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Relationship of Colon & Lung Cancer Susceptibility Genes

冒号的关系

基本信息

批准号：
8038370
负责人：
PETER DEMANT
金额：
$ 31.42万
依托单位：
ROSWELL PARK CANCER INSTITUTE CORP
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-07-02 至 2013-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8038370
关键词：
Alleles Animals Atlas of Cancer Mortality in the United States Cancer Control Cancer-Predisposing Gene Candidate Disease Gene Colon Colon Carcinoma Colonic Neoplasms Congenic Strain Data Databases Effectiveness Frequencies Future Genes Genetic Genetic Polymorphism Genetic Recombination Genetic Risk Genome Genomic Segment Genomics Germ Lines Homologous Gene Human Human Identifications Hybrids In Vitro Inbred BALB C Mice Individual Laboratories Length Link Location Lung Lung Neoplasms Malignant Neoplasms Malignant neoplasm of lung Maps Measures Microsatellite Repeats Modification Molecular Molecular Genetics Molecular Target Morbidity - disease rate Mus Organ PTPRJ gene Pattern Penetrance Predisposition Preventive Probability Publishing Quantitative Trait Loci RNA Interference Recombinant Haplotype Recombinants Resistance Risk Rodent Role Site Somatic Mutation Specificity Staging Step Tests Structure Susceptibility Gene Testing Transfection Tumor Cell Line cancer prevention cancer risk cancer therapy cancer type cell growth human PTPRJ protein malignant breast neoplasm mortality mouse genome mouse model novel tumor tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): Project Summary: Risk of sporadic cancer in humans and animals varies greatly due to polymorphism of multiple genes, which are largely unknown. Identification of cancer susceptibility genes in the mice will permit to define their human homologues and their role in individual cancer risk. Until now in mouse models cancers in different organs were believed to be controlled by different genes. However, the large number of susceptibility genes for colon (Sec) and lung (Slue) cancer defined in this laboratory (15 and 30, respectively) allowed us to uncover an unexpected relationship between them. We found that Sec and Slue loci frequently co-localize in the same region. This pair-wise association of the Sec and Slue loci is not compatible with their expected independent distribution (P = 0.0036). This finding suggests that the two types of genes are either identical, or that they form at a number of genomic sites clusters of closely linked functionally related genes. Aims: We will determine rigorously the relationship between Sec and Slue genes by precision-mapping four Sec -Slue pairs and identifying their candidate gene(s). We will establish whether they are identical, and if not, we'll define the tightness of their linkage and degree of their similarity. This will be achieved by mapping both lung and colon tumor susceptibility to successively shorter genomic segments. The mosaic structure of the mouse genome, defined in our strains by more than 15,000 microsatellite and SNP markers, will help to locate the Sec - Slue genes to very short genomic segments. Genes in these segments will be screened by a number of molecular and functional criteria (polymorphism, expression pattern, effect on cell growth, somatic mutations in tumors) and the selected candidate gene will be validated by germ-line manipulation. We aim to identify one or more cancer susceptibility genes, but in addition we will contribute to understanding of across- organ control of cancer susceptibility. This will provide qualitatively novel information about the general and organ-specific control of tumorigenesis. Relevance: Human homologues of mouse cancer susceptibility genes are likely to influence individual risk of sporadic cancer. We identified previously Ptprj (Protein tyrosine phosphatase receptor type J) as candidate for mouse colon cancer susceptibility gene Seel. Recently PTPRJ was shown to control individual risk for sporadic breast cancer in humans. Moreover, two human susceptibility genes for colon and for lung cancer map very close to sites homologous to Slue genes. The probability of such apposition by chance is 0.04. This data strongly supports the importance of defining mouse tumor susceptibility genes as an approach towards definition of genetic risk of cancer in humans. If susceptibility genes for two or several frequent human cancers could be shown to be largely the same or clustered , as our mouse data suggest, rather than separate for each cancer type, their identification could be achieved faster and with much less effort.

描述（由申请人提供）：项目摘要：由于多种基因的多态性，人类和动物散发性癌症的风险差异很大，而这些基因在很大程度上是未知的。小鼠癌症易感性基因的鉴定将有助于确定它们的人类同源物及其在个体癌症风险中的作用。迄今为止，在小鼠模型中，不同器官的癌症被认为是由不同的基因控制的。然而，该实验室定义的大量结肠癌 (Sec) 和肺癌 (Slue) 易感基因（分别为 15 个和 30 个）让我们发现了它们之间意想不到的关系。我们发现 Sec 和 Slue 位点经常共定位于同一区域。 Sec 和 Slue 位点的这种成对关联与其预期的独立分布不兼容 (P = 0.0036)。这一发现表明，这两种类型的基因要么是相同的，要么它们在许多基因组位点形成紧密相连的功能相关基因簇。目标：我们将通过精确绘制四个 Sec -Slue 对并识别其候选基因，严格确定 Sec 和 Slue 基因之间的关系。我们将确定它们是否相同，如果不同，我们将定义它们之间联系的紧密程度和相似程度。这将通过将肺和结肠肿瘤的易感性映射到相继较短的基因组片段来实现。小鼠基因组的镶嵌结构（在我们的品系中由超过 15,000 个微卫星和 SNP 标记定义）将有助于将 Sec - Slue 基因定位到非常短的基因组片段。这些片段中的基因将通过许多分子和功能标准（多态性、表达模式、对细胞生长的影响、肿瘤中的体细胞突变）进行筛选，并且选定的候选基因将通过种系操作进行验证。我们的目标是识别一种或多种癌症易感基因，但除此之外，我们还将有助于理解癌症易感性的跨器官控制。这将提供有关肿瘤发生的一般和器官特异性控制的定性新颖信息。相关性：小鼠癌症易感基因的人类同源物可能会影响个体患散发性癌症的风险。我们之前确定 Ptprj（J 型蛋白酪氨酸磷酸酶受体）作为小鼠结肠癌易感基因 Seel 的候选基因。最近，PTPRJ 被证明可以控制人类散发性乳腺癌的个体风险。此外，两个人类结肠癌和肺癌易感基因与Slue基因的同源位点非常接近。这种偶然并置的概率是 0.04。该数据有力地支持了定义小鼠肿瘤易感基因作为定义人类癌症遗传风险的方法的重要性。如果两种或几种常见人类癌症的易感基因能够被证明在很大程度上相同或聚集，正如我们的小鼠数据所表明的那样，而不是针对每种癌症类型分开，那么它们的识别可以更快、更省力地实现。