Genomic analysis of metastatic cutaneous squamous cell carcinoma

Clin Cancer Res. 2015 Mar 15;21(6):1447-56. doi: 10.1158/1078-0432.CCR-14-1773. Epub 2015 Jan 14.


Purpose: A rare 5% of cutaneous squamous cell carcinomas (cSCC) metastasize, lack FDA-approved therapies, and carry a poor prognosis. Our aim was to identify recurrent genomic alterations in this little-studied population of metastatic cSCCs.

Experimental design: We performed targeted sequencing of 504 cancer-associated genes on lymph node metastases in 29 patients with cSCC and identified mutations and somatic copy-number alterations associated with metastatic cSCC. We determined significantly mutated, deleted, and amplified genes and associated genomic alterations with clinical variables.

Results: The cSCC genome is heterogeneous with widely varying numbers of genomic alterations and does not appear to be associated with human papillomavirus. We found previously identified recurrently altered genes (TP53, CDKN2A, NOTCH1/2) but also a wide spectrum of oncogenic mutations affecting RAS/RTK/PI3K, squamous differentiation, cell cycle, and chromatin remodeling pathway genes. Specific mutations in known oncogenic drivers and pathways were correlated with inferior patient outcomes. Our results suggest potential therapeutic targets in metastatic cSCC, including PIK3CA, FGFR3, BRAF, and EGFR, similar to those reported in SCCs of the lung and head and neck, suggesting that clinical trials could be developed to accrue patients with SCCs from multiple sites of origin.

Conclusions: We have genomically characterized a rare cohort of 29 metastatic cSCCs and identified a diverse array of oncogenic alterations that can guide future studies of this disease.

Publication types

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

MeSH terms

  • Aged
  • Aged, 80 and over
  • Base Sequence
  • Carcinoma, Squamous Cell / genetics*
  • Class I Phosphatidylinositol 3-Kinases
  • Cyclin-Dependent Kinase Inhibitor p16 / genetics
  • Female
  • Gene Expression Profiling
  • Humans
  • Lymphatic Metastasis / genetics*
  • Male
  • Middle Aged
  • Mutation / genetics*
  • Phosphatidylinositol 3-Kinases / genetics
  • Receptor, Notch1 / genetics
  • Receptor, Notch2 / genetics
  • Sequence Analysis, DNA
  • Skin Neoplasms / genetics*
  • Tumor Suppressor Protein p53 / genetics
  • ras GTPase-Activating Proteins / genetics


  • Cyclin-Dependent Kinase Inhibitor p16
  • NOTCH1 protein, human
  • NOTCH2 protein, human
  • Receptor, Notch1
  • Receptor, Notch2
  • TP53 protein, human
  • Tumor Suppressor Protein p53
  • ras GTPase-Activating Proteins
  • Phosphatidylinositol 3-Kinases
  • Class I Phosphatidylinositol 3-Kinases
  • PIK3CA protein, human