Potential methylation-regulated genes and pathways in hepatocellular neoplasm, not otherwise specified

Shengmei Zhou; Meng Li; Dejerianne Ostrow; David Ruble; Leo Mascarenhas; Bruce Pawel; Jonathan David Buckley; Timothy J Triche

doi:10.3389/fonc.2022.952325

Potential methylation-regulated genes and pathways in hepatocellular neoplasm, not otherwise specified

Front Oncol. 2022 Sep 21:12:952325. doi: 10.3389/fonc.2022.952325. eCollection 2022.

Authors

Shengmei Zhou^{1

2}, Meng Li³, Dejerianne Ostrow¹, David Ruble¹, Leo Mascarenhas^{2

4}, Bruce Pawel^{1

2}, Jonathan David Buckley^{1

2}, Timothy J Triche^{1

2}

Affiliations

¹ Department of Pathology and Laboratory Medicine, Children's Hospital Los Angeles, Los Angeles, CA, United States.
² Keck School of Medicine, University of Southern California, Los Angeles, CA, United States.
³ USC Libraries Bioinformatics Services, University of Southern California, Los Angeles, CA, United States.
⁴ Cancer and Blood Disease Institute, Division of Hematology/Oncology, Department of Pediatrics, Children's Hospital Los Angeles, Los Angeles, CA, United States.

Abstract

Background and aims: The molecular basis of hepatocellular neoplasm, not otherwise specified (HCN-NOS) is unknown. We aimed to identify gene expression patterns, potential methylation-regulated genes and pathways that characterize the tumor, and its possible relationship to hepatoblastoma and hepatocellular carcinoma (HCC).

Approach & results: Parallel genome-wide profiling of gene expression (RNAseq) and DNA methylation (EPIC850) was performed on 4 pairs of pre-treatment HCN-NOS tumors and adjacent non-tumor controls. 2530 significantly differentially expressed genes (DEGs) were identified between tumors and controls. Many of these DEGs were associated with hepatoblastoma and/or HCC. Analysis Match in Ingenuity Pathway Analysis determined that the gene expression profile of HCN-NOS was unique but significantly similar to that of both hepatoblastoma and HCC. A total of 27,195 CpG sites (CpGs) were significantly differentially methylated (DM) between tumors and controls, with a global hypomethylation pattern and predominant CpG island hypermethylation in promotor regions. Aberrant DNA methylation predominated in Developmental Process and Molecular Function Regulator pathways. Embryonic stem cell pathways were significantly enriched. In total, 1055 aberrantly methylated (at CpGs) and differentially expressed genes were identified, including 25 upstream regulators and sixty-one potential CpG island methylation-regulated genes. Eight methylation-regulated genes (TCF3, MYBL2, SRC, HMGA2, PPARGC1A, SLC22A1, COL2A1 and MYCN) had highly consistent gene expression patterns and prognostic value in patients with HCC, based on comparison to publicly available datasets.

Conclusions: HCN-NOS has a unique, stem-cell like gene expression and DNA methylation profile related to both hepatoblastoma and HCC but distinct therefrom. Further, 8 methylation-regulated genes associated with prognosis in HCC were identified.

Keywords: EPIC850; RNAseq; genome-wide DNA methylation; hepatoblastoma; hepatocellular carcinoma; hepatocellular neoplasm; not otherwise specified.