Molecular pathways associated with micro-vascular invasion HCC.

Abstract

249 Background: Microvascular invasion (MVI) in hepatocellular carcinoma (HCC) has a reported incidence of 15-57%. It is associated with decreased overall and recurrence free survival in post-surgical resection and transplant patients. Currently, the biology of MVI+ HCC remains unknown and the absence of effective adjuvant therapy limits management options to prevent recurrence. Aim: To correlate gene signatures observed at the transcriptomic level with the presence of MVI in HCC, analyze molecular pathways with gene expression tools and validate with TCGA database. Methods: Whole genome expression was studied in two groups of Asian resected HCC tumour specimens: (i) MVI present (MVI+) (n = 14) and (ii) MVI absent (MVI-) (n = 33) both without macrovascular invasion on radiological imaging. 2 distinct pathway analysis tools – gene set enrichment analysis (GSEA) and ingenuity pathway analysis (IPA) were performed to identify significantly enriched pathways potentially explaining the observed MVI+ HCC phenotype. Selected gene sets from the identified pathways were subjected to in-silico validation with TCGA data to confirm their enrichment within MVI+ HCC. Results: Within 14 MVI+ and 33 MVI- HCC studied, we have found a total of 1401 significantly differentially expressed genes between them; 766 genes were up-regulated and 635 genes were down-regulated in MVI+ HCC. At p < 0.05 and FDR < 0.25, GSEA and IPA analyses identified enrichment of PI3K/AKT/mTOR, HIF1α, AMPK signaling and actin-mediated cell kinetics pathways: actiny, Cdc42 signaling and actin pathways regulated by Rho. A 90 gene signature derived from these enriched pathways, created on the basis of biological function was used to compare between average expression within the MVI+ vs MVI- HCCs in the TCGA Asian cohort. Genes found differentially expressed at p < 0.05 corresponded with the enriched pathways: actiny, AMPK signaling and PI3K/AKT/mTOR. Conclusions: These pathways underscore functions in regulation of cell metabolism, growth, proliferation, survival, protein synthesis and cytoskeleton organization in MVI+ HCC. Further studies in these pathways may assist in development of molecular targeted therapies for MVI+ HCC. We propose to carry out a prospective study to validate this.