes with germline mutations of DNA repair genes, genetic factors responsible for sporadic cases have not been determined. In the present study we undertook a case-control study and analyzed possible associations between the susceptibility to BSTS and the single nucleotide polymorphisms (SNPs) in DNA repair genes. Genomic DNAs extracted from case and control peripheral blood leukocytes were genotyped by pyrosequencing. For candidate polymorphisms, we chose 50 non-synonymous missense SNPs, which we have previously been identified by resequencing 36 DNA repair genes among the Japanese population. In the first screening, we analyzed 240 cases and 685 controls and selected six SNPs at the significance level of P < 0.1 (Fisher's exact test). The six SNPs were further analyzed in the second genotyping on an additional set of 304 cases and 834 controls. In the joint analysis (the first and second genotyping combined) of 544 cases and 1378 controls, Cys1367Arg of the WRN gene was found to be a protective factor of BSTS (odds ratio = 0.66, 95% confidence interval = 0.49-0.88, P = 0.005). An exploratory subgroup analysis without multiple comparison adjustment suggested that the WRN-Cys1367Arg SNP is associated with soft tissue sarcomas, sarcomas with reciprocal chromosomal translocations and malignant fibrous histiocytoma.
authors.affiliation: Genetics Division, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan.
authors.forename: Robert
authors.initials: R
authors.lastname: Nakayama
authors.forename: Yasunori
authors.initials: Y
authors.lastname: Sato
authors.forename: Mitsuko
authors.initials: M
authors.lastname: Masutani
authors.forename: Hideki
authors.initials: H
authors.lastname: Ogino
authors.forename: Fumihiko
authors.initials: F
authors.lastname: Nakatani
authors.forename: Hirokazu
authors.initials: H
authors.lastname: Chuman
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Beppu
authors.forename: Hideo
authors.initials: H
authors.lastname: Morioka
authors.forename: Hiroo
authors.initials: H
authors.lastname: Yabe
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Hirose
authors.forename: Haruhiko
authors.initials: H
authors.lastname: Sugimura
authors.forename: Hiromi
authors.initials: H
authors.lastname: Sakamoto
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Ohta
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Toyama
authors.forename: Teruhiko
authors.initials: T
authors.lastname: Yoshida
authors.forename: Akira
authors.initials: A
authors.lastname: Kawai
mesh_terms: D000328:Adult; D000483:Alleles; D001120:Arginine / Q000235:genetics*; D001483:Base Sequence; D001859:Bone Neoplasms / Q000235:genetics* / Q000378:metabolism; D016022:Case-Control Studies; D003545:Cysteine / Q000235:genetics*; D005090:Exodeoxyribonucleases / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D007564:Japan; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D020641:Polymorphism, Single Nucleotide; D053484:RecQ Helicases / Q000235:genetics*; D012509:Sarcoma / Q000235:genetics* / Q000378:metabolism; D000071657:Werner Syndrome Helicase
chemical_list: D001120:Arginine; D005090:Exodeoxyribonucleases; D053484:RecQ Helicases; C098785:WRN protein, human; D000071657:Werner Syndrome Helicase; D003545:Cysteine