A novel therapeutic target in tongue cancer

Clinical collaborator: Dr. Sudhir Nair (ACTREC/ TMH)

Recent large-scale genome sequencing efforts of oral cancer have found inactivating mutations at NOTCH1 in 10% to 15% tumors among Caucasian patients but no therapeutically relevant ‘oncogenic driver’ gene were identified. More recently, oral cancer studies among Chinese patients have revealed potential activating NOTCH1 mutations in 50% patients—suggesting somatic NOTCH1 mutations may reflect diversity of etiological complexity across ethnicities, with divergent role in oral cancer biology.

Here, we describe Notch family members alterations across 68 early staged primary tongue squamous cell carcinoma samples (TSCC) by whole-exome, whole transcriptome sequencing, real-time PCR for copy number, along with transcript expression, and immune-histochemical analysis. Our results demonstrate that NOTCH1 harbors significantly lower inactivating mutations compared to TCGA oral cancer data set, and that a considerable fraction of TSCC tumors have upregualted Notch pathway that may be important in maintenance of stem cell component in these tumors. Inhibition of NOTCH activation by gamma secretase inhibitor or shRNA mediated knockdown of NOTCH1 inhibits spheroid forming capacity, transformation, survival and migration of the HNSCC cells suggesting an oncogenic role of NOTCH1 in TSCC. Clinically, Notch pathway activation is higher in tumors of non-smokers compared to smokers and is also associated with greater nodal positivity compared to its non- activation. We anticipate that these results could be the basis for therapeutic targeting of NOTCH1 in tongue cancer