Candidate driver genes in focal chromosomal aberrations of stage II colon cancer

Abstract

Chromosomal instable colorectal cancer is marked by specific large chromosomal copy number aberrations. Recently, focal aberrations of 3 Mb or smaller have been identified as a common phenomenon in cancer. Inherent to their limited size, these aberrations harbour one or few genes. The aim of this study was to identify recurrent focal chromosomal aberrations and their candidate driver genes in a well-defined series of stage II colon cancers and assess their potential clinical relevance. High-resolution DNA copy number profiles were obtained from 38 formalin-fixed, paraffin-embedded colon cancer samples with matched normal mucosa as a reference using array comparative genomic hybridization. In total, 81 focal chromosomal aberrations were identified that harboured 177 genes. Statistical validation of focal aberrations and identification of candidate driver genes were performed by enrichment analysis and mapping copy number and mutation data of colorectal, breast, and pancreatic cancer and glioblastomas to loci of focal aberrations in stage II colon cancer. This analysis demonstrated a significant overlap with previously identified focal amplifications in colorectal cancer, but not with cancers from other sites. In contrast, focal deletions seemed less tumour type-specific since they also showed significant overlap with focal deletions of other sites. Focal deletions detected were significantly enriched for cancer genes and genes frequently mutated in colorectal cancer. The mRNA expression of these genes was significantly correlated with DNA copy number status, supporting the relevance of focal aberrations. Loss of 5q34 and gain of 13q22.1 were identified as independent prognostic factors of survival in this series of patients. In conclusion, focal chromosomal copy number aberrations in stage II colon cancer are enriched in cancer genes that contribute to and drive the process of colorectal cancer development. DNA copy number status of these genes correlates with mRNA expression and some are associated with clinical outcome.

Chromosome 5q Loss in Colorectal Flat Adenomas

“…The high resolution array platform used in this study has excellent performance for detecting DNA copy number changes when using FFPE material (58), in contrast to the SNP array platforms available at the time of the study. However, this platform cannot detect copy-neutral LOH, an event frequently reported in CRC (59), and therefore this could not be investigated.…”

The adenoma hunt in colorectal cancer screening: defining the target

“…CIN is the main type of genomic instability in CRC, occurring in about 85% of colorectal tumours. CIN is characterized by chromosomal gains and losses that lead to gene dosage effects on tumour suppressor genes, oncogenes and miRNAs [13][14][15].…”

Dissecting the gray zone between follicular lymphoma and marginal zone lymphoma using morphological and genetic features

“…11,12 To remove common germ-line copy number variants from the dataset all focal DNA copy number differences smaller than 3 Mb were compared with copy number variants in the healthy population as archived in the database of genomic variants (http://projects.tcag.ca/variation/). [13][14][15][16][17] Further details of data pre-processing and the statistical analysis are given in the Online Supplementary Data. Raw data of all arrays are publicly available in the GEO database (accession number GSE40641).…”