Comprehensive genomic profiling of anal squamous cell carcinoma reveals distinct genomically defined classes

Ann Oncol. 2016 Jul;27(7):1336-41. doi: 10.1093/annonc/mdw152. Epub 2016 Apr 6.


Background: Squamous cell cancers of the anal canal (ASCC) are increasing in frequency and lack effective therapies for advanced disease. Although an association with human papillomavirus (HPV) has been established, little is known about the molecular characterization of ASCC. A comprehensive genomic analysis of ASCC was undertaken to identify novel genomic alterations (GAs) that will inform therapeutic choices for patients with advanced disease.

Patients and methods: Hybrid-capture-based next-generation sequencing of exons from 236 cancer-related genes and intronic regions from 19 genes commonly rearranged in cancer was performed on 70 patients with ASCC. HPV status was assessed by aligning tumor sequencing reads to HPV viral genomes. GAs were identified using an established algorithm and correlated with HPV status.

Results: Sixty-one samples (87%) were HPV-positive. A mean of 3.5 GAs per sample was identified. Recurrent alterations in phosphoinositol-3-kinase pathway (PI3K/AKT/mTOR) genes including amplifications and homozygous deletions were present in 63% of cases. Clinically relevant GAs in genes involved in DNA repair, chromatin remodeling, or receptor tyrosine kinase signaling were observed in 30% of cases. Loss-of-function mutations in TP53 and CDKN2A were significantly enhanced in HPV-negative cases (P < 0.0001).

Conclusions: This is the first comprehensive genomic analysis of ASCC, and the results suggest new therapeutic approaches. Differing genomic profiles between HPV-associated and HPV-negative ASCC warrants further investigation and may require novel therapeutic and preventive strategies.

Keywords: HPV; PI3KCA; anal squamous cell carcinoma; comprehensive genomic profiling; targeted therapy.

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Anus Neoplasms / genetics*
  • Anus Neoplasms / pathology
  • Anus Neoplasms / virology
  • Carcinoma, Squamous Cell / genetics*
  • Carcinoma, Squamous Cell / pathology
  • Carcinoma, Squamous Cell / virology
  • Cyclin-Dependent Kinase Inhibitor p16
  • Cyclin-Dependent Kinase Inhibitor p18 / genetics*
  • Exons / genetics
  • Female
  • Genomics*
  • High-Throughput Nucleotide Sequencing
  • Humans
  • Male
  • Middle Aged
  • Mutation
  • Neoplasm Proteins / genetics
  • Nuclear Proteins / genetics
  • Papillomaviridae / genetics
  • Papillomaviridae / isolation & purification
  • Papillomaviridae / pathogenicity
  • Transcription Factors / genetics
  • Tumor Suppressor Protein p53 / genetics*


  • CDKN2A protein, human
  • Cyclin-Dependent Kinase Inhibitor p16
  • Cyclin-Dependent Kinase Inhibitor p18
  • Neoplasm Proteins
  • Nuclear Proteins
  • PI3KCA protein, human
  • TP53 protein, human
  • Transcription Factors
  • Tumor Suppressor Protein p53