Chromosomal instability analysis and regional tumor heterogeneity in colon cancer

Abstract

Chromosomal instability (CIN) is classically defined as an increase in the rate at which numerical or structural chromosomal aberrations are acquired in a cancer cell. The number of somatic copy number abnormalities (CNAs) revealed by high resolution genomic array can be considered as a surrogate marker for CIN, but several points, related to sample processing and data analysis, need to be standardized. In this work we analyzed 51 CRC samples and matched normal mucosae by whole genome SNP arrays and compared different bioinformatics tools in order to identify broad (>25% of a chromosomal arm) and focal somatic copy number abnormalities (BCNAs and FCNAs respectively). In 15 tumors, two samples, separated by at least 1 cm, were taken from the same tumor mass (double-sampling pairs) in order to evaluate differences in detection of chromosomal abnormalities between distant regions of the same tumor and their influence on CIN quantitative and qualitative analysis. Our data show a high degree of correlation of the quantitative CIN index (somatic BCNA number) between distant tumor regions. On the contrary, a lower correlation is observed in terms of chromosomal distribution of BCNAs, as summarized by a simplified cytogenetic table. Quantitative or qualitative analysis of FCNAs, including homozygous deletions and high level amplifications, did not add further information on the CIN status. The use of the index "somatic BCNA number" can be proposed for a robust classification of tumors as CIN positive or negative even in the presence of a significant tumor regional heterogeneity.