Nakayama Robert, Sato Yasunori, Masutani Mitsuko, Ogino Hideki, Nakatani Fumihiko, Chuman Hirokazu, Beppu Yasuo, Morioka Hideo, Yabe Hiroo, Hirose Hiroshi, Sugimura Haruhiko, Sakamoto Hiromi, Ohta Tsutomu, Toyama Yoshiaki, Yoshida Teruhiko, Kawai Akira
Genetics Division, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan.
Cancer Sci. 2008 Feb;99(2):333-9. doi: 10.1111/j.1349-7006.2007.00692.x.
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.
骨肉瘤和软组织肉瘤（BSTSs）是罕见的间充质来源恶性肿瘤。尽管BSTSs常发生于一些具有DNA修复基因种系突变的遗传性癌症综合征中，但散发性病例的遗传因素尚未确定。在本研究中，我们进行了一项病例对照研究，分析了BSTS易感性与DNA修复基因单核苷酸多态性（SNPs）之间的可能关联。通过焦磷酸测序对从病例和对照外周血白细胞中提取的基因组DNA进行基因分型。对于候选多态性，我们选择了50个非同义错义SNPs，这些是我们之前通过对日本人群中的36个DNA修复基因进行重测序而鉴定出来的。在首次筛查中，我们分析了240例病例和685例对照，并在P<0.1（Fisher精确检验）的显著水平下选择了6个SNPs。在对另外304例病例和834例对照进行的第二次基因分型中，对这6个SNPs进行了进一步分析。在对544例病例和1378例对照的联合分析（首次和第二次基因分型合并）中，发现WRN基因的Cys1367Arg是BSTS的一个保护因素（优势比=0.66，95%置信区间=0.49-0.88，P=0.005）。一项未经多重比较调整的探索性子组分析表明，WRN-Cys1367Arg SNP与软组织肉瘤、具有相互染色体易位的肉瘤以及恶性纤维组织细胞瘤相关。
