BACKGROUND: The incidence of squamous cell carcinoma of the oral tongue (SCCOT) is increasing in people under age 40. There is an urgent need to identify prognostic markers that help identify young SCCOT patients with poor prognosis in order to select these for individualized treatment. MATERIALS AND METHODS: To identify genetic markers that can serve as prognostic markers for young SCCOT patients, we first investigated four young (≤40 years) and five elderly patients (≥50 years) using global RNA sequencing and whole-exome sequencing. Next, we combined our data with data on SCCOT from the cancer genome atlas (TCGA), giving a total of 16 young and 104 elderly, to explore the correlations between genomic variations and clinical outcomes. RESULTS: In agreement with previous studies, we found that SCCOT from young and elderly patients was transcriptomically and also genomically similar with no significant differences regarding cancer driver genes, germline predisposition genes, or the burden of somatic single nucleotide variations (SNVs). However, a disparate copy number variation (CNV) was found in young patients with distinct clinical outcome. Combined with data from TCGA, we found that the overall survival was significantly better in young patients with low-CNV (n = 5) compared to high-CNV (n = 11) burden (P = 0.044). CONCLUSIONS: Copy number variation burden is a useful single prognostic marker for SCCOT from young, but not elderly, patients. CNV burden thus holds promise to form an important contribution when selecting suitable treatment protocols for young patients with SCCOT.

Cancer Research UK Edinburgh Centre MRC Institute of Genetics and Molecular Medicine The University of Edinburgh Edinburgh UK

Department of Clinical Sciences ENT Umeå University Umeå Sweden

Department of Medical Biosciences Pathology Umeå University Umeå Sweden

Institute of Molecular Genetics University Paris 7 St Louis Hospital Paris France

RECAMO Masaryk Memorial Cancer Institute Brno Czech Republic

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Kamangar F, Dores GM, Anderson WF. Patterns of cancer incidence, mortality, and prevalence across five continents: defining priorities to reduce cancer disparities in different geographic regions of the world. J Clin Oncol. 2006;24:2137‐2150. PubMed

Vigneswaran N, Williams MD. Epidemiologic trends in head and neck cancer and aids in diagnosis. Oral Maxillofac Surg Clin North Am. 2014;26:123‐141. PubMed PMC

Annertz K, Anderson H, Biorklund A, et al. Incidence and survival of squamous cell carcinoma of the tongue in Scandinavia, with special reference to young adults. Int J Cancer. 2002;101:95‐99. PubMed

Tota JE, Anderson WF, Coffey C, et al. Rising incidence of oral tongue cancer among white men and women in the United States, 1973‐2012. Oral Oncol. 2017;67:146‐152. PubMed

Dos Santos Costa SF, Brennan PA, Gomez RS, et al. Molecular basis of oral squamous cell carcinoma in young patients: is it any different from older patients? J Oral Pathol Med. 2018;47:541‐546. PubMed

Pickering CR, Zhang J, Neskey DM, et al. Squamous cell carcinoma of the oral tongue in young non‐smokers is genomically similar to tumors in older smokers. Clin Cancer Res. 2014;20:3842‐3848. PubMed PMC

Sarkaria JN, Harari PM. Oral tongue cancer in young‐adults less‐than 40 years of age ‐ rationale for aggressive therapy. Head Neck‐J Sci Spec. 1994;16:107‐111. PubMed

Jeon JH, Kim MG, Park JY, et al. Analysis of the outcome of young age tongue squamous cell carcinoma. Maxillofac Plast Reconstr Surg. 2017;39:41. PubMed PMC

Goldenberg D, Brooksby C, Hollenbeak CS. Age as a determinant of outcomes for patients with oral cancer. Oral Oncol. 2009;45:E57‐E61. PubMed

Lundqvist L, Stenlund H, Laurell G, Nylander K. The importance of stromal inflammation in squamous cell carcinoma of the tongue. J Oral Pathol Med. 2012;41:379‐383. PubMed

Pertea M, Kim D, Pertea GM, Leek JT, Salzberg SL. Transcript‐level expression analysis of RNA‐seq experiments with HISAT. Nat Protoc. 2016;11:1650‐1667. PubMed PMC

