title: Cleaved NOTCH1 Expression Pattern in Head and Neck Squamous Cell Carcinoma Is Associated with NOTCH1 Mutation, HPV Status, and High-Risk Features.
abstract: The Notch pathway is frequently altered in head and neck squamous cell carcinomas (HNSCC); however, the clinical significance of NOTCH1 dysregulation is poorly understood. This study was designed to characterize expression of the transcriptionally active NOTCH1 intracellular domain (NICD1) in HNSCCs and evaluate its association with NOTCH1 mutation status and clinical parameters. IHC for NICD1 was performed on 79 previously sequenced archival HNSCCs with known NOTCH1 mutation status. Three distinct immunohistochemical staining patterns were identified: positive/peripheral (47%), positive/nonperipheral (34%), and negative (19%). NICD1 expression was associated with NOTCH1 mutation status (P < 0.001). Most NOTCH1-wild-type tumors were peripheral (55%), whereas mutated NOTCH1 tumors were most commonly negative (47%). Nonperipheral tumors were more likely than peripheral tumors to have extracapsular spread [adjusted odds ratio (aOR), 16.01; 95% confidence interval (CI), 1.92-133.46; P = 0.010] and poor differentiation (aOR, 5.27; 95% CI, 0.90-30.86; P = 0.066). Negative staining tumors tended to be poorly differentiated (aOR, 24.71; 95% CI, 1.53-399.33; P = 0.024) and were less likely to be human papillomavirus (HPV) positive (aOR, 0.043; 95% CI, 0.001-1.59; P = 0.087). NOTCH1 mutagenesis was significantly associated with HPV status, with NOTCH1-wild-type tumors more likely to be HPV positive than NOTCH1-mutated tumors (aOR, 19.06; 95% CI, 1.31-276.15; P = 0.031). TP53 disruptive mutations were not associated with NICD1 expression or NOTCH1 mutation. In conclusion, NICD1 is expressed in three distinct patterns in HNSCC that are significantly associated with high-risk features. These findings further support a dual role for NOTCH1 as both tumor suppressor and oncogene in HNSCC. Further research is necessary to clarify the role of NOTCH1 in HNSCC and understand the clinical and therapeutic implications therein.
authors: Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors: Eleni M
authors: EM
authors: Rettig
authors: Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland. Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland. Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors: Christine H
authors: CH
authors: Chung
authors: Department of Pathology, Johns Hopkins School of Medicine, Johns Hopkins Medicine, Baltimore, Maryland.
authors: Justin A
authors: JA
authors: Bishop
authors: Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors: Jason D
authors: JD
authors: Howard
authors: Department of Pathology, Johns Hopkins School of Medicine, Johns Hopkins Medicine, Baltimore, Maryland.
authors: Rajni
authors: R
authors: Sharma
authors: Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors: Ryan J
authors: RJ
authors: Li
authors: Johns Hopkins Institute for Computational Medicine and Department of Biomedical Engineering, Baltimore, Maryland.
authors: Christopher
authors: C
authors: Douville
authors: Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland. Johns Hopkins Institute for Computational Medicine and Department of Biomedical Engineering, Baltimore, Maryland.
authors: Rachel
authors: R
authors: Karchin
authors: Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors: Evgeny
authors: E
authors: Izumchenko
authors: Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors: David
authors: D
authors: Sidransky
authors: Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors: Wayne
authors: W
authors: Koch
authors: Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland. Milton J. Dance Jr. Head and Neck Center, Greater Baltimore Medical Center, Baltimore, Maryland.
authors: Joseph
authors: J
authors: Califano
authors: Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland. Johns Hopkins University School of Medicine Ludwig Center for Cancer Genetics and Therapeutics, Baltimore, Maryland. cfakhry1@jhmi.edu nagrawal@jhmi.edu.
authors: Nishant
authors: N
authors: Agrawal
authors: Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland. Milton J. Dance Jr. Head and Neck Center, Greater Baltimore Medical Center, Baltimore, Maryland. Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland. cfakhry1@jhmi.edu nagrawal@jhmi.edu.
authors: Carole
authors: C
authors: Fakhry
mesh_terms: D014408:Biomarkers, Tumor; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000378:metabolism / Q000473:pathology* / Q000821:virology; D005260:Female; D005500:Follow-Up Studies; D006258:Head and Neck Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology* / Q000821:virology; D006801:Humans; D007124:Immunoenzyme Techniques; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D009361:Neoplasm Invasiveness; D009364:Neoplasm Recurrence, Local / Q000235:genetics / Q000378:metabolism / Q000473:pathology* / Q000821:virology; D009367:Neoplasm Staging; D027383:Papillomaviridae / Q000235:genetics; D030361:Papillomavirus Infections / Q000235:genetics / Q000378:metabolism / Q000473:pathology* / Q000821:virology; D011379:Prognosis; D051881:Receptor, Notch1 / Q000235:genetics* / Q000378:metabolism*; D012189:Retrospective Studies; D012307:Risk Factors; D016159:Tumor Suppressor Protein p53
chemical_list: D014408:Biomarkers, Tumor; C497761:NOTCH1 protein, human; D051881:Receptor, Notch1; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53
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