Novel Insight into Mutational Landscape of Head and Neck Squamous Cell Carcinoma

Abstract

Development of head and neck squamous cell carcinoma (HNSCC) is characterized by accumulation of mutations in several oncogenes and tumor suppressor genes. We have formerly described the mutation pattern of HNSCC and described NOTCH signaling pathway alterations. Given the complexity of the HNSCC, here we extend the previous study to understand the overall HNSCC mutation context and to discover additional genetic alterations. We performed high depth targeted exon sequencing of 51 highly actionable cancer-related genes with a high frequency of mutation across many cancer types, including head and neck. DNA from primary tumor tissues and matched normal tissues was analyzed for 37 HNSCC patients. We identified 26 non-synonymous or stop-gained mutations targeting 11 of 51 selected genes. These genes were mutated in 17 out of 37 (46%) studied HNSCC patients. Smokers harbored 3.2-fold more mutations than non-smokers. Importantly, TP53 was mutated in 30%, NOTCH1 in 8% and FGFR3 in 5% of HNSCC. HPV negative patients harbored 4-fold more TP53 mutations than HPV positive patients. These data confirm prior reports of the HNSCC mutational profile. Additionally, we detected mutations in two new genes, CEBPA and FES, which have not been previously reported in HNSCC. These data extend the spectrum of HNSCC mutations and define novel mutation targets in HNSCC carcinogenesis, especially for smokers and HNSCC without HPV infection.

Integrated Analysis of Whole-Genome ChIP-Seq and RNA-Seq Data of Primary Head and Neck Tumor Samples Associates HPV Integration Sites with Open Chromatin Marks

“…HPV integration in the UM-SCC-047 cell line was located in close proximity (5.5Mb) to the fragile FRA3C site, which is known to have a high double-stranded break rate (10, 11). Additionally, sites of HPV integration were near known cancer-related genes in our samples: TP63 (18) (047 cell line); FOXE1 (53) (090 cell line); NOTCH1 (8) (PDX2); and EGFL7 (54) (PDX2). This suggests that HPV integration occurs near genes that play a central role in HNSCC development (Tables S3–S6).…”

“…Several high-throughput genomic analyses, aimed at facilitating the development of cancer-related therapy, revealed that HPV+ tumors have fewer genetic alterations than non-HPV-related HNSCCs (3, 8). The virus-related dysfunction of the APOBEC complex in HPV+ HNSCC (9) leads to accumulation of the non-synonymous mutations within the isolated hot-spots, resulting in genetically-homogeneous disease and narrowing down the number of potential targeting candidates.…”

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

“…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.…”

Genomic Characterization of Vulvar (Pre)cancers Identifies Distinct Molecular Subtypes with Prognostic Significance

“…A targeted NGS panel (the VC NGS panel) was designed using previously published data on somatic mutations in VC, its precursors (12), and in HNC (13,14,(19)(20)(21). The panel consists of 176 amplicons covering 97% of the coding region of 17 genes with a role in critical cellular pathways, such as differentiation, proliferation, and apoptosis .…”