This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Progression of colorectal cancer through stages of increasing malignancy is caused by the stepwise accumulation of mutations in specific genes. Much is known about the genes responsible for initial steps in tumor formation. In contrast to this, the genes that control transitions through later stages of malignancy are largely unknown. In this proposal, we seek to characterize the genetic alterations that are responsible for tumor's ability to infiltrate regional lymph nodes. We will utilize human colorectal cancer surgical specimens of defined clinical stages and identify chromosomal structural alterations, gene expression changes, and specific gene mutations that are unique to lymph node positive disease. These studies will be conducted by accomplishing the following specific aims.
Aim 1 will be a comprehensive analysis of loss of heterozygosity of chromosome 8p in colorectal tumors, and the identification of a minimally-deleted region common to invasive cancers.
Aim 2 will be a comprehensive analysis of alterations in gene expression that occur in tumors with loss of heterozygosity on chromosome 8p.
Aim 3 will be the identification of somatically acquired mutations of 8p candidate tumor suppressor genes in lymph node positive tumors. The overall hypothesis being tested is that a single gene, located on the p arm of chromosome 8, is mutated in node-positive colorectal tumors. This mutation can be detected indirectly through loss of heterozygosity and alterations in gene expression. Finally, the mutation can be detected specifically by direct sequence analysis of the gene. These studies will reveal significant mechanistic insight into the process of lymph node invasion, and will provide prognostic tools and targets for the development of chemotherapeutic agents that specifically target metastatic disease.
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