Characterisation of genomic alterations in proximal and distal colorectal cancer patients

Background: Colorectal cancer (CRC) is one of the commonest cancers in Malaysia and majority of the patients will present with advanced disease at diagnosis particularly in cases of proximal CRCs. Little is known about the relationship between the genetic landscape and the anatomical location of the tumour as well as the prognostication in CRC patients. Objectives: The objectives of this study were to determine the somatic single nucleotide variants (SNV) and the cellular pathways between the proximal and distal CRCs. Methods: : Whole exome sequencing was performed using the Ion Proton platform on 10 pairs of normal and CRC samples. The sequencing results were analysed using the Torrent Suite Software and the variants were annotated using ANNOVAR followed by validation with Sanger sequencing. Results: : The commonly altered genes in CRCs are KRAS, APC, TP53 and ATM. APC is the most frequently altered gene in both proximal and distal CRCs. KRAS and ATM genes were exclusively altered in the proximal CRCs with a frequency of 60% and 40%, respectively. On the other hand, TP53 mutations did not show any CRC anatomical predominance. There were five recurrent novel variants in proximal CRCs and one recurrent novel variant in distal CRC. Wnt signalling pathway was the most frequently altered pathway in both proximal and distal CRCs whereas TGF-β and PI3K signalling pathways were predominantly altered in the proximal CRCs. Conclusion: We found that proximal CRCs presented with more variants and altered pathways as compared to distal CRCs. We also discovered that the TGF-Beta signalling (four mutations) and PI3K signalling (two mutations) pathways were exclusively altered in proximal CRCs. However, further study in larger series of samples coupled with functional studies will be needed to confirm the identified variants and determine their role in the genesis of proximal and distal CRCs.