Long-term survival post-transplant is significantly impacted by malignancy. mTOR-inhibitors (mTORis) have anti-neoplastic properties and are associated with a decreased incidence of certain malignancies compared to calcineurin inhibitors (CNIs). Our aim was to elucidate the molecular basis of this difference in susceptibility to malignancy. Liver transplant (LT) recipients who had undergone direct conversion from tacrolimus to sirolimus monotherapy as part of a prior study were included. Gene expression profiling (PBMC RNA) was performed with Affymetrix GeneChip 1.0 ST arrays before and 6 months after conversion. We determined key dysregulated genes and pathways with conversion, using Ingenuity Pathway Analysis (IPA) software. Overlap with genes and pathways from PBMCs and tissue hepatocellular carcinoma (HCC) was assessed, based on data from Gene Expression Omnibus (GEO).

Twenty non-immune, non-viremic patients (age 57.2±8; 3.5±2.1 years post-LT) were included. Upon conversion from tacrolimus to sirolimus, 57 genes were downmodulated and 36 were upregulated. Upon assessing overlap between sirolimus and dysregulated genes in PBMCs and tumors of HCC patients, we identified 23 downmodulated genes in HCC to be upmodulated by sirolimus. Conversely, 12 genes upmodulated in HCC were downmodulated by sirolimus. These genes are involved in cell proliferation (FDR p=0.000274), signal transduction (FDR p=0.00198) and DNA replication initiation (FDR p=0.000274).

Using integrative analysis, we found that decreased susceptibility to malignancy with mTOR-inhibitor conversion may be explained by decreased representation of pro-carcinogenic biological processes. Future validation will include assessing whether these gene expression patterns predict malignancy risk in patients, and whether patients with higher-risk gene profiles should be converted from CNIs to mTORis.

CITATION INFORMATION: Bhat M., Pasini E., Baciu C., Kurian S., Levitsky J. Decreased Expression of Pro-Carcinogenic Genes Following Tacrolimus to Sirolimus Conversion in Liver Transplant Recipients Am J Transplant. 2017;17 (suppl 3).

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