Meta-analysis identifies upregulation of several novel genes that have not been previously described, and suggests the potential role of ERBB2 and extracellular genes in the pathogenesis of CCA.
There is great need for development of novel therapeutic strategies in CCA. A meta-analysis was conducted to better understand the pathobiology of CCA and identify novel candidate genes that might be potential targets for therapeutic intervention; results of this analysis were presented at the ASCO 2020 Gastrointestinal Cancers Symposium and summarized here.
In this analysis, the STARGEO platform was utilized to conduct a meta-analysis of public data from the National Center for Biotechnology Information’s Gene Expression Omnibus. The meta-analysis was performed with 259 CCA tumor samples and 16 normal intrahepatic duct samples (control). The gene signature of the samples was analyzed using Ingenuity Pathway Analysis.
The meta-analysis found that farnesoid X receptor/retinoid X receptor, liver X receptor/retinoid X receptor activation, coagulation system, and acute-phase response signaling, intrinsic prothrombin activation pathway were key canonical pathways implicated in pathogenesis of CCA. Several genes were found to be unregulated in CCA, many that have not been described in CCA, including extracellular matrix proteins (COL1A1, LAMC2), KRT17 (a keratin), and LAMB3 (PI3K/AKT signaling), as well as the immunophilin FKBP1A that is involved in mTOR activation, the ubiquitin-associated gene UBASH3B that inhibits endocytosis in EGFR. Significant upregulation of immune checkpoint proteins such as CTLA4 (P = .0289), TIGIT (P = .000310), and BTLA (P = .00949) were also observed. In addition, upregulation of SIGLEC7 (P = .0155) was documented, which is implicated in suppression of immune function. Several genes were also found to be downregulated, such as CELA3B, CPA1, CTRC, PLA2G1B, PRSS2, APOC2/4, CAP2, TTR, TAT, and F9. The potential role of ERBB2 in the regulation of oncogenes in CCA, including TP53, MYC, CDKN2A, and STAT3, was demonstrated.
These results suggest the potential role of ERBB2 and extracellular genes in the pathogenesis of CCA and identified novel genes that were not previously described in CCA.
Source: Aljabban N, et al. J Clin Oncol. 2020;38(4_suppl). Abstract 584.