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

• Published in: The Journal of pathology Vol. 221; no. 4; pp. 411 - 424
• Main Authors: Brosens, Rebecca PM, Haan, Josien C, Carvalho, Beatriz, Rustenburg, François, Grabsch, Heike, Quirke, Philip, Engel, Alexander F, Cuesta, Miguel A, Maughan, Nicola, Flens, Marcel, Meijer, Gerrit A, Ylstra, Bauke
• Format: Journal Article
• Language: English
• Published: Chichester, UK John Wiley & Sons, Ltd 01.08.2010; Wiley
• Subjects: Aged; Aged, 80 and over; Biological and medical sciences; candidate genes; Chromosome Aberrations; Colon cancer; Colonic Neoplasms - genetics; Colonic Neoplasms - pathology; Colorectal cancer; Comparative Genomic Hybridization; copy number; Data processing; DNA; DNA, Neoplasm - genetics; Female; FFPE; focal chromosomal aberrations; Follow-Up Studies; Gastroenterology. Liver. Pancreas. Abdomen; Gene expression; Gene mapping; Genetic Association Studies - methods; genomics; Glioblastoma; Humans; Investigative techniques, diagnostic techniques (general aspects); Male; Medical sciences; Middle Aged; mRNA expression; Mucosa; Mutation; Neoplasm Staging; outcome prediction; Pancreatic cancer; Pathology. Cytology. Biochemistry. Spectrometry. Miscellaneous investigative techniques; Prognosis; stage II; Statistics; Stomach. Duodenum. Small intestine. Colon. Rectum. Anus; Survival; Survival Analysis; Tumors; Chromosomal aberration; focal chromosomal aberrations; Prognosis; Prediction; Early stage; Malignant tumor; Gene expression; mRNA expression; Colonic disease; outcome prediction; Anatomic pathology; Colon cancer; Messenger RNA; Comparative genomic hybridization; FFPE; candidate genes; Digestive diseases; Intestinal disease; Evolution; Candidate gene; stage II; Predictive factor; Cancer
• ISSN: 0022-3417; 1096-9896
• DOI: 10.1002/path.2724

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. Copyright © 2010 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.