The Mutational Landscape of Head and Neck Squamous Cell Carcinoma

Abstract

Head and neck squamous cell carcinoma (HNSCC) is a common, morbid, and frequently lethal malignancy. To uncover its mutational spectrum, we analyzed whole-exome sequencing data from 74 tumor-normal pairs. The majority exhibited a mutational profile consistent with tobacco exposure; human papilloma virus was detectable by sequencing of DNA from infected tumors. In addition to identifying previously known HNSCC genes (TP53, CDKN2A, PTEN, PIK3CA, and HRAS), the analysis revealed many genes not previously implicated in this malignancy. At least 30% of cases harbored mutations in genes that regulate squamous differentiation (e.g., NOTCH1, IRF6, and TP63), implicating its dysregulation as a major driver of HNSCC carcinogenesis. More generally, the results indicate the ability of large-scale sequencing to reveal fundamental tumorigenic mechanisms.

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

“…In 2011, two independent studies about mutational landscape of HNSCC revealed that NOTCH is frequently mutated in HNSCC 6, 7. By whole‐exome sequencing of 74 HNSCC tumor‐normal pairs 6, mutations of NOTCH1 , NOTCH2 , and NOTCH3 were identified in 14%, 5%, and 4% of HNSCC samples.…”

“…By whole‐exome sequencing of 74 HNSCC tumor‐normal pairs 6, mutations of NOTCH1 , NOTCH2 , and NOTCH3 were identified in 14%, 5%, and 4% of HNSCC samples. In an independent exome‐sequencing study of 32 HNSCC primary tumors 7, NOTCH1 somatic mutations were identified in 15% of patients, and following TP53, NOTCH1 was identified as the second most frequently mutated gene.…”

“…Consistently, early this year, a comprehensive genomic characterization of 279 HNSCCs 53 also revealed frequent NOTCH1 mutations (19%). Among the identified mutations, considerable nonsense or splice‐site mutations were revealed which may have generated truncation sequences lacking the critical regions, while a bunch of missense mutations clustered in the NECD ligand‐binding region 6, 7, suggesting a tumor suppressive role for NOTCH in HNSCC.…”

“…Notch inhibition by DNMAML1 promotes invasive growth of transformed esophageal epithelial cells with EGFR overexpression and p53 dysfunction 68. Moreover, TP53 was frequently mutated in HNSCC cases 6, 7, 53, and the inactivation of p53 plays important role in HNSCC tumorigenesis 43, 69, 70. But it has not been clarified yet whether Notch signaling is closely involved in this.…”

“…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.…”