title: A distinct DNA methylation profile associated with microsatellite and chromosomal stable sporadic colorectal cancers.
abstract: Aberrant DNA methylation, microsatellite instability (MSI) and chromosomal instability (CIN) are well-characterised molecular features of sporadic colorectal cancers (CRCs). In addition to CpG island methylator phenotype (CIMP) associated with MSI, an intermediate methylation subgroup is also a feature of non-MSI cancers. A large proportion of CRCs have no evidence of either MSI or CIN, here called Microsatellite and Chromosomal Stable (MACS), and require their methylation profile to be established. The clinical and molecular features of 170 sporadic CRC patients were investigated and stratified into MSI, CIN and MACS groups. MACS were most often found in the left colon and had a significantly lower BRAF mutation frequency (p < 0.001) compared with MSI. MACS had better survival [hazard ratio (HR) = 0.244, p = 0.017] compared with CIN, but were similar to MSI. The methylation status of 1,505 CpG loci from cancer-related genes was analysed in a subset of CRCs (n = 44 normal-tumour pairs) and compared with CIN, MSI and MACS status. Using two-way hierarchical clustering, three subgroups were identified, which associated with CIN, MSI and MACS status. Using significance analysis of microarray, 16 CpG loci demonstrating methylation changes associated with MACS were identified. A combination of six loci identified MACS with 81% sensitivity and 93% specificity. This result now requires independent validation. Hypomethylation of a CpG locus within the sonic hedgehog (SHH) promoter correlated with increased gene expression and was associated significantly with MACS cancers. In conclusion, we propose that MACS have distinct clinicopathological features and can be distinguished from other CRCs by a specific set of methylation loci.
authors: Centre for Digestive Diseases, Blizard Institute for Cell and Molecular Sciences, Barts and The London, Whitechapel, London, United Kingdom.
authors: Andrew
authors: A
authors: Silver
authors: Neel
authors: N
authors: Sengupta
authors: David
authors: D
authors: Propper
authors: Peter
authors: P
authors: Wilson
authors: Thorsten
authors: T
authors: Hagemann
authors: Asif
authors: A
authors: Patel
authors: Alexandra
authors: A
authors: Parker
authors: Anil
authors: A
authors: Ghosh
authors: Roger
authors: R
authors: Feakins
authors: Sina
authors: S
authors: Dorudi
authors: Nirosha
authors: N
authors: Suraweera
mesh_terms: D043171:Chromosomal Instability; D015179:Colorectal Neoplasms / Q000235:genetics*; D019175:DNA Methylation; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D053842:Microsatellite Instability; D008875:Middle Aged; D009154:Mutation; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics
chemical_list: C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf