Comprehensive analysis of copy number aberrations in microsatellite stable colon cancer in view of stromal component

Abstract

Background: Somatic copy number aberrations (CNA) are common acquired changes in cancer cells playing an important role in the progression of colon cancer (CRC). This study aimed to perform a characterization of CNA and their impact in gene expression.Methods: CNA were inferred from SNP array data in a series of 99 CRC. CNA events were calculated and used to assess the association between copy number dosage, clinical and molecular characteristics of the tumours, and gene expression changes. All analyses were adjusted for the quantity of stroma in each sample, that was inferred from gene expression data.Results: High heterogeneity among samples was observed, the proportion of altered genome ranged between 0.04 and 26.6%. Recurrent CNA regions with gains were frequent in chromosomes 7p, 8q, 13q, and 20 while 8p, 17p, and 18 cumulated loses. A significant positive correlation was observed between the number of somatic mutations and total CNA (Spearman r=0.42, P=0.006). Approximately 37% of genes located in CNA regions changed their level of expression, and the average partial correlation (adjusted for stromal content) with copy number was 0.54 (inter-quartile range 0.20 to 0.81). Altered genes showed enrichment in pathways relevant for colorectal cancer. Tumours classified as CMS2 and CMS4 by the consensus molecular subtyping showed higher frequency of CNA. Loses of one small region in 1p36.33, with gene CDK11B, were associated with poor prognosis. More than 66% of the recurrent CNA were validated in the TCGA data when analysed with the same procedure. Also 79% of the genes with altered expression in our data were validated in the TCGA.Conclusion: Though CNA are frequent events in MSS CRC, few focal recurrent regions were found. These aberrations have strong effects on gene expression and contribute to deregulate relevant cancer pathways. Due to the diploid nature of stromal cells, it is important to consider the purity of tumour samples to accurately calculate CNA events in CRC.