Genomic analysis reveals recurrent deletion of JAK-STAT signaling inhibitors HNRNPK and SOCS1 in mycosis fungoides

Genes Chromosomes Cancer. 2018 Dec;57(12):653-664. doi: 10.1002/gcc.22679. Epub 2018 Oct 25.

Abstract

Mycosis fungoides (MF) is the most common cutaneous T-cell lymphoma (CTCL). Causative genetic alterations in MF are unknown. The low recurrence of pathogenic small-scale mutations (ie, nucleotide substitutions, indels) in the disease, calls for the study of additional aspects of MF genetics. Here, we investigated structural genomic alterations in tumor-stage MF by integrating whole-genome sequencing and RNA-sequencing. Multiple genes with roles in cell physiology (n = 113) and metabolism (n = 92) were found to be impacted by genomic rearrangements, including 47 genes currently implicated in cancer. Fusion transcripts involving genes of interest such as DOT1L, KDM6A, LIFR, TP53, and TP63 were also observed. Additionally, we identified recurrent deletions of genes involved in cell cycle control, chromatin regulation, the JAK-STAT pathway, and the PI-3-K pathway. Remarkably, many of these deletions result from genomic rearrangements. Deletion of tumor suppressors HNRNPK and SOCS1 were the most frequent genetic alterations in MF after deletion of CDKN2A. Notably, SOCS1 deletion could be detected in early-stage MF. In agreement with the observed genomic alterations, transcriptome analysis revealed up-regulation of the cell cycle, JAK-STAT, PI-3-K and developmental pathways. Our results position inactivation of HNRNPK and SOCS1 as potential driver events in MF development.

Keywords: JAK-STAT signaling; RNA sequencing; cutaneous T-cell lymphoma; genomic rearrangements; mycosis fungoides; whole-genome sequencing.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aneuploidy
  • Gene Deletion*
  • Gene Dosage
  • Gene Expression Profiling
  • Gene Expression Regulation, Neoplastic
  • Gene Fusion
  • Gene Rearrangement
  • Heterogeneous-Nuclear Ribonucleoprotein K / genetics*
  • Humans
  • Janus Kinases / antagonists & inhibitors
  • MAP Kinase Signaling System* / genetics
  • Mycosis Fungoides / enzymology
  • Mycosis Fungoides / genetics*
  • Polymorphism, Single Nucleotide
  • RNA, Neoplasm
  • Sequence Analysis, RNA
  • Skin Neoplasms / enzymology
  • Skin Neoplasms / genetics*
  • Suppressor of Cytokine Signaling 1 Protein / genetics*
  • Whole Genome Sequencing

Substances

  • Heterogeneous-Nuclear Ribonucleoprotein K
  • RNA, Neoplasm
  • SOCS1 protein, human
  • Suppressor of Cytokine Signaling 1 Protein
  • HNRNPK protein, human
  • Janus Kinases