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Clin Cancer Res. 2015 Feb 1;21(3):632-41. doi: 10.1158/1078-0432.CCR-13-3310. Epub 2014 Jul 23.

Integrative and comparative genomic analysis of HPV-positive and HPV-negative head and neck squamous cell carcinomas.

Author information

1
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.
2
Section of Hematology/Oncology, Department of Medicine, The University of Chicago, Chicago, Illinois.
3
Broad Institute of Harvard and MIT, Cambridge, Massachusetts. Department of Medical Oncology, Dana Farber Cancer Institute, Boston, Massachusetts.
4
Department of Pathology, Microbiology, and Immunology, Vanderbilt University, Nashville, Tennessee.
5
Department of Genetics, University of Pennsylvania, Philadelphia, Pennsylvania.
6
Broad Institute of Harvard and MIT, Cambridge, Massachusetts.
7
The University of Chicago Comprehensive Cancer Center, Chicago, Illinois. Department of Radiation Oncology, The University of Chicago, Chicago, Illinois.
8
The University of Chicago Comprehensive Cancer Center, Chicago, Illinois. Department of Otolaryngology/Head and Neck Surgery, The University of Chicago, Chicago, Illinois.
9
The University of Chicago Comprehensive Cancer Center, Chicago, Illinois. Department of Pathology, University of Chicago, Chicago, Illinois.
10
Section of Hematology/Oncology, Department of Medicine, The University of Chicago, Chicago, Illinois. The University of Chicago Comprehensive Cancer Center, Chicago, Illinois.
11
The University of Chicago Comprehensive Cancer Center, Chicago, Illinois. Institute for Genomics and Systems Biology, University of Chicago, Chicago, Illinois.

Abstract

PURPOSE:

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.

EXPERIMENTAL DESIGN:

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.

PMID:
25056374
PMCID:
PMC4305034
DOI:
10.1158/1078-0432.CCR-13-3310
[Indexed for MEDLINE]
Free PMC Article
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