The head and neck cancer cell oncogenome: a platform for the development of precision molecular therapies.

Daniel Martin,Yardena Samuels,Alfredo A Molinolo,Moraima Zaida,Lynn Vitale-Cross,Zhiyong Wang,J Silvio Gutkind,Martin C Abba,Naomi C Delic,J Guy Lyons

doi:10.18632/oncotarget.2417

Abstract

The recent elucidation of the genomic landscape of head and neck squamous cell carcinoma (HNSCC) has provided a unique opportunity to develop selective cancer treatment options. These efforts will require the establishment of relevant HNSCC models for preclinical testing. Here, we performed full exome and transcriptome sequencing of a large panel of HNSCC-derived cells from different anatomical locations and human papillomavirus (HPV) infection status. These cells exhibit typical mutations in TP53, FAT1, CDK2NA, CASP8, and NOTCH1, and copy number variations (CNVs) and mutations in PIK3CA, HRAS, and PTEN that reflect the widespread activation of the PI3K-mTOR pathway. SMAD4 alterations were observed that may explain the decreased tumor suppressive effect of TGF-β in HNSCC. Surprisingly, we identified HPV+ HNSCC cells harboring TP53 mutations, and documented aberrant TP53 expression in a subset of HPV+ HNSCC cases. This analysis also revealed that most HNSCC cells harbor multiple mutations and CNVs in epigenetic modifiers (e.g., EP300, CREBP, MLL1, MLL2, MLL3, KDM6A, and KDM6B) that may contribute to HNSCC initiation and progression. These genetically-defined experimental HNSCC cellular systems, together with the identification of novel actionable molecular targets, may now facilitate the pre-clinical evaluation of emerging therapeutic agents in tumors exhibiting each precise genomic alteration.

Highlights

head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide, with more than 500,000 new cases each year, of which only 40–50% will survive for 5 years
We selected a group of HNSCC cells ( referred as oral and pharyngeal cancer (OPC)-22 panel) and subjected them to a thorough characterization involving short tandem repeat (STR) analysis, whole exome capture sequencing, and mRNA sequencing
We confirmed the correct identity of previously reported cell lines (CAL27, CAL33, Detroit 562, UM-SCC-47, SCC-25, SCC-9, UM-SCC-11B and UMSCC-17B) [6], while the information generated about previously unreported HNSCC cell lines should serve as a bona fide reference for future studies

Summary

INTRODUCTION

HNSCC is the sixth most common cancer worldwide, with more than 500,000 new cases each year, of which only 40–50% will survive for 5 years. The lack of information regarding the primary molecular alterations in these cell lines has hampered the possibility of interpreting the emerging pre-clinical activity of recently developed therapeutic agents with the underlying mechanisms driving HNSCC progression This is relevant in the new era of precision medicine, in which the genetic alterations in each HNSCC lesions can be assessed in a clinically relevant setting. Building on prior multi institutional cancer sequencing efforts [9,10,11,12], we have characterized the genetic alterations and expressed messages of a large collection of representative HNSCC lines, including normal immortalized oral keratinocytes as well as cell lines derived from HPV- and HPV+ oral tumor lesions This HNSCC panel includes cell lines harboring the most frequent HNSCC alterations, which may provide a valuable tool for the future development and evaluation of molecular-guided therapeutic options for HNSCC

RESULTS

DISCUSSION

METHODS