Identification of susceptibility genes for cancer in a whole genome scan utilizing novel phenotypes under the assumption of genetic heterogeneity

The purpose of this dissertation is to analyze a genome-wide linkage scan on a unique collection of families identified by the Cleveland Colon Neoplasia Sibling Study, utilizing novel phenotypes and the assumption of genetic heterogeneity. The intent is to identify, previously unmapped regions of the genome that may harbor susceptibility genes that increase the risk for colorectal cancer (CRC), and to examine evidence for a general tumor suppressor gene in these families. This is accomplished by utilizing a systematic approach with new statistical tools, under the assumption of genetic heterogeneity. I have used a unique repository of families each of which has been identified as having at least two sibs diagnosed with invasive cancer or adenomatous polyps before the age of 65. This analysis has successfully identified a region on chromosome 9 that may be linked to colon neoplasia in families that exhibit “severe pathology”. A region on chromosome 17p in families with a colon/breast phenotype was also localized in a region long suspected of harboring a breast cancer tumor suppressor. This analysis was successful in generating new hypotheses and providing new directions for future research, which was the primary objective of this dissertation. Analyses were conducted to determine if locus heterogeneity existed in the dataset and our findings are suggestive that locus heterogeneity may be present, but that further theoretical work will be necessary to fully answer this question, as the focus has been on the allele distribution in affected sib pairs and little to no work has been done on what happens to the allele sharing distribution in discordant sibships when there is locus heterogeneity.