Chandrani P, Kulkarni V, Iyer P, et al. NGS‐based approach to determine the presence of HPV and their sites of integration in human cancer genome. Br J Cancer. 2015;112:1958‐1965. PubMed PMC

Cibulskis K, Lawrence MS, Carter SL, et al. Sensitive detection of somatic point mutations in impure and heterogeneous cancer samples. Nat Biotechnol. 2013;31:213‐219. PubMed PMC

D'Aurizio R, Pippucci T, Tattini L, Giusti B, Pellegrini M, Magi A. Enhanced copy number variants detection from whole‐exome sequencing data using EXCAVATOR2. Nucleic Acids Res. 2016;44:e154. PubMed PMC

Cerami E, Gao J, Dogrusoz U, et al. The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data. Cancer Discov. 2012;2:401‐404. PubMed PMC

McKenna A, Hanna M, Banks E, et al. The genome analysis toolkit: a MapReduce framework for analyzing next‐generation DNA sequencing data. Genome Res. 2010;20:1297‐1303. PubMed PMC

Huang KL, Mashl RJ, Wu Y, et al. Pathogenic germline variants in 10,389 adult cancers. Cell. 2018;173(355–370):e314. PubMed PMC

Cancer Genome Atlas N . Comprehensive genomic characterization of head and neck squamous cell carcinomas. Nature. 2015;517:576‐582. PubMed PMC

Sgaramella N, Coates PJ, Strindlund K, et al. Expression of p16 in squamous cell carcinoma of the mobile tongue is independent of HPV infection despite presence of the HPV‐receptor syndecan‐1. Br J Cancer. 2015;113:321‐326. PubMed PMC

Tokheim CJ, Papadopoulos N, Kinzler KW, Vogelstein B, Karchin R. Evaluating the evaluation of cancer driver genes. Proc Natl Acad Sci U S A. 2016;113:14330‐14335. PubMed PMC

Zarrei M, MacDonald JR, Merico D, Scherer SW. A copy number variation map of the human genome. Nat Rev Genet. 2015;16:172‐183. PubMed

Daakour S, Hajingabo LJ, Kerselidou D, et al. Systematic interactome mapping of acute lymphoblastic leukemia cancer gene products reveals EXT‐1 tumor suppressor as a Notch1 and FBWX7 common interactor. BMC Cancer. 2016;16:335. PubMed PMC

Jhiang SM. The RET proto‐oncogene in human cancers. Oncogene. 2000;19:5590‐5597. PubMed

Lu C, Xie M, Wendl MC, et al. Patterns and functional implications of rare germline variants across 12 cancer types. Nat Commun. 2015;6:10086. PubMed PMC

Llewellyn CD, Johnson NW, Warnakulasuriya KA. Risk factors for squamous cell carcinoma of the oral cavity in young people–a comprehensive literature review. Oral Oncol. 2001;37:401‐418. PubMed

Toporcov TN, Znaor A, Zhang ZF, et al. Risk factors for head and neck cancer in young adults: a pooled analysis in the INHANCE consortium. Int J Epidemiol. 2015;44:169‐185. PubMed PMC

Smeets SJ, Brakenhoff RH, Ylstra B, et al. Genetic classification of oral and oropharyngeal carcinomas identifies subgroups with a different prognosis. Cell Oncol. 2009;31:291‐300. PubMed PMC

Zack TI, Schumacher SE, Carter SL, et al. Pan‐cancer patterns of somatic copy number alteration. Nat Genet. 2013;45:1134‐1140. PubMed PMC

Hieronymus H, Schultz N, Gopalan A, et al. Copy number alteration burden predicts prostate cancer relapse. Proc Natl Acad Sci U S A. 2014;111:11139‐11144. PubMed PMC

Wangsa D, Chowdhury SA, Ryott M, et al. Phylogenetic analysis of multiple FISH markers in oral tongue squamous cell carcinoma suggests that a diverse distribution of copy number changes is associated with poor prognosis. Int J Cancer. 2016;138:98‐109. PubMed PMC

Upregulation of Apoptosis Related Genes in Clinically Normal Tongue Contralateral to Squamous Cell Carcinoma of the Oral Tongue, an Effort to Maintain Tissue Homeostasis