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：人类和动物零星癌的风险由于多种基因的多态性而变化很大，这些基因基本上未知。小鼠中癌症敏感性基因的鉴定将允许定义其人类同源物及其在个体癌症风险中的作用。到目前为止，在不同器官中的小鼠模型癌症中，人们被认为由不同的基因控制。但是，在该实验室定义的结肠（SEC）和肺（SEC）癌（分别为15和30）的大量易感基因（分别为15和30）使我们能够发现它们之间的意外关系。我们发现SEC和SLUE基因座经常在同一区域共定位。 SEC和SLUE基因座的这种成对关联与它们的预期独立分布不兼容（P = 0.0036）。这一发现表明，两种类型的基因要么是相同的，要么在许多基因组位点形成密切相关的功能相关基因的簇。目的：我们将通过精确映射四秒钟对并识别其候选基因来严格确定SEC和SLUE基因之间的关系。我们将确定它们是否相同，如果没有，我们将定义其链接的紧密性和相似性的程度。这将通过将肺和结肠肿瘤易感性依次映射到较短的基因组段来实现。小鼠基因组的镶嵌结构在我们的菌株中定义为15,000多个微卫星和SNP标记，将有助于将SEC基因定位到非常短的基因组段。这些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）筛选，并且选定的候选基因将通过种系操作验证。我们旨在识别一个或多个癌症敏感性基因，但此外，我们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信息。相关性：小鼠癌易感性基因的人类同源物可能会影响个体的零星癌风险。我们以前鉴定了PTPRJ（蛋白酪氨酸磷酸酶受体J）为小鼠结肠癌易感性基因SEEL的候选。最近，PTPRJ可控制人类零星乳腺癌的个人风险。此外，两个人类敏感性基因和肺癌图非常靠近与SLUE基因同源的位置。这种偶然申请的可能性为0.04。该数据强烈支持将小鼠肿瘤敏感性基因定义为人类癌症遗传风险的方法的重要性。如我们的小鼠数据所表明的那样，可以证明两种或几种频繁的人类癌的敏感性基因在很大程度上是相同的或聚集的，而不是针对每种癌症类型的分开，则可以更快地实现它们的识别，并且努力更少。