Colorectal cancer: Genomic variations in insulin-like growth factor-1 and -2

Insulin-like Growth Factor (IGF)-1 and -2 promote cancer growth. Upregulation of IGF1 and IGF2 may mediate the effects of "western lifestyle" on cancer. While IGF1 and IGF2 are genetically determined, known genetic variations at these loci are not sufficient to account for the observed phenotypic variation. This dissertation concentrates on the genomic variations in IGF1 (genetic) and IGF2 (epigenetic) that potentially explain cancer incidence rates in a rapidly westernising population, the Singapore Chinese. The Singapore Chinese population affords a wide variation of "western lifestyle factors", including the lower ranges not available in the occidental populations. The Singapore Chinese Health Study is a population-based residential cohort study. From this ongoing cohort, a case-cohort sampling of participants with available biospecimens forms the study population in this dissertation. The first section of the dissertation is on IGF1 cis-acting genetic variations. A resequencing survey of the IGF1 upstream regulatory region, based on a comparative genomics strategy, identified two IGF1 single nucleotide polymorphisms at positions -533 and -2995 base pair relative to the IGF1 transcriptional start site (+1). In both single marker analyses and in diplotype analyses, the IGF1-533 C>T and IGF1-2995 G>A were associated with colorectal cancer risk. These associations are the first reports of IGF1 SNPs and colorectal cancer risk. Physical inactivity modified the effect of these SNPs. These observations support the role of IGF1 and western lifestyle factors in colorectal cancer. The second section of this dissertation is on the epigenetic variation of the imprinted IGF2 gene. The current measurement of loss of imprinting requires intact RNA - unavailable in existing epidemiologic biorepositories. Therefore, we developed an assay for IGF2 imprinting based on allele-specific DNA methylation in the H19 imprinting center. The allele-specific methylation assay will facilitate future case-control studies of IGF2 germline LOI and cancer risk and may represent a new platform for the development of high-throughput methods to screen for allele-specific variation that is regulated by epigenetic processes.