title: 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.
authors.affiliation: Department of Surgery, VU University Medical Centre, Amsterdam, The Netherlands.
authors.forename: Rebecca P M
authors.initials: RP
authors.lastname: Brosens
authors.forename: Josien C
authors.initials: JC
authors.lastname: Haan
authors.forename: Beatriz
authors.initials: B
authors.lastname: Carvalho
authors.forename: François
authors.initials: F
authors.lastname: Rustenburg
authors.forename: Heike
authors.initials: H
authors.lastname: Grabsch
authors.forename: Philip
authors.initials: P
authors.lastname: Quirke
authors.forename: Alexander F
authors.initials: AF
authors.lastname: Engel
authors.forename: Miguel A
authors.initials: MA
authors.lastname: Cuesta
authors.forename: Nicola
authors.initials: N
authors.lastname: Maughan
authors.forename: Marcel
authors.initials: M
authors.lastname: Flens
authors.forename: Gerrit A
authors.initials: GA
authors.lastname: Meijer
authors.forename: Bauke
authors.initials: B
authors.lastname: Ylstra
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D002869:Chromosome Aberrations; D003110:Colonic Neoplasms / Q000235:genetics* / Q000473:pathology; D055028:Comparative Genomic Hybridization; D004273:DNA, Neoplasm / Q000235:genetics; D005260:Female; D005500:Follow-Up Studies; D056726:Genetic Association Studies / Q000379:methods; D006801:Humans; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D011379:Prognosis; D016019:Survival Analysis
chemical_list: D004273:DNA, Neoplasm