Characterizing regions associated with genomic instability in colon cancer
Dutt, Smitha S
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Most cancers can be considered to be the consequence of an unstable genome, where the instability can arise exogenously from carcinogens or endogenously from defects in systems that maintain genomic integrity. Genomic instability manifests itself in various ways such as chromosomal instability, intrachromosomal instability, microsatellite instability and epigenetic changes. To study instability, I chose to examine single nucleotide polymorphism using SNP arrays. The 10K SNP array consists of 11,500 SNP (single nucleotide polymorphism) markers distributed across the entire genome at an average distance of ~210kb. The data generated are in the form of homozygous and heterozygous genotypes across the chromosomes for the genome. When tumor and normal genotypes were compared for each chromosome, complete homozygosity was seen across entire or partial lengths of certain chromosomes in the tumor. This phenomenon is termed uniparentalism (UP). Five out of thirteen patients showed UP in more than one chromosome in the genome. Duplication was confirmed in these cases with the help of parallel analyses using BAC (bacterial artificial chromosome) arrays and fluorescent in-situ hybridization (FISH). Chromosomes 14 and 18 showed coordinate uniparentalism in the sporadic colorectal cancer pathway through these analyses. The effect of a naturally occurring polymorphism on genomic instability was studied in the transforming growth factor receptor ( TGF [beta] R-I ) gene. The receptor binds the cytokine TGF-[beta], which is a growth inhibitor. Genomic instability was lower in sporadic colorectal cancer patients with the TGF [beta] R-I polymorphism, which encodes only 6 alanines in the receptor protein. This was highly significant as compared to genomic instability status of sporadic colorectal cancer patients with wild type TGF [beta] R-I gene.