title: Integrative and comparative genomic analysis of HPV-positive and HPV-negative head and neck squamous cell carcinomas.
abstract: OBJECTIVE
  The genetic differences between human papilloma virus (HPV)-positive and -negative head and neck squamous cell carcinomas (HNSCC) remain largely unknown. To identify differential biology and novel therapeutic targets for both entities, we determined mutations and copy-number aberrations in a large cohort of locoregionally advanced HNSCC.
  
  
  METHODS
  We performed massively parallel sequencing of 617 cancer-associated genes in 120 matched tumor/normal samples (42.5% HPV-positive). Mutations and copy-number aberrations were determined and results validated with a secondary method.
  
  
  RESULTS
  The overall mutational burden in HPV-negative and HPV-positive HNSCC was similar with an average of 15.2 versus 14.4 somatic exonic mutations in the targeted cancer-associated genes. HPV-negative tumors showed a mutational spectrum concordant with published lung squamous cell carcinoma analyses with enrichment for mutations in TP53, CDKN2A, MLL2, CUL3, NSD1, PIK3CA, and NOTCH genes. HPV-positive tumors showed unique mutations in DDX3X, FGFR2/3 and aberrations in PIK3CA, KRAS, MLL2/3, and NOTCH1 were enriched in HPV-positive tumors. Currently targetable genomic alterations were identified in FGFR1, DDR2, EGFR, FGFR2/3, EPHA2, and PIK3CA. EGFR, CCND1, and FGFR1 amplifications occurred in HPV-negative tumors, whereas 17.6% of HPV-positive tumors harbored mutations in fibroblast growth factor receptor genes (FGFR2/3), including six recurrent FGFR3 S249C mutations. HPV-positive tumors showed a 5.8% incidence of KRAS mutations, and DNA-repair gene aberrations, including 7.8% BRCA1/2 mutations, were identified.
  
