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Published on: July 22, 2020
Candidate driver genes in focal chromosomal aberrations of stage II colon cancer
Rebecca P M Brosens1, Josien C Haan, Beatriz Carvalho
1Department of Surgery, VU University Medical Centre, Amsterdam, The Netherlands.
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.
Insights
This study identifies small focal chromosomal copy number aberrations in stage II colon cancer, finding they harbor driver genes and impact patient survival. These genetic changes are crucial for understanding colorectal cancer development and prognosis.
Area of Science:
- Genomics
- Cancer Biology
- Oncology
Background:
- Chromosomal instability is a hallmark of colorectal cancer, characterized by large copy number aberrations.
- Focal aberrations (≤3 Mb) are increasingly recognized in cancer, harboring one or few genes.
- Understanding these focal aberrations is key to identifying cancer drivers and therapeutic targets.
Purpose of the Study:
- To identify recurrent focal chromosomal aberrations and candidate driver genes in stage II colon cancer.
- To assess the clinical relevance and prognostic potential of these focal aberrations.
- To investigate the relationship between DNA copy number, gene expression, and clinical outcome.
Main Methods:
- High-resolution array comparative genomic hybridization (aCGH) on 38 stage II colon cancer samples.
- Statistical enrichment analysis and cross-cancer data mapping to identify driver genes.
- Correlation analysis of DNA copy number with mRNA expression and survival data.
Main Results:
- Identified 81 focal chromosomal aberrations harboring 177 genes in stage II colon cancer.
- Focal amplifications showed overlap with colorectal cancer, while deletions were less tumor-specific and enriched for cancer genes.
- Loss of 5q34 and gain of 13q22.1 were independent prognostic factors for patient survival.
Conclusions:
- Focal chromosomal copy number aberrations in stage II colon cancer are enriched in cancer driver genes.
- DNA copy number status of these genes correlates with mRNA expression, supporting their functional relevance.
- Specific focal aberrations (5q34 loss, 13q22.1 gain) are associated with clinical outcome in stage II colon cancer.
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