Utility of exome sequencing in routine care for metastatic colorectal cancer

Metastatic colorectal cancer (mCRC) is a heterogenous disease and its prognosis depends on clinical features, such as tumor sidedness, and whether it is metachronous or synchronous. However, little is known about the overall genomic characterization of mCRC in these clinical subtypes. This single-center observational study included 77 patients with mCRC who underwent somatic and germline exome analysis during the first or second line of therapy in 2018. Somatic and germline variants were determined in addition to tumor mutational burden, ploidy, clonality, human leucocyte antigen typing, neoantigens, and mutational and copy number signatures. Variables associated with sidedness, synchronous status and RAS status were determined using Fisher's test; and variables associated with overall survival were determined using univariate Cox survival models. The present study successfully generated whole exome sequencing analysis in 77 mCRC cases. Among them, 50 were left- and rectal-sided, while 27 were right-sided. Furthermore, 27 were metachronous and 46 were RAS-mutated. The median OS was 3.75 years. It was observed that signature single nucleotide variation (SNV) 26, oncogenic alterations in receptor tyrosine kinase and nucleotide excision repair pathways were associated with tumor sidedness. SNV signature 3, Hedgehog signaling and mismatch repair pathways were associated with synchronous status. Phosphatidylinositol signaling system, ERK signaling and chromatin organization pathways were associated with RAS mutant status. In the whole cohort, metachronous metastasis was associated with improved survival. On gene variation, PTEN, PDGFRA, MYCN and SMAD4 were associated with poor prognosis, as was SNV signature 15. In conclusion, this study highlighted that structural and pathway genomic features are associated with sidedness, synchronous status, RAS status and overall survival and could be helpful to improve the stratification of patients with colorectal cancer. Keywords: RAS status; biomarkers; colorectal cancer; exome; genomic characterisation; metachronous; sidedness; synchronous.