Exome Sequencing of Head and Neck Squamous Cell Carcinoma Reveals Inactivating Mutations in NOTCH1

Abstract

Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide. To explore the genetic origins of this cancer, we used whole exome sequencing and gene copy number analyses to study 32 primary tumors. Tumors from patients with a history of tobacco use had more mutations than did tumors from patients who did not use tobacco, and tumors that were negative for human papilloma virus (HPV) had more mutations than did HPV-positive tumors. Six of the genes that were mutated in multiple tumors were assessed in up to 88 additional HNSCCs. In addition to previously described mutations in TP53, CDKN2A, PIK3CA and HRAS, we identified mutations in FBXW7 and NOTCH1. Interestingly, nearly 40% of the 28 mutations identified in NOTCH1 were predicted to truncate the gene product, suggesting that NOTCH1 may function as a tumor suppressor gene rather than an oncogene in this tumor type.

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%).…”

“…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.…”