Identification of candidate driver genes in common focal chromosomal aberrations of microsatellite stable colorectal cancer

Abstract

Colorectal cancer (CRC) is a leading cause of cancer deaths worldwide. Chromosomal instability (CIN) is a major driving force of microsatellite stable (MSS) sporadic CRC. CIN tumours are characterised by a large number of somatic chromosomal copy number aberrations (SCNA) that frequently affect oncogenes and tumour suppressor genes. The main aim of this work was to identify novel candidate CRC driver genes affected by recurrent and focal SCNA. High resolution genome-wide comparative genome hybridisation (CGH) arrays were used to compare tumour and normal DNA for 53 sporadic CRC cases. Context corrected common aberration (COCA) analysis and custom algorithms identified 64 deletions and 32 gains of focal minimal common regions (FMCR) at high frequency (>10%). Comparison of these FMCR with published genomic profiles from CRC revealed common overlap (42.2% of deletions and 34.4% of copy gains). Pathway analysis showed that apoptosis and p53 signalling pathways were commonly affected by deleted FMCR, and MAPK and potassium channel pathways by gains of FMCR. Candidate tumour suppressor genes in deleted FMCR included RASSF3, IFNAR1, IFNAR2 and NFKBIA and candidate oncogenes in gained FMCR included PRDM16, TNS1, RPA3 and KCNMA1. In conclusion, this study confirms some previously identified aberrations in MSS CRC and provides in silico evidence for some novel candidate driver genes.

Figure 1. Distribution of CNA in 40 CIN tumour samples.

Data from the 180K format array are shown. Red represents gains and green represents deletions. The y-axis reflects frequency.

Figure 2. CNA identified in 40 CIN tumour samples (180K format array).

Representation of all the CNA identified in 40 chromosomally unstable cases analysed using the 180K platform. Red represents gain and green represents deletion. Dotted lines mark centromeres. Molecular and clinical features in order from top; PIK3CA, APC, TP53, KRAS and BRAF mutation status (blue and white represents mutant and WT respectively), CIMP (red, orange and green represent CIMP-H, CIMP-L and CIMP-N respectively), patient’s gender (pink and grey represent female and male respectively) and tumour location (yellow and cyan represent proximal and distal respectively).