Genome-wide analyses to identify genes involved in gastric cancer

全基因组分析以确定与胃癌有关的基因

基本信息

批准号：
12212002
负责人：
SASAZUKI Tekehiko
金额：
$ 168.9万
依托单位：
International Medical Center of Japan (2001-2004)Kyushu University (2000)
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research on Priority Areas
财政年份：
2000
资助国家：
日本
起止时间：
2000 至 2004
项目状态：
已结题

项目摘要

Identification of genes predisposing to cancer is an essential step toward a better understanding of molecular events underlying tumorigenesis and for a more pertinent clinical management of patients. To search for regions of human genome containing gastric cancer-susceptibility genes, we did a genome-wide screen in 170 affected sibpairs using 392 microsatellite markers spanning the entire genome. Nonparametric linkage analysis of the entire data set identified four regions, Ip32, 2q33-q35, I1p13-p14 and 21q21, showing evidence for linkage with multipoint LOD score 【greater than or equal】1.18 (P 【less than or equal】0.01). The signal of linkage to 2q33-q35 increased to a multipoint and two-point LOD score 3.61 and 2.93, respectively in an analysis of a subgroup with proximal gastric cancer. Since chromosome 21q have been reported to show LOH frequently in gastric cancer in Japanese, we further analyzed 70 expressing genes on this candidate chromosome using sporadic cases by marker SNPs. We found unknown but the structure is related to HSP70 which is shown to be involved in carcinogenesis of several types of cancer. In addition, we genotyped SNPs in 41 candidate genes which have been suggested to be related to gastric carcinogenesis. We found significant association between ATM and female cases. According to the threshold theory of a multifactorial trait, heritability of female cases of gastric cancer might be higher than that of male cases. Taken together, STCH and ATM might be important target genes of further analyses to elucidate molecular mechanisms of gastric cancer pathogenesis.

识别易患癌症的基因是更好地了解肿瘤发生的分子事件和对患者进行更相关的临床管理的重要一步。为了寻找含有胃癌易感基因的人类基因组区域，我们进行了全基因组筛选。在 170 个受影响的同胞中，使用跨越整个基因组的 392 个微卫星标记对整个数据集进行非参数连锁分析，确定了四个区域：Ip32、2q33-q35、 I1p13-p14和21q21，显示多点LOD评分【大于或等于】1.18（P【小于或等于】0.01）连锁的证据，与2q33-q35的连锁信号增加至多点和两点LOD评分。自从 21q 染色体被报道以来，在对近端胃癌亚组的分析中分别为 3.61 和 2.93。在日本胃癌中经常显示 LOH，我们通过标记 SNP 分析了该候选染色体上的 70 个表达基因，我们发现未知但结构与 HSP70 相关，HSP70 被证明进一步参与多种癌症的致癌作用。此外，我们对 41 个被认为与胃癌发生相关的候选基因中的 SNP 进行了基因分型，根据多因素性状遗传性的阈值理论，我们发现 ATM 与女性病例之间存在显着关联。女性胃癌发病率可能高于男性，STCH和ATM可能是进一步分析阐明胃癌发病分子机制的重要靶基因。