Cancer, DNA repair and chromatin structure

Abstract

Colorectal cancer, the most common cancer in males and females who do not smoke, is diagnosed in approximately 3,500 Scots each year. Despite having a large environmental contribution, the substantial genetic basis of colorectal tumours is still poorly understood. In this project we have adopted a number of approaches to try and further characterise this genetic contribution of colorectal cancer.To begin to understand tumour progression, we first characterised the gene ex¬ pression changes observed in various tumours using SAGE, EST and microarray data. Although many genes were identified as differentially expressed in cancers, little congruence was observed between tumour types and even expression platforms. We next compared gene expression changes observed along chromosomes to local chromatin structure, and showed that regions of constit.utively open structure generally show an increase in gene expression in cancer. Despite the lack of congruence between expression data shown previously, we illustrated that such a correlation between gene expression change in tumours and chromatin structure can be observed using various expression platforms and across a variety of tumours.congruence was observed between tumour types and even expression platforms. We next compared gene expression changes observed along chromosomes to local chromatin structure, and showed that regions of constit.utively open structure generally show an increase in gene expression in cancer. Despite the lack of congruence between expression data shown previously, we illustrated that such a correlation between gene expression change in tumours and chromatin structure can be observed using various expression platforms and across a variety of tumours.To further characterise the role of chromatin structure in tumours, we also investigated the rates of mutation and selection across chromatin categories. DNA damage and repair is a key process in cancer progression and we have shown, through inter species alignments, that although chromosomal regions of a relatively more open chromatin structure undergo lower rates of mutation, levels of purifying selection on synonymous sites are highest in regions of closed chromatin.As part of the COGS/SOCCS group the role of DNA repair in colorectal cancer was finally further investigated through a case-control association study. Tagging SNPs in genes predicted to be associated with DNA repair were selected and subsequently typed by the group in approximately 1000 cases and 1000 controls. The nature of SNPs with evidence of an association with colorectal cancer was finally characterised.