Relationship of Colon & Lung Cancer Susceptibility Genes

项目简介：由于多种基因的多态性，人类和动物的散发性癌症风险差异很大，而这些基因在很大程度上是未知的。对小鼠癌症易感基因的鉴定将有助于确定它们在人类中的同系物及其在个体癌症风险中的作用。到目前为止，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，本实验室确定的结肠癌（Sec）和肺癌（Slue）的大量易感基因（分别为15个和30个）使我们发现了它们之间意想不到的关系。我们发现Sec和Slue位点经常在同一区域共定位。Sec和Slue基因座的这种成对关联与它们预期的独立分布不相容（P = 0.0036）。这一发现表明，这两种类型的基因要么是相同的，要么是它们在许多基因组位点形成了紧密相连的功能相关基因簇。目的：我们将通过精确定位4对Sec -Slue基因并鉴定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，如果不相同，我们将定义它们联系的紧密程度和它们的相似程度。这将通过绘制肺部和结肠肿瘤易感性到连续较短的基因组片段来实现。在我们的菌株中，超过15,000个微卫星和SNP标记定义了小鼠基因组的马赛克结构，这将有助于将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一系列分子和功能标准（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，选定的候选基因将通过种系操作进行验证。我们的目标是确定一个或多个癌症易感基因，但除此之外，我们将有助于了解癌症易感的跨器官控制。这将提供关于肿瘤发生的一般和器官特异性控制的定性新信息。相关性：小鼠癌症易感基因的人类同源物可能影响散发性癌症的个体风险。我们先前确定Ptprj（蛋白酪氨酸磷酸酶受体J型）是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，人类结肠癌和肺癌的两个易感基因与Slue基因的同源位点非常接近。这种偶发的概率是0.04。这些数据有力地支持了确定小鼠肿瘤易感基因作为确定人类癌症遗传风险方法的重要性。如果两种或几种常见的人类癌症的易感基因可以被证明在很大程度上是相同的或聚集的，就像我们的小鼠数据所显示的那样，而不是每种癌症类型分开，那么它们的识别就可以更快，更省力。

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.