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

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.

Critical genes in head and neck squamous cell carcinoma revealed by bioinformatic analysis of gene expression data

“…E1A binding protein p300 (EP300) is a histone acetyltransferase that regulates transcription via chromatin remodeling and is important in the processes of cell proliferation and differentiation. Alteration in EP300 expression is much more prominent in HNSCC lines (Martin et al, 2014) and we speculate it might play a role in the development of HNSCC. Matrix metallopeptidase 2 (MMP2) is capable of cleaving components of the extracellular matrix and is thus involved in signal transduction.…”

CTLA4 blockade reduces immature myeloid cells in head and neck squamous cell carcinoma

“…HPV infection is considered one of the most important etiologic cases of HNSCC. 28 A recent study indicated that different patterns of intratumor immune cell infiltrates in HPVC HNSCC compared with HPV¡ HNSCC. 29 Interestingly, we found that CD8 C / CTLA4 remained correlated with the immunosuppressive cell population in HPV¡ HNSCC.…”

Survival of Head and Neck Cancer Cells Relies upon LZK Kinase-Mediated Stabilization of Mutant p53

“…The exception is PIK3CA, which is mutated in $20% of HNSCC samples (1, 10), representing a cohort of patients that may benefit from treatment with PI3K/AKT inhibitors. In addition, recent studies have indicated that inhibitors targeting the mTOR and ERK pathways hold promise for treatment of HNSCC patients, including patients positive for PIK3CA mutations (52)(53)(54).…”