Transposon mutagenesis identifies cooperating genetic drivers during keratinocyte transformation and cutaneous squamous cell carcinoma progression

PLoS Genet. 2021 Aug 16;17(8):e1009094. doi: 10.1371/journal.pgen.1009094. eCollection 2021 Aug.


The systematic identification of genetic events driving cellular transformation and tumor progression in the absence of a highly recurrent oncogenic driver mutation is a challenge in cutaneous oncology. In cutaneous squamous cell carcinoma (cuSCC), the high UV-induced mutational burden poses a hurdle to achieve a complete molecular landscape of this disease. Here, we utilized the Sleeping Beauty transposon mutagenesis system to statistically define drivers of keratinocyte transformation and cuSCC progression in vivo in the absence of UV-IR, and identified both known tumor suppressor genes and novel oncogenic drivers of cuSCC. Functional analysis confirms an oncogenic role for the ZMIZ genes, and tumor suppressive roles for KMT2C, CREBBP and NCOA2, in the initiation or progression of human cuSCC. Taken together, our in vivo screen demonstrates an extremely heterogeneous genetic landscape of cuSCC initiation and progression, which can be harnessed to better understand skin oncogenic etiology and prioritize therapeutic candidates.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Biomarkers, Tumor / genetics*
  • CREB-Binding Protein / genetics
  • Carcinoma, Squamous Cell / genetics*
  • Carcinoma, Squamous Cell / pathology
  • Cell Transformation, Neoplastic / genetics*
  • Cell Transformation, Neoplastic / pathology
  • DNA Transposable Elements
  • DNA-Binding Proteins / genetics
  • Disease Progression
  • Gene Expression Profiling
  • Gene Expression Regulation, Neoplastic
  • High-Throughput Nucleotide Sequencing
  • Humans
  • Keratinocytes / pathology*
  • Mutagenesis, Insertional / methods*
  • Nuclear Receptor Coactivator 2 / genetics
  • Sequence Analysis, DNA / methods*
  • Skin Neoplasms / genetics*
  • Skin Neoplasms / pathology


  • Biomarkers, Tumor
  • DNA Transposable Elements
  • DNA-Binding Proteins
  • KMT2C protein, human
  • NCOA2 protein, human
  • Nuclear Receptor Coactivator 2
  • CREB-Binding Protein
  • CREBBP protein, human

Associated data

  • figshare/10.5061/dryad.2v6wwpznv