title: Integrated analysis of oral tongue squamous cell carcinoma identifies key variants and pathways linked to risk habits, HPV, clinical parameters and tumor recurrence.
abstract: Oral tongue squamous cell carcinomas (OTSCC) are a homogeneous group of tumors characterized by aggressive behavior, early spread to lymph nodes and a higher rate of regional failure. Additionally, the incidence of OTSCC among younger population (<50yrs) is on the rise; many of whom lack the typical associated risk factors of alcohol and/or tobacco exposure. We present data on single nucleotide variations (SNVs), indels, regions with loss of heterozygosity (LOH), and copy number variations (CNVs) from fifty-paired oral tongue primary tumors and link the significant somatic variants with clinical parameters, epidemiological factors including human papilloma virus (HPV) infection and tumor recurrence. Apart from the frequent somatic variants harbored in TP53, CASP8, RASA1, NOTCH and CDKN2A genes, significant amplifications and/or deletions were detected in chromosomes 6-9, and 11 in the tumors. Variants in CASP8 and CDKN2A were mutually exclusive. CDKN2A, PIK3CA, RASA1 and DMD variants were exclusively linked to smoking, chewing, HPV infection and tumor stage. We also performed a whole-genome gene expression study that identified matrix metalloproteases to be highly expressed in tumors and linked pathways involving arachidonic acid and NF-k-B to habits and distant metastasis, respectively. Functional knockdown studies in cell lines demonstrated the role of CASP8 in a HPV-negative OTSCC cell line. Finally, we identified a 38-gene minimal signature that predicts tumor recurrence using an ensemble machine-learning method. Taken together, this study links molecular signatures to various clinical and epidemiological factors in a homogeneous tumor population with a relatively high HPV prevalence.
authors.affiliation: Ganit Labs, Bio-IT Centre, Institute of Bioinformatics and Applied Biotechnology, Bangalore, 560 100, India.
authors.forename: Neeraja
authors.initials: N
authors.lastname: Krishnan
authors.affiliation: Ganit Labs, Bio-IT Centre, Institute of Bioinformatics and Applied Biotechnology, Bangalore, 560 100, India.
authors.forename: Saurabh
authors.initials: S
authors.lastname: Gupta
authors.affiliation: Ganit Labs, Bio-IT Centre, Institute of Bioinformatics and Applied Biotechnology, Bangalore, 560 100, India.
authors.forename: Vinayak
authors.initials: V
authors.lastname: Palve
authors.affiliation: Ganit Labs, Bio-IT Centre, Institute of Bioinformatics and Applied Biotechnology, Bangalore, 560 100, India.
authors.forename: Linu
authors.initials: L
authors.lastname: Varghese
authors.affiliation: Ganit Labs, Bio-IT Centre, Institute of Bioinformatics and Applied Biotechnology, Bangalore, 560 100, India.
authors.forename: Swetansu
authors.initials: S
authors.lastname: Pattnaik
authors.affiliation: Ganit Labs, Bio-IT Centre, Institute of Bioinformatics and Applied Biotechnology, Bangalore, 560 100, India.
authors.forename: Prach
authors.initials: P
authors.lastname: Jain
authors.affiliation: Ganit Labs, Bio-IT Centre, Institute of Bioinformatics and Applied Biotechnology, Bangalore, 560 100, India.
authors.forename: Costerwell
authors.initials: C
authors.lastname: Khyriem
authors.affiliation: Ganit Labs, Bio-IT Centre, Institute of Bioinformatics and Applied Biotechnology, Bangalore, 560 100, India.
authors.forename: Arun
authors.initials: A
authors.lastname: Hariharan
authors.affiliation: Ganit Labs, Bio-IT Centre, Institute of Bioinformatics and Applied Biotechnology, Bangalore, 560 100, India.
authors.forename: Kunal
authors.initials: K
authors.lastname: Dhas
authors.affiliation: Ganit Labs, Bio-IT Centre, Institute of Bioinformatics and Applied Biotechnology, Bangalore, 560 100, India.
authors.forename: Jayalakshmi
authors.initials: J
authors.lastname: Nair
authors.affiliation: Ganit Labs, Bio-IT Centre, Institute of Bioinformatics and Applied Biotechnology, Bangalore, 560 100, India.
authors.forename: Manisha
authors.initials: M
authors.lastname: Pareek
authors.affiliation: Ganit Labs, Bio-IT Centre, Institute of Bioinformatics and Applied Biotechnology, Bangalore, 560 100, India.
authors.forename: Venkatesh
authors.initials: V
authors.lastname: Prasad
authors.affiliation: Integrated Head and Neck Oncology Program, Mazumdar Shaw Centre for Translational Research, Bangalore, 560 099, India.
authors.forename: Gangotri
authors.initials: G
authors.lastname: Siddappa
authors.affiliation: Integrated Head and Neck Oncology Program, Mazumdar Shaw Centre for Translational Research, Bangalore, 560 099, India.
authors.forename: Amritha
authors.initials: A
authors.lastname: Suresh
authors.affiliation: Head and Neck Oncology, Mazumdar Shaw Medical Centre, Bangalore, 560 099, India.
authors.forename: Vikram
authors.initials: V
authors.lastname: Kekatpure
authors.affiliation: Integrated Head and Neck Oncology Program, Mazumdar Shaw Centre for Translational Research, Bangalore, 560 099, India; Head and Neck Oncology, Mazumdar Shaw Medical Centre, Bangalore, 560 099, India.
authors.forename: Moni
authors.initials: M
authors.lastname: Kuriakose
authors.affiliation: Ganit Labs, Bio-IT Centre, Institute of Bioinformatics and Applied Biotechnology, Bangalore, 560 100, India; Strand Life Sciences, Bangalore, 560 024, India.
authors.forename: Binay
authors.initials: B
authors.lastname: Panda
keywords: CASP8; HPV; RASA1; TP53; gene expression; oral tongue squamous cell carcinoma; somatic variants; tumor recurrence
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