Genome-Wide DNA Methylation Profiling of Sporadic and Familial Colorectal Cancer
MA Milewski, DT Leahy, J Conroy, S Ennis, H Mulcahy, J Hyland, D O'Donoghue, K Sheahan. University College Dublin, Dublin, Ireland; St. Vincent's University Hospital, Dublin, Ireland
Background: Evolution of familial and sporadic colorectal cancers is variously driven by the processes of microsatellite instability (MSI), chromosomal instability and the epigenetic consequences of aberrant DNA methylation. In this study, we seek to determine how genome wide methylation patterns relate to the currently accepted classifications of colorectal cancer.
Design: We studied a cohort of 72 cases of colorectal cancer with matching adjacent normal tissue. This cohort was well characterised in terms of clinicopathological features including MSI, and BRAF and KRAS mutation status. Sixteen confirmed cases of hereditary non-polyposis colorectal cancer were included in the study. Genomic DNA was extracted from formalin fixed paraffin embedded tissue and subjected to sodium bisulfite modification. The Illumina GoldenGate Methylation array with Cancer Panel was used to interrogate the methylation status at 1,505 CpG loci from 807 cancer associated genes.
Results: Cluster analysis using BeadStudio Methylation software showed distinct epigenetic profiles underlying the traditional group classifications of colorectal cancer. More than seventy genes showed marked differential methylation across the groups. The discriminant methylated genes included some which have been previously described in this regard, such as BMP3, p16, MGMT and MLH1. The adjacent normal samples clustered separately to the tumors. Validation of array results was performed using methylation specific PCR.
Conclusions: The identification of methylation patterns that further discriminate between sporadic and familial subsets of colorectal cancer should lead to improved diagnosis and prognosis and also provide a basis for future molecular target-based intervention studies.
Tuesday, March 23, 2010 9:30 AM
Poster Session III # 122, Tuesday Morning