Integrative Genomic Characterization of Oral Squamous Cell Carcinoma Identifies Frequent Somatic Drivers

Abstract

The survival of patients with oral squamous cell carcinoma (OSCC) has not changed significantly in several decades, leading clinicians and investigators to search for promising molecular targets. To this end, we performed comprehensive genomic analysis of gene expression, copy number, methylation and point mutations in OSCC. Integrated analysis revealed more somatic events than previously reported, identifying four major driver pathways (mitogenic signaling, Notch, cell cycle, TP53) and two additional key genes (FAT1, CASP8). The Notch pathway was defective in 66% of patients, and in follow-up studies of mechanism, functional NOTCH1 signaling inhibited proliferation of OSCC cell lines. Frequent mutation of CASP8 defines a new molecular subtype of OSCC with few copy number changes. Although genomic alterations are dominated by loss of tumor suppressor genes, 80% of patients harbored at least one genomic alteration in a targetable gene, suggesting that novel approaches to treatment may be possible for this debilitating disease.

Mutation and Transcriptional Profiling of Formalin-Fixed Paraffin Embedded Specimens as Companion Methods to Immunohistochemistry for Determining Therapeutic Targets in Oropharyngeal Squamous Cell Carcinoma (OPSCC): A Pilot of Proof of Principle

“…Interestingly, the p.R88Q mutation identified in one of our HPV-positive samples (HPV?_4) was found in one tumor in the TCGA dataset, a HPVpositive sample (ID# TCGA-CR-6471) that also had a p.M1043V mutation. The p.R88Q (COSM746) and p.M1043V (COSM12591) have been reported in other cancers [27,28], but to the best of our knowledge, not as co-occurring in a HNSCC tumor. There was no evidence of the p.M1043V mutation in our HPV?_4 specimen, and therefore the p.R88Q may be recurrent in a minor population of HPV-positive tumors.…”

“…With several highly cited genomic studies in head and neck tumors and a soon to be released TCGA study, it is clear that there is an opportunity to identify mutation, copy number and differential gene expression in these tumors to better inform treatment and prognosis than by HPV status alone [27][28][29][48][49][50][51]. The mutational spectrum shown in the HPV-negative tumors of this small study demonstrated a high mutational burden in these tumors and a source of potential difficulty in interpreting and reporting using exome or many ([100) gene diagnostic panels which could yield hundreds or thousands of variant calls.…”

Does Notch play a tumor suppressor role across diverse squamous cell carcinomas?

“…Activation of Notch signaling by expressing full‐length NOTCH1 or its activated form ICN in human OSCC or HNSCC cell lines leads to cell growth arrest 9, 27, 60. Consistently, inhibition of NOTCH activation promoted tumor growth in a HNSCC cell line harboring wild‐type NOTCH1[ 27], whereas activation of NOTCH1 resulted in reduced tumorigenicity in a mouse cancer model 9, 27 .…”

“…Activation of Notch signaling by expressing full‐length NOTCH1 or its activated form ICN in human OSCC or HNSCC cell lines leads to cell growth arrest 9, 27, 60. Consistently, inhibition of NOTCH activation promoted tumor growth in a HNSCC cell line harboring wild‐type NOTCH1[ 27], whereas activation of NOTCH1 resulted in reduced tumorigenicity in a mouse cancer model 9, 27 . Similarly, it was reported that Notch inhibition can promote transdifferentiation of normal esophageal squamous epithelial cells toward a BE (Barrett's esophagus, a precursor of esophageal adenocarcinoma)‐like metaplasia 61.…”

“…However, Notch signaling activation can be tumor suppressive or oncogenic, depending on cellular context 4. Recently, considerable NOTCH gene mutations were identified in different types of squamous cell carcinoma 5, 6, 7, 8, 9, questioning the general role of Notch pathway in SCCs.…”