  
  CONCLUSIONS
  The mutational makeup of HPV-positive and HPV-negative HNSCC differs significantly, including targetable genes. HNSCC harbors multiple therapeutically important genetic aberrations, including frequent aberrations in the FGFR and PI3K pathway genes. See related commentary by Krigsfeld and Chung, p. 495.
authors: Section of Hematology/Oncology, Department of Medicine, The University of Chicago, Chicago, Illinois. The University of Chicago Comprehensive Cancer Center, Chicago, Illinois. Institute for Genomics and Systems Biology, University of Chicago, Chicago, Illinois. tseiwert@medicine.bsd.uchicago.edu.
authors: Tanguy Y
authors: TY
authors: Seiwert
authors: Section of Hematology/Oncology, Department of Medicine, The University of Chicago, Chicago, Illinois.
authors: Zhixiang
authors: Z
authors: Zuo
authors: Section of Hematology/Oncology, Department of Medicine, The University of Chicago, Chicago, Illinois.
authors: Michaela K
authors: MK
authors: Keck
authors: Section of Hematology/Oncology, Department of Medicine, The University of Chicago, Chicago, Illinois.
authors: Arun
authors: A
authors: Khattri
authors: Broad Institute of Harvard and MIT, Cambridge, Massachusetts. Department of Medical Oncology, Dana Farber Cancer Institute, Boston, Massachusetts.
authors: Chandra S
authors: CS
authors: Pedamallu
authors: Department of Pathology, Microbiology, and Immunology, Vanderbilt University, Nashville, Tennessee.
authors: Thomas
authors: T
authors: Stricker
authors: Department of Genetics, University of Pennsylvania, Philadelphia, Pennsylvania.
authors: Christopher
authors: C
authors: Brown
authors: Broad Institute of Harvard and MIT, Cambridge, Massachusetts. Department of Medical Oncology, Dana Farber Cancer Institute, Boston, Massachusetts.
authors: Trevor J
authors: TJ
authors: Pugh
authors: Broad Institute of Harvard and MIT, Cambridge, Massachusetts.
authors: Petar
authors: P
authors: Stojanov
authors: Broad Institute of Harvard and MIT, Cambridge, Massachusetts.
authors: Juok
authors: J
authors: Cho
authors: Broad Institute of Harvard and MIT, Cambridge, Massachusetts.
authors: Michael S
authors: MS
authors: Lawrence
authors: Broad Institute of Harvard and MIT, Cambridge, Massachusetts.
authors: Gad
authors: G
authors: Getz
authors: Section of Hematology/Oncology, Department of Medicine, The University of Chicago, Chicago, Illinois.
authors: Johannes
authors: J
authors: Brägelmann
authors: Section of Hematology/Oncology, Department of Medicine, The University of Chicago, Chicago, Illinois.
authors: Rebecca
authors: R
authors: DeBoer
authors: The University of Chicago Comprehensive Cancer Center, Chicago, Illinois. Department of Radiation Oncology, The University of Chicago, Chicago, Illinois.
authors: Ralph R
authors: RR
authors: Weichselbaum
authors: The University of Chicago Comprehensive Cancer Center, Chicago, Illinois. Department of Otolaryngology/Head and Neck Surgery, The University of Chicago, Chicago, Illinois.
authors: Alexander
authors: A
authors: Langerman
authors: The University of Chicago Comprehensive Cancer Center, Chicago, Illinois. Department of Otolaryngology/Head and Neck Surgery, The University of Chicago, Chicago, Illinois.
authors: Louis
authors: L
authors: Portugal
authors: The University of Chicago Comprehensive Cancer Center, Chicago, Illinois. Department of Otolaryngology/Head and Neck Surgery, The University of Chicago, Chicago, Illinois.
authors: Elizabeth
authors: E
authors: Blair
authors: The University of Chicago Comprehensive Cancer Center, Chicago, Illinois. Department of Otolaryngology/Head and Neck Surgery, The University of Chicago, Chicago, Illinois.
authors: Kerstin
authors: K
authors: Stenson
authors: The University of Chicago Comprehensive Cancer Center, Chicago, Illinois. Department of Pathology, University of Chicago, Chicago, Illinois.
authors: Mark W
authors: MW
authors: Lingen
authors: Section of Hematology/Oncology, Department of Medicine, The University of Chicago, Chicago, Illinois. The University of Chicago Comprehensive Cancer Center, Chicago, Illinois.
authors: Ezra E W
authors: EE
authors: Cohen
authors: Section of Hematology/Oncology, Department of Medicine, The University of Chicago, Chicago, Illinois. The University of Chicago Comprehensive Cancer Center, Chicago, Illinois.
authors: Everett E
authors: EE
authors: Vokes
authors: The University of Chicago Comprehensive Cancer Center, Chicago, Illinois. Institute for Genomics and Systems Biology, University of Chicago, Chicago, Illinois.
authors: Kevin P
authors: KP
authors: White
authors: Broad Institute of Harvard and MIT, Cambridge, Massachusetts. Department of Medical Oncology, Dana Farber Cancer Institute, Boston, Massachusetts.
authors: Peter S
authors: PS
authors: Hammerman
mesh_terms: D000328:Adult; D000368:Aged; D002294:Carcinoma, Squamous Cell / Q000209:etiology* / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D015331:Cohort Studies; D056915:DNA Copy Number Variations; D005260:Female; D020869:Gene Expression Profiling; D023281:Genomics; D006258:Head and Neck Neoplasms / Q000209:etiology* / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D052162:Human papillomavirus 16; D052161:Human papillomavirus 18; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009367:Neoplasm Staging; D027383:Papillomaviridae; D030361:Papillomavirus Infections / Q000150:complications*; D011379:Prognosis; D060066:Protein Interaction Maps; D012307:Risk Factors; D015398:Signal Transduction; D000077195:Squamous Cell Carcinoma of Head and Neck; D014412:Tumor Virus Infections / Q000150:complications*