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

Abstract

Background:Somatic copy number aberrations (CNAs) are common acquired changes in cancer cells having an important role in the progression of colon cancer (colorectal cancer, CRC). This study aimed to perform a characterisation of CNA and their impact in gene expression.Methods:Copy number aberrations were inferred from SNP array data in a series of 99 CRC. Copy number aberration 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, which 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, whereas 8p, 17p, and 18 cumulated losses. A significant positive correlation was observed between the number of somatic mutations and total CNA (Spearman’s 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 (interquartile range 0.20 to 0.81). Altered genes showed enrichment in pathways relevant for CRC. Tumours classified as CMS2 and CMS4 by the consensus molecular subtyping showed higher frequency of CNA. Losses 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 The Cancer Genome Atlas (TCGA) data when analysed with the same procedure. Furthermore, 79% of the genes with altered expression in our data were validated in the TCGA.Conclusions:Although CNA are frequent events in microsatellite stable CRC, few focal recurrent regions were found. These aberrations have strong effects on gene expression and contribute to deregulate relevant cancer pathways. Owing to the diploid nature of stromal cells, it is important to consider the purity of tumour samples to accurately calculate CNA events in CRC.

Redefining synchronous colorectal cancers based on tumor clonality

“…Moreover, the majority of the specific altered chromosomal regions related with the four defined categories have been related with CRC and/or a higher risk of its development as well (e.g. gain on 8q24 or deletions on 1p21, 1p13 or 1p36) . But more remarkable are gains on 20q13 and deletions on 18p11, two of the most frequently altered regions in PM group, that have been already described by Di et al, presenting similarly within their sample of 15 SCRC patients, in which they defined that synchronous tumors were of different genetic origins, therefore polyclonal.…”

“…gain on 8q24 or deletions on 1p21, 1p13 or 1p36). [37][38][39] But more remarkable are gains on 20q13 and deletions on 18p11, two of the most frequently altered regions in PM group, that have been already described by Di et al, 15 presenting similarly within their sample of 15 SCRC patients, in which they defined that synchronous tumors were of different genetic origins, therefore polyclonal.…”

Tumour purity as a prognostic factor in colon cancer

“…Unlike glioma, where increased SCNA events were detected in high purity tumours, SCNAs in CC were not significantly associated with purity (16). In line with our findings, a recent report showed that for microsatellite stable (MSS) CC, stroma proportion was not correlated with SCNA events (40). As high stromal proportion may disturb the measurement of SCNAs, the correlation between tumour purity and SCNAs need to be further investigated.…”

Screening the Cancer Genome Atlas Database for Genes of Prognostic Value in Acute Myeloid Leukemia

“…In this algorithm, the expression characteristics of specific genes in immune cells and stromal cells are analyzed to calculate immune and stromal score to predict non-tumor cell invasion. Recent reports indicate that ESTIMATE is used in the study of prostate cancer (20), breast cancer (21), and colon cancer (22). However, the characteristics of the TME evaluated by ESTIMATE were not observed in the AML.…”