Chromosome 3q26 Gain Is an Early Event Driving Coordinated Overexpression of the PRKCI, SOX2, and ECT2 Oncogenes in Lung Squamous Cell Carcinoma

Cell Rep. 2020 Jan 21;30(3):771-782.e6. doi: 10.1016/j.celrep.2019.12.071.

Abstract

Lung squamous cell carcinoma (LSCC) is a prevalent form of lung cancer exhibiting distinctive histological and genetic characteristics. Chromosome 3q26 copy number gain (CNG) is a genetic hallmark of LSCC present in >90% of tumors. We report that 3q26 CNGs occur early in LSCC tumorigenesis, persist during tumor progression, and drive coordinate overexpression of PRKCI, SOX2, and ECT2. Overexpression of PRKCI, SOX2, and ECT2 in the context of Trp53 loss is sufficient to transform mouse lung basal stem cells into tumors with histological and genomic features of LSCC. Functionally, PRKCI and SOX2 collaborate to activate an extensive transcriptional program that enforces a lineage-restricted LSCC phenotype, whereas PRKCI and ECT2 collaborate to promote oncogenic growth. Gene signatures indicative of PKCι-SOX2 and PKCι-ECT2 signaling activity are enriched in the classical subtype of human LSCC and predict distinct therapeutic vulnerabilities. Thus, the PRKCI, SOX2, and ECT2 oncogenes represent a multigenic driver of LSCC.

Keywords: 3q26 copy number gain; CNG; ECT2; LSCC; PRKCI; SOX2; lung basal stem cells; lung squamous cell carcinoma; oncogenic transformation.

Publication types

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

MeSH terms

  • Carcinogenesis / genetics
  • Carcinogenesis / pathology
  • Carcinoma, Non-Small-Cell Lung / genetics*
  • Carcinoma, Non-Small-Cell Lung / pathology
  • Carcinoma, Squamous Cell / genetics*
  • Carcinoma, Squamous Cell / pathology
  • Cell Line, Tumor
  • Cell Proliferation / genetics
  • Cell Transformation, Neoplastic
  • Chromosomes, Human, Pair 3 / genetics*
  • Gene Dosage
  • Gene Expression Regulation, Neoplastic
  • Gene Silencing
  • Humans
  • Isoenzymes / genetics*
  • Lung Neoplasms / genetics*
  • Lung Neoplasms / pathology
  • Male
  • Oncogenes*
  • Protein Kinase C / genetics*
  • Proto-Oncogene Proteins / genetics*
  • SOXB1 Transcription Factors / genetics*
  • Signal Transduction
  • Transcription, Genetic

Substances

  • ECT2 protein, human
  • Isoenzymes
  • Proto-Oncogene Proteins
  • SOX2 protein, human
  • SOXB1 Transcription Factors
  • Protein Kinase C
  • protein kinase C lambda