Studies on the Genetic Factors Influencing Predisposition to Cancer in High-risk Groups.

影响高危人群癌症易感性的遗传因素的研究。

• 批准号: 12213084
• 负责人: SHIMIZU Kenji
• 金额: $ 34.88万
• 依托单位: OKAYAMA UNIVERSITY
• 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
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-12213084/
• 关键词: Cancer-predisposition; Genetic Polymorphism; Cancer-related Genes; missense-SNP; Case-control Study; Odds Ratio; Cumulative Odds Ratio; 発がん高リスク遺伝子; ミスセンス1塩基多型; ms-SNP; DNA修復遺伝子; ミスセンス単塩基多型; 発がん高リスク遺伝; がん体質遺伝子; 発がん高リスク遺伝子多型; 遺伝的素因; ミスセンス単塩基

To explore the molecular nature of "Cancer Predisposition", we have performed comprehensive analyses on the differential distribution of missense-single nucleotide polymorphism (ms-SNP) of cancer-related genes between cases and healthy controls. Since 1999, we have done case-control studies on 103 ms-SNP in 335 cancer cases and 110 healthy controls and we found that 22 SNP significantly associated with cancer-risk including lung adenocarcinoma (LAD), lung squamous cell carcinoma (LSC), head and neck cancer (HNSC), colorectal cancer (CRC) and esophageal cancer (ECC). These risk-related 22 SNP included 3 SNP previously reported (in genes ADH1B, ALDH2 and TP53) and 19 SNP thus far undescribed in the literature and distributed among 20 genes consisting of 6 DNA-repair genes, 5 tumor suppressor genes, 5 chromosome-segregation genes and 4 others. Of these 22 SNP, 16 were of high-risk (SNP-H) with odds ratio (OR) 1.87-18.0 and 6 were protective SNP (SNP-L) with OR 0.18-0.54. In respect to eac … More h cancer-type, number of the affecting SNP including common ones were follows; LAD (8 SNP-H and 4 SNP-L), LSC (7 SNP-H and 2 SNP-L), HNSC (3 SNP-H and 2 SNP-L), CRC (3 SNP-H and 3 SNP-L) and ECC (2 SNP-H). Because all analyses were performed with the same specimens, it was possible to examine individually the perfect overlapping of the genotype at risk on these 22 SNP. A cumulative odds ratio (COR) was calculated for each individual by multiplying OR of their all overlapping SNP at risk. As to the LAD risk calculated by 10 SNP, the frequency of individuals showing COR > 4.0 was 4.5% in healthy controls, whereas 39% in LAD patients (P = 5 x 10^<-9>, OR = 13.4 ). Similarly, for the LSC risk based on 7 SNP, the frequency of persons with COR > 4.0 in healthy controls was 13%, while 66% in LSC patients (P = 8.5 x 10^<-8>, OR = 12.0 ).Thus, our results demonstrated that many ms-SNP including those with novel findings are involved in the predisposition to cancer-incidence, suggesting the hereditary cancer-predisposition is determined, at least in part, by the sum effects of many ms-SNP in cancer-related genes. Our results suggested also that each individual's cancer-risk may be predicted by calculating COR in some cases. Less

为了探讨癌症易感性的分子本质，我们对癌症相关基因的错义-单核苷酸多态(ms-SNP)在病例和健康对照之间的差异分布进行了全面的分析。自1999年以来，我们对335例癌症患者和110例健康对照进行了103ms-SNP的病例对照研究，发现22个SNP与肺癌(LAD)、肺鳞状细胞癌(LSC)、头颈部癌(HNSC)、结直肠癌(CRC)和食道癌(ECC)显著相关。这些与风险相关的22个SNP包括3个已报道的SNP(在基因ADH1B、ALDH2和TP53中)和19个SNP，它们分布在20个基因中，包括6个DNA修复基因、5个抑癌基因、5个染色体分离基因和4个其他基因。其中16个为高危(SNP-H)，OR值为1.87~18.0；6个为保护性SNP(SNP-L)，OR0.18~0.54。关于eAC…肿瘤类型较多，影响SNP的个数依次为LAD(8个SNP-H和4个SNP-L)、LSC(7个SNP-H和2个SNP-L)、hNSC(3个SNP-H和2个SNP-L)、CRC(3个SNP-H和3个SNP-L)和ECC(2个SNP-H)。因为所有的分析都是用相同的样本进行的，所以有可能单独检查这22个SNP上风险基因的完美重叠。每个个体的累积优势比(COR)是通过乘以他们所有重叠的风险SNP的OR来计算的。以10个SNP计算的LAD风险，健康对照组为4.5%，LAD组为39%(P=5×10；-9&gt；，OR=13.4)。同样，对于基于7SNP的LSC风险，健康对照组中携带COR&GT；4.0的人的频率为13%，而LSC患者中携带COR&GT；4.0的人的频率为66%(P=8.5x10；-8&gt；，OR=12.0)。因此，我们的结果表明，许多ms-SNP，包括那些新发现的SNP，与癌症的易感性有关，这表明遗传性癌症的易感性至少部分由癌症相关基因中许多ms-SNP的总和决定。我们的结果还表明，在某些情况下，可以通过计算COR来预测每个人的癌症风险。较少

项目成果

Gene silencing of the tyrosine phosphatase SHP1 gene by aberrant methylation in leukemias/lymphomas.

• 发表时间: 2002-11
• 期刊: Cancer research
• 影响因子: 11.2
• 作者: T. Oka;M. Ouchida;M. Koyama;Y. Ogama;S. Takada;Yoko Nakatani;Takehiro Tanaka;T. Yoshino;K. Hayashi;N. Ohara;E. Kondo;Kiyoshi Takahashi;J. Tsuchiyama;M. Tanimoto;K. Shimizu;T. Akagi

Single nucleotide polymorphism in fibroblast growth factor 4 at codon 388 is associated with prognosis in high-grade soft tissue sarcoma.

成纤维细胞生长因子 4 密码子 388 处的单核苷酸多态性与高级别软组织肉瘤的预后相关。

• 发表时间: 2003
• 期刊: Cancer 98
• 作者: Morimoto Y;ほか
• 通讯作者: ほか

Genetic alterations of the ornithine decarboxylase gene in human colorectal cancers.

人类结直肠癌中鸟氨酸脱羧酶基因的遗传改变。

• 发表时间: 2002
• 期刊: J.Exp.Clin.Cancer Res. 21
• 作者: Matsubara;N.;ほか
• 通讯作者: ほか

Ohtsuka, Y., ほか: "Paroxysmal movement disorders in severe myoclonic epilepsy in infancy"Brain & Development. 25. 401-405 (2003)

Ohtsuka, Y. 等人：“婴儿期严重肌阵挛性癫痫的阵发性运动障碍”Brain & Development 25. 401-405 (2003)。

Genome-wide analyses on loss of heterozygosity in head and neck squamous cell carcinomas

• DOI: 10.1097/01.lab.0000047489.26246.e1
• 发表时间: 2003-01-01
• 期刊: LABORATORY INVESTIGATION
• 影响因子: 5
• 作者: Beder, LB;Gunduz, M;Shimizu, K
• 通讯作者: Shimizu, K