Project description:Chromosomal instable colorectal cancer is marked by specific large chromosomal copy number aberrations. Recently, focal aberrations of 3Mb 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 is 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 was performed by enrichment analysis and mapping copy number and mutation data of colorectal-, breast-, 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 seem less tumour type specific since they also show significant overlap with focal deletions of other sites. Focal deletions detected are significantly enriched for cancer genes and genes frequently mutated in colorectal cancer. The mRNA expression of these genes is 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 which contribute to and drive the process of colorectal cancer development. DNA copy number status of these genes correlate with mRNA expression and some are associated with clinical outcome.

Project description:Chromosomal instable colorectal cancer is marked by specific large chromosomal copy number aberrations. Recently, focal aberrations of 3Mb 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 is 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 was performed by enrichment analysis and mapping copy number and mutation data of colorectal-, breast-, 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 seem less tumour type specific since they also show significant overlap with focal deletions of other sites. Focal deletions detected are significantly enriched for cancer genes and genes frequently mutated in colorectal cancer. The mRNA expression of these genes is 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 which contribute to and drive the process of colorectal cancer development. DNA copy number status of these genes correlate with mRNA expression and some are associated with clinical outcome. 38 Stage II colorectal cancer (CRC) tissue samples (FFPE) of which 19 were done on expression arrays. One sample (Stage II colorectal cancer tissue samples (FFPE) 26) was also done on the 135K NimbleGen array. Fresh frozen and FFPE of the same CRC stage I sample was done on 105K agilent. The fresh frozen was across array in silico set out against a pool of blood of 18 healthy females.

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Targeted genomic screen reveals focal long non-coding RNA copy number alterations in cancer

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