Investigating Aberrations of KMT2C and RGS3 Genes in Head and Neck cancer through Whole Exome Sequencing among Pakistani Population

Abstract

Head and Neck cancer is 7 th top-most prominent malignancy throughout the world, develops in epithelial mucosa of head and neck region, result in effecting 6 million people and 3.5 million deaths per Anum worldwide. In Pakistan, it is the most frequent cancer in men and second most prevalent in women. Main reason of this prevalence is frequent use of alcohol and tobacco. HNSCC can also be referred as oral carcinoma because around 90% of HNSCC develops in oral cavity, lips, pharynx, larynx and sinuses regions. Reported mutated driver genes in HNC include TP53, KMT2D, CDKN2A, NOTCH1, NSD1 and PI3KCA. Along with these driver genes, other genes which are also altered in HNC include: RGS3, KMT2C and ARF genes. The main purpose of this research is to genetically characterize HNC sample particularly focusing on mutations of KMT2C and RGS3 genes. Molecular profiling of both tumor and control samples was done through WES, which provided data of disease-causing variants. Furthermore, using in silico tools, we identified 28 non-synonymous exonic variants in KMT2C gene and 2 novel mutations in RGS3 gene. Non-synonymous variations were found in SET domain of KMT2C gene and C2 domain of RGS3 gene. Homology modeling was further used to confirm effect of these variations on secondary structure of functional proteins. Data from all applied tools showed that variations in KMT2C and RGS3 genes were highly deleterious and disease causing with highest damage prediction score. Mutation in these genes as verified by in silico tools have also tumor causing role in breast and lung cancers thus take part in loss of heterozygosity and causing HNC. Keywords: HNSCC (Head and Neck Squamous Cell Carcinoma), KMT2C (Lysine Methyltransferase 2C), RGS3 (Regulator of G-protein Signaling 3), WES (Whole Exome Sequencing).