Majority of the proximal colorectal cancer (CRC) patients are presented with advanced disease at diagnosis. Little is known about the differences in the genomic landscape between proximal and the more common distal CRCs. The objectives of this study are to investigate the somatic single nucleotide variants (SNV) and the hypothetically affected cellular pathways between the proximal and distal CRC patients.Methods
Whole exome sequencing was performed on DNA extracted from 10 paired cancer-normal adjacent fresh frozen tissues using the Ion Proton platform. Sanger sequencing was performed to validate the variants identified in proximal and distal CRCs. In addition, in silico validation was performed on 619 CRC patients from The Cancer Genome Atlas (TCGA) study.Results
We obtained a total of 4835 and 4177 variants in proximal and distal CRC, respectively. In proximal CRC, 539 were protein-altering variants in 508 genes while the distal CRCs had 245 protein-altering mutations in 180 genes. The proximal CRCs showed significantly more protein-altering variants as compared to distal CRCs (p value=0.0001). We performed a comparison between mutation frequency in proximal versus distal CRCs from 619 TCGA patients and validated 37 predominantly altered genes in proximal CRCs. We observed that 90% (n=9) of the CRC patients shared an affected Wnt signalling pathway with five genes being altered (12 mutations). RTK-RAS and TP53 signalling pathways were also found to be altered in both proximal and distal CRCs with six mutations in both pathways. TGF-Beta signalling (four mutations) and PI3K signalling (two mutations) pathways were only altered in our proximal CRCs. There were more altered pathways in proximal as compared to distal CRCs but the difference was not significant (p=0.66).Conclusions
We found that proximal CRCs were presented with more variants and involved different pathways as compared to distal CRCs. Our findings suggest different pathways to tumourigenesis in proximal and distal CRCs that may be the cause of clinical differences. 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.