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Cancer Prev Res (Phila). 2015 Apr;8(4):287-95. doi: 10.1158/1940-6207.CAPR-14-0366. Epub 2015 Jan 29.

Cleaved NOTCH1 Expression Pattern in Head and Neck Squamous Cell Carcinoma Is Associated with NOTCH1 Mutation, HPV Status, and High-Risk Features.

Author information

1
Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland.
2
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.
3
Department of Pathology, Johns Hopkins School of Medicine, Johns Hopkins Medicine, Baltimore, Maryland.
4
Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland.
5
Johns Hopkins Institute for Computational Medicine and Department of Biomedical Engineering, Baltimore, Maryland.
6
Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland. Johns Hopkins Institute for Computational Medicine and Department of Biomedical Engineering, Baltimore, Maryland.
7
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.
8
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.
9
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.

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.

PMID:
25633867
PMCID:
PMC4383699
DOI:
10.1158/1940-6207.CAPR-14-0366
[Indexed for MEDLINE]
Free PMC Article

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