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

By N. Agrawal, M. Frederick, C. Pickering, C. Bettegowda, Kyle Chang, Ryan J Li, C. Fakhry, T. Xie, Jiexin Zhang, Jing Wang and 21 more. Science, 2011

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The mutational profile of head and neck cancer is complex and may pose challenges to the development of targeted therapies. 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.

Subfields: Molecular Biology

View Paper: https://www.semanticscholar.org/paper/d2a0d880031d674e3847a062297f138be1333686

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Citations in the corpus

The clonal and mutational evolution spectrum of primary triple-negative breast cancers (2012, background): “Additional recurrent mutations of note occurred in the synucleingenes( SYNE1 and SYNE2 , 9.2% 6/65, recently implicated in squamous head and neck cancers 18,19 ), BRCA2 (three cases), and several other well known oncogenes ( BRAF , NRAS , ERBB2 and ERBB3 ) with mutations in two cases each.”
Lessons from the cancer genome. (2013, neutral): “Squamous Differentiation Exome-sequencing studies in head and neck squamous cell carcinoma (HNSCC) revealed unexpected roles for pathways involved in squamous cell differentiation (Agrawal et al., 2011; Stransky et al., 2011).”
Next-generation sequencing data interpretation: enhancing reproducibility and accessibility (2012, background): “Numerous cancer resequencing studies have been published in 2011, including two in patients with head and neck squamous cell carcinoma (HNSCC).”
Head and Neck Squamous Cell Carcinoma: Update on Epidemiology, Diagnosis, and Treatment. (2016, background): “Whole-genome sequencing has identified, apart from TP53 mutation, additional mutations-specifically, the tumor survival (PIK3CA-AKT1-MTOR-PTEN, EGFR and MET pathways), tumor proliferation (p16, RB, MET, CCND1, CDKN2A/CDKN2B), and tumor differentiation (NOTCH1) pathways.(19,20) The Cancer Genome Atla”
Oral squamous cell carcinomas: state of the field and emerging directions (2023, background): “Notch signaling has been demonstrated as a tumor suppressor in epithelial SCC malignancies (lung, bladder, and esophageal tumors) and several in vivo models.(159) Nevertheless, in vitro assays with HNSCC cell lines have shown a requirement for an increase in Notch signaling activity to maintain mali”
Integrative and comparative genomic analysis of HPV-positive and HPV-negative head and neck squamous cell carcinomas (2014, background): “Copy number analysis demonstrated many previously demonstrated regions of amplification and deletion including focal gains of EGFR, REL, BCL6, PIK3CA, TP63, CCDN1 and MDM2 and losses of ATM, CDKN2A, RB1, NOTCH1 and NF1 (Figures 1C, 1D)(12-15, 29).”