Abstract
Head and neck squamous cell carcinomas (HNSCC) include heterogeneous group of tumors, classified according to their anatomical site. It is the sixth most prevalent cancer globally. Among South Asian countries, India accounts for 40% of HNC malignancies with significant morbidity and mortality. In the present study, we have performed exome sequencing and analysis of 51 Head and Neck squamous cell carcinoma samples. Besides known mutations in the oncogenes and tumour suppressors, we have identified novel gene signatures differentiating buccal, alveolar, and tongue cancers. Around 50% of the patients showed mutation in tumour suppressor genes TP53 and TP63. Apart from the known mutations, we report novel mutations in the genes AKT1, SPECC1, and LRP1B, which are linked with tumour progression and patient survival. A highly curated process was developed to identify survival signatures. 36 survival-related genes were identified based on the correlation of functional impact of variants identified using exome-seq with gene expression from transcriptome data (GEPIA database) and survival. An independent LASSO regression analysis was also performed. Survival signatures common to both the methods led to identification of 4 dead and 3 alive gene signatures, the accuracy of which was confirmed by performing a ROC analysis (AUC=0.79 and 0.91, respectively). Also, machine learning-based driver gene prediction tool resulted in the identification of IRAK1 as the driver (p-value = 9.7 e-08) and also as an actionable mutation. Modelling of the IRAK1 mutation showed a decrease in its binding to known IRAK1 inhibitors.
Highlights
Head and Neck cancer (HNC) is a heterogeneous disease that encompasses tumors of majorly three regions, oral cavity, oropharynx, and larynx, and together they account for more than 660000 new cases and over 320000 deaths worldwide wide, while India has contributed to 36%, 20.9% and 18.8% of the total cases of each type respectively, in 2020 [1]
Variant analysis was performed for 50 Head and Neck Squamous Cell Carcinoma (HNSCC) tumor samples using exome-seq
On referring to the Head and neck squamous cell carcinomas (HNSCC) whole exome data of these 114 genes from TCGA database we found that only 8 of them were a part of the Cancer Gene Census of which only 3 genes, AKT1, LRP1B, and SPECC1 showed a significant difference in survival from the TCGA whole exome data associated with these genes (Figure 8A)
Summary
Head and Neck cancer (HNC) is a heterogeneous disease that encompasses tumors of majorly three regions, oral cavity, oropharynx, and larynx, and together they account for more than 660000 new cases and over 320000 deaths worldwide wide, while India has contributed to 36%, 20.9% and 18.8% of the total cases of each type respectively, in 2020 (https://gco.iarc.fr) [1]. Several studies have reported drivers of Head and Neck cancer oncogenesis. Alterations in oncogene families like ras family of genes, myc family and EGFR family have been implicated in oral and head and neck cancers. High frequency of mutations in HRAS, copy number alterations and aberrant expression levels in KRAS, NRAS, MYC and EGFR have been reported in relation with development of many squamous cell carcinomas. Driver Genes like CCND1, MAPK family and PIK3CA are involved in the progression of HNSCC [4, 6, 7]. HPV+ve HNSCC cancers are characterized by frequent mutations and chromosomal deletions in tumor suppressors like PTEN, E-cadherins and RB1 [4, 6, 8]. IRAK1 is a kinase, activated downstream of TLRs and is activated upon radiation therapy in HNSCC [10, 11]
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