title: Targeted next-generation sequencing of head and neck squamous cell carcinoma identifies novel genetic alterations in HPV+ and HPV- tumors.
abstract: BACKGROUND
  Human papillomavirus positive (HPV+) head and neck squamous cell carcinoma (HNSCC) is an emerging disease, representing a distinct clinical and epidemiological entity. Understanding the genetic basis of this specific subtype of cancer could allow therapeutic targeting of affected pathways for a stratified medicine approach.
  
  
  METHODS
  Twenty HPV+ and 20 HPV- laser-capture microdissected oropharyngeal carcinomas were used for paired-end sequencing of hybrid-captured DNA, targeting 3,230 exons in 182 genes often mutated in cancer. Copy number alteration (CNA) profiling, Sequenom MassArray sequencing and immunohistochemistry were used to further validate findings.
  
  
  RESULTS
  HPV+ and HPV- oropharyngeal carcinomas cluster into two distinct subgroups. TP53 mutations are detected in 100% of HPV negative cases and abrogation of the G1/S checkpoint by CDKN2A/B deletion and/or CCND1 amplification occurs in the majority of HPV- tumors.
  
  
  CONCLUSIONS
  These findings strongly support a causal role for HPV, acting via p53 and RB pathway inhibition, in the pathogenesis of a subset of oropharyngeal cancers and suggest that studies of CDK inhibitors in HPV- disease may be warranted. Mutation and copy number alteration of PI3 kinase (PI3K) pathway components appears particularly prevalent in HPV+ tumors and assessment of these alterations may aid in the interpretation of current clinical trials of PI3K, AKT, and mTOR inhibitors in HNSCC.
authors.affiliation: UCL Cancer Institute, University College London, 72 Huntley Street, London, WC1E 6BT, UK ; Head and Neck Centre, University College London Hospitals NHS Trust, Euston Road, London, NW1 2PG, UK.
authors.forename: Matthias
authors.initials: M
authors.lastname: Lechner
authors.affiliation: Foundation Medicine, One Kendall Square, Suite B3501, Cambridge, MA 02139, USA.
authors.forename: Garrett M
authors.initials: GM
authors.lastname: Frampton
authors.affiliation: UCL Cancer Institute, University College London, 72 Huntley Street, London, WC1E 6BT, UK.
authors.forename: Tim
authors.initials: T
authors.lastname: Fenton
authors.affiliation: UCL Cancer Institute, University College London, 72 Huntley Street, London, WC1E 6BT, UK.
authors.forename: Andrew
authors.initials: A
authors.lastname: Feber
authors.affiliation: Foundation Medicine, One Kendall Square, Suite B3501, Cambridge, MA 02139, USA.
authors.forename: Gary
authors.initials: G
authors.lastname: Palmer
authors.affiliation: Department of Histopathology, University College London Hospitals NHS Trust, Rockefeller Building, University Street, London, WC1E 6JJ, UK.
authors.forename: Amrita
authors.initials: A
authors.lastname: Jay
authors.affiliation: UCL Cancer Institute, University College London, 72 Huntley Street, London, WC1E 6BT, UK.
authors.forename: Nischalan
authors.initials: N
authors.lastname: Pillay
authors.affiliation: UCL Cancer Institute, University College London, 72 Huntley Street, London, WC1E 6BT, UK ; Head and Neck Centre, University College London Hospitals NHS Trust, Euston Road, London, NW1 2PG, UK.
authors.forename: Martin
authors.initials: M
authors.lastname: Forster
authors.affiliation: Foundation Medicine, One Kendall Square, Suite B3501, Cambridge, MA 02139, USA.
authors.forename: Maureen T
authors.initials: MT
authors.lastname: Cronin
authors.affiliation: Foundation Medicine, One Kendall Square, Suite B3501, Cambridge, MA 02139, USA.
authors.forename: Doron
authors.initials: D
authors.lastname: Lipson
authors.affiliation: Foundation Medicine, One Kendall Square, Suite B3501, Cambridge, MA 02139, USA.
authors.forename: Vincent A
authors.initials: VA
authors.lastname: Miller
authors.affiliation: Foundation Medicine, One Kendall Square, Suite B3501, Cambridge, MA 02139, USA.
authors.forename: Timothy A
authors.initials: TA
authors.lastname: Brennan
authors.affiliation: UCL Cancer Institute, University College London, 72 Huntley Street, London, WC1E 6BT, UK.
authors.forename: Stephen
authors.initials: S
authors.lastname: Henderson
authors.affiliation: Head and Neck Centre, University College London Hospitals NHS Trust, Euston Road, London, NW1 2PG, UK.
authors.forename: Francis
authors.initials: F
authors.lastname: Vaz
authors.affiliation: Head and Neck Centre, University College London Hospitals NHS Trust, Euston Road, London, NW1 2PG, UK.
authors.forename: Paul
authors.initials: P
authors.lastname: O'Flynn
authors.affiliation: Head and Neck Centre, University College London Hospitals NHS Trust, Euston Road, London, NW1 2PG, UK.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Kalavrezos
authors.affiliation: Foundation Medicine, One Kendall Square, Suite B3501, Cambridge, MA 02139, USA.
authors.forename: Roman
authors.initials: R
authors.lastname: Yelensky
authors.affiliation: UCL Cancer Institute, University College London, 72 Huntley Street, London, WC1E 6BT, UK.
authors.forename: Stephan
authors.initials: S
authors.lastname: Beck
authors.affiliation: Foundation Medicine, One Kendall Square, Suite B3501, Cambridge, MA 02139, USA.
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Stephens
authors.affiliation: UCL Cancer Institute, University College London, 72 Huntley Street, London, WC1E 6BT, UK.
authors.forename: Chris
authors.initials: C
authors.lastname: Boshoff