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 HNSCCs, 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. Immunohistochemistry 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/non-peripheral (34%) and negative (19%). NICD1 expression was associated with NOTCH1 mutation status (p<0.001). Most NOTCH1-wild type tumors were peripheral (55%), while mutated NOTCH1 tumors were most commonly negative (47%). Non-peripheral tumors were more likely than peripheral tumors to have extracapsular spread (aOR 16.01, 95% 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 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.

Whole-Genome Sequencing of Salivary Gland Adenoid Cystic Carcinoma

“…(42, 43) NOTCH1 alterations can result in either tumor suppression or oncogenesis, depending on the tumor type. (44–46) Additional characterization of Notch signaling alterations in ACC is indicated, particularly because Notch signaling is a potentially targetable pathway. (42) Our findings also corroborate a high prevalence of somatic mutations in genes related to chromatin remodeling, including MLL2, MLL3, and EP300, among others.…”

Genomic Characterization of Vulvar (Pre)cancers Identifies Distinct Molecular Subtypes with Prognostic Significance

“…All these data strongly suggest that aberrant Notch signaling is involved in the carcinogenesis of a subset of HPV À squamous cell carcinomas from both vulvar and head and neck origin. Aberrant notch function has been found in many other tumor types (14,(28)(29)(30)(31) and intriguingly is associated with both tumor suppressor as well as an oncogenic function (29,32). Previous studies found a clear association in HNCs between inactivating mutations in NOTCH1 and carcinogenesis.…”

MicroR-140-5p suppresses tumor cell migration and invasion by targeting ADAM10-mediated Notch1 signaling pathway in hypopharyngeal squamous cell carcinoma

“…It is well known that ADAM10 is the vital sheddase for several molecules associated with cancer differentiation, adhesion and migration such as Notch, E-cadherin, CD44 and L1 adhesion molecular to activate the corresponding signaling pathways (Crawford et al, 2009). Recently, Notch1 was identified as the second most frequently mutated gene in HNSCC after TP53, the Notch1 protein played key roles in the regulation of cell differentiation, proliferation and survival between the four Notch transmembrane signaling protein paralogs (Agrawal et al, 2011;Rettig et al, 2015). Interestingly, a recent report suggested that Notch1 signaling pathway activated by ADAM10 shedding played non-small cell lung cancer in the migration and invasion of non-small cell lung cancer (Guo et al, 2012).…”