title: Notch1 mutations are drivers of oral tumorigenesis.
abstract: Disruption of NOTCH1 signaling was recently discovered in head and neck cancer. This study aims to evaluate NOTCH1 alterations in the progression of oral squamous cell carcinoma (OSCC) and compare the occurrence of these mutations in Chinese and Caucasian populations. We used a high-throughput PCR-based enrichment technology and next-generation sequencing (NGS) to sequence NOTCH1 in 144 samples collected in China. Forty-nine samples were normal oral mucosa from patients undergoing oral surgery, 45 were oral leukoplakia biopsies, and 50 were chemoradiation-naïve OSCC samples with 22 paired-normal tissues from the adjacent unaffected areas. NOTCH1 mutations were found in 54% of primary OSCC and 60% of premalignant lesions. Importantly, almost 60% of patients with leukoplakia with mutated NOTCH1 carried mutations that were also identified in OSCC, indicating an important role of these clonal events in the progression of early neoplasms. We then compared all known NOTCH1 mutations identified in Chinese patients with OSCC with those reported in Caucasians to date. Although we found obvious overlaps in critical regulatory NOTCH1 domains alterations and identified specific mutations shared by both groups, possible gain-of-function mutations were predominantly seen in Chinese population. Our findings demonstrate that premalignant lesions display NOTCH1 mutations at an early stage and are thus bona fide drivers of OSCC progression. Moreover, our results reveal that NOTCH1 promotes distinct tumorigenic mechanisms in patients from different ethnical populations.
authors.affiliation: Department of Otolaryngology-Head and Neck Surgery and Oncology, Johns Hopkins University School of Medicine, Baltimore, MD.
authors.forename: Evgeny
authors.initials: E
authors.lastname: Izumchenko
authors.affiliation: Department of Oral Mucosal Diseases, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200011, China.
authors.forename: Kai
authors.initials: K
authors.lastname: Sun
authors.affiliation: Personal Genome Diagnostics, Inc. 2809 Boston St, Suite 503, Baltimore, MD.
authors.forename: Sian
authors.initials: S
authors.lastname: Jones
authors.affiliation: Department of Otolaryngology-Head and Neck Surgery and Oncology, Johns Hopkins University School of Medicine, Baltimore, MD.
authors.forename: Mariana
authors.initials: M
authors.lastname: Brait
authors.affiliation: Department of Otolaryngology-Head and Neck Surgery and Oncology, Johns Hopkins University School of Medicine, Baltimore, MD.
authors.forename: Nishant
authors.initials: N
authors.lastname: Agrawal
authors.affiliation: Department of Otolaryngology-Head and Neck Surgery and Oncology, Johns Hopkins University School of Medicine, Baltimore, MD.
authors.forename: Wayne
authors.initials: W
authors.lastname: Koch
authors.affiliation: Personal Genome Diagnostics, Inc. 2809 Boston St, Suite 503, Baltimore, MD.
authors.forename: Christine L
authors.initials: CL
authors.lastname: McCord
authors.affiliation: Personal Genome Diagnostics, Inc. 2809 Boston St, Suite 503, Baltimore, MD.
authors.forename: David R
authors.initials: DR
authors.lastname: Riley
authors.affiliation: Personal Genome Diagnostics, Inc. 2809 Boston St, Suite 503, Baltimore, MD.
authors.forename: Samuel V
authors.initials: SV
authors.lastname: Angiuoli
authors.affiliation: Department of Otolaryngology-Head and Neck Surgery and Oncology, Johns Hopkins University School of Medicine, Baltimore, MD.
authors.forename: Victor E
authors.initials: VE
authors.lastname: Velculescu
authors.affiliation: Department of Oral Mucosal Diseases, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200011, China.
authors.forename: Wei-Wen
authors.initials: WW
authors.lastname: Jiang
authors.affiliation: Department of Otolaryngology-Head and Neck Surgery and Oncology, Johns Hopkins University School of Medicine, Baltimore, MD.
authors.forename: David
authors.initials: D
authors.lastname: Sidransky
mesh_terms: D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000473:pathology*; D002471:Cell Transformation, Neoplastic / Q000378:metabolism / Q000473:pathology*; D002681:China; D018450:Disease Progression; D006801:Humans; D007972:Leukoplakia, Oral / Q000235:genetics / Q000473:pathology*; D009061:Mouth Mucosa / Q000378:metabolism*; D009062:Mouth Neoplasms / Q000235:genetics / Q000473:pathology*; D009154:Mutation / Q000235:genetics*; D051881:Receptor, Notch1 / Q000235:genetics*
chemical_list: C497761:NOTCH1 protein, human; D051881:Receptor, Notch1