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 papillomavirus (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. 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.

Fig. 1

Schematic depiction of mutations in NOTCH1. (A) Previously observed NOTCH1 mutations in hematopoietic malignancies. EGF = Epidermal growth factor, LNR = Lin12-Notch repeats, TMD = trans-membrane domain, RAM = Recombination signal-binding protein 1 for J-Kappa (RBPjk) association module, NLS = nuclear localization signal, PEST = proline, glutamic acid, serine/threonine-rich motifs. Red bars represent previously described mutation hotspots (amino acids 1575–1630 and 2250–2550). (B) Previously observed NOTCH1 mutations in solid tumors. Colored arrow (missense mutation) and “X” (truncating mutation) depict mutations found in different tumor types: pink = breast cancer, black = glioma, blue = lung cancer, green = pancreatic adenocarcinoma, red = esophageal squamous cell carcinoma, purple = tongue squamous cell carcinoma. (C) Mutations in NOTCH1 in HNSCC observed in this study. Black arrow = missense mutation, red “X” = truncating mutation (, –24).