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Integrative and comparative genomic analysis of HPV-positive and HPV-negative head and neck squamous cell carcinomas.
|Publication Type||Journal Article|
|Authors||Seiwert, TY, Zuo Z., Keck MK, Khattri A., Pedamallu CS, Stricker TP, Brown CD, Pugh TJ, Stojanov P., Cho J., Lawrence M., Getz G., Bragelmann J., DeBoer R., Weichselbaum RR, Langerman A., Portugal LD, Blair EA, Stenson KM, Lingen MW, Cohen EE, Vokes EE, White KP, and Hammerman PS|
|Abstract||Purpose: The genetic differences between Human papilloma Virus (HPV)-positive and negative head and neck squamous cell carcinomas (HNSCC) remain largely unknown. In order 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, while 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.|
|Year of Publication||2014|
|Journal||Clinical cancer research : an official journal of the American Association for Cancer Research|
|Date Published (YYYY/MM/DD)||2014/07/23|