Research Paper Volume 12, Issue 13 pp 12703—12725

Epigenomic and genomic analysis of transcriptome modulation in skin cutaneous melanoma

Wuzhen Chen1,6, , Pu Cheng2,6, , Jingxin Jiang1,6, , Yunqing Ren2,3, , Dang Wu4,6, , Dan Xue5,6, ,

  • 1 Department of Surgical Oncology, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou Zhejiang, P.R. China
  • 2 Department of Gynecology, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou Zhejiang, P.R. China
  • 3 Department of Dermatology, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou Zhejiang, P.R. China
  • 4 Department of Radiation Oncology, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou Zhejiang, P.R. China
  • 5 Department of Plastic Surgery, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou Zhejiang, P.R. China
  • 6 Key Laboratory of Tumor Microenvironment and Immune Therapy of Zhejiang Province, Hangzhou, China

Received: December 30, 2019       Accepted: March 31, 2020       Published: July 7, 2020      

https://doi.org/10.18632/aging.103115
How to Cite

Copyright © 2020 Chen et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Abstract

Skin cutaneous melanoma (SKCM) is characterized by both epigenetic DNA methylation (MET) abnormalities and genomic copy number variations (CNVs). The resulting transcriptome dysregulation promotes progression of many cancers. In this study, DNA copy numbers and MET, as well as mRNA expression, were examined in 466 SKCM samples from The Cancer Genome Atlas. Our results indicate that CNVs-correlated (CNVcor) genes and MET-correlated (METcor) genes are coregulated to a remarkable degree. In addition, integrative multi-omics analysis of both METcor and CNVcor genes revealed four SKCM subtypes with differing prognoses; these subtypes were validated with independent data. Immune cell scores were markedly elevated in the iC1 subtype, which had the best prognosis. Immune cell infiltration correlated with DNA MET or CNV level in SKCM. In the iC3 subtype, which was associated with the most aggressive SKCM cases, FAM135B gene mutation frequencies were increased, while CD8A, GBP5, KIAA0040, and SAMHD1 expression were downregulated, suggesting that these genes play important roles in cancer development and immune responses. Taken together, the results of our epigenetic and genomic transcriptome modulation analysis improve our understanding of SKCM pathobiology and may aid in the development of more effective therapies.

Abbreviations

CNV: copy number variation; DEG: differentially expressed gene; GBP: guanylate-binding protein; GTPases: guanosine triphosphate hydrolases; MET: methylation; mRNA: messenger RNA; NMF: negative matrix factorization; OS: overall survival; PPI: protein-protein interaction; SKCM: skin cutaneous melanoma.