Genomic Analysis Identifies New Drivers and Progression Pathways in Skin Basal Cell Carcinoma

Nat Genet. 2016 Apr;48(4):398-406. doi: 10.1038/ng.3525. Epub 2016 Mar 7.

Abstract

Basal cell carcinoma (BCC) of the skin is the most common malignant neoplasm in humans. BCC is primarily driven by the Sonic Hedgehog (Hh) pathway. However, its phenotypic variation remains unexplained. Our genetic profiling of 293 BCCs found the highest mutation rate in cancer (65 mutations/Mb). Eighty-five percent of the BCCs harbored mutations in Hh pathway genes (PTCH1, 73% or SMO, 20% (P = 6.6 × 10(-8)) and SUFU, 8%) and in TP53 (61%). However, 85% of the BCCs also harbored additional driver mutations in other cancer-related genes. We observed recurrent mutations in MYCN (30%), PPP6C (15%), STK19 (10%), LATS1 (8%), ERBB2 (4%), PIK3CA (2%), and NRAS, KRAS or HRAS (2%), and loss-of-function and deleterious missense mutations were present in PTPN14 (23%), RB1 (8%) and FBXW7 (5%). Consistent with the mutational profiles, N-Myc and Hippo-YAP pathway target genes were upregulated. Functional analysis of the mutations in MYCN, PTPN14 and LATS1 suggested their potential relevance in BCC tumorigenesis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anilides / therapeutic use
  • Antineoplastic Agents / therapeutic use
  • Carcinogenesis / genetics
  • Carcinoma, Basal Cell / drug therapy
  • Carcinoma, Basal Cell / genetics*
  • Carcinoma, Basal Cell / pathology
  • DNA Mutational Analysis
  • Disease Progression
  • Exome
  • Genetic Association Studies
  • Genetic Predisposition to Disease
  • HEK293 Cells
  • Humans
  • Mutation
  • Pyridines / therapeutic use
  • Signal Transduction / radiation effects*
  • Skin Neoplasms / drug therapy
  • Skin Neoplasms / genetics*
  • Skin Neoplasms / pathology
  • Transcriptome

Substances

  • Anilides
  • Antineoplastic Agents
  • HhAntag691
  • Pyridines