Oral Cancer Incidence (New Cases) by Age, Race, and Gender. National Institute of Dental and Craniofacial Research https://www.nidcr.nih.gov/research/data-statistics/oral-cancer/incidence.
Nokovitch, L. et al. Oral cavity squamous cell carcinoma risk factors: state of the art. J. Clin. Med. 12, 3264 (2023).
Google ScholarÂ
Johnson, D. E. et al. Head and neck squamous cell carcinoma. Nat. Rev. Dis. Prim. 6, 1–22 (2020).
Menezes, F. D. S., Fernandes, G. A., Antunes, J. L. F., Villa, L. L. & Toporcov, T. N. Global incidence trends in head and neck cancer for HPV-related and -unrelated subsites: A systematic review of population-based studies. Oral. Oncol. 115, 105177 (2021).
Google ScholarÂ
Mirghani, H., Amen, F., Moreau, F. & Lacau St Guily, J. Do high-risk human papillomaviruses cause oral cavity squamous cell carcinoma?. Oral. Oncol. 51, 229–236 (2015).
Google ScholarÂ
Kawakita, D. et al. Trends in the incidence of head and neck cancer by subsite between 1993 and 2015 in Japan. Cancer Med. 11, 1553–1560 (2022).
Google ScholarÂ
Satgunaseelan, L. et al. The incidence of squamous cell carcinoma of the oral tongue is rising in young non-smoking women: An international multi-institutional analysis. Oral. Oncol. 110, 104875 (2020).
Google ScholarÂ
Deneuve, S. et al. Diverging incidence trends of oral tongue cancer compared to other head and neck cancers in young adults in France. Int. J. Cancer 150, 1301–1309 (2022).
Google ScholarÂ
Kim, Y.-J. & Kim, J. H. Increasing incidence and improving survival of oral tongue squamous cell carcinoma. Sci. Rep. 10, 7877 (2020).
Google ScholarÂ
Ng, J. H., Iyer, N. G., Tan, M.-H. & Edgren, G. Changing epidemiology of oral squamous cell carcinoma of the tongue: A global study. Head. Neck 39, 297–304 (2017).
Google ScholarÂ
Cohen Goldemberg, D., de Araújo, L. H. L., Antunes, H. S., de Melo, A. C. & Santos Thuler, L. C. Tongue cancer epidemiology in Brazil: incidence, morbidity and mortality. Head. Neck 40, 1834–1844 (2018).
Google ScholarÂ
Li, R., Koch, W. M., Fakhry, C. & Gourin, C. G. Distinct epidemiologic characteristics of oral tongue cancer patients. Otolaryngol. Head. Neck Surg. 148, 792–796 (2013).
Google ScholarÂ
Braakhuis, B. J. M., Leemans, C. R. & Visser, O. Incidence and survival trends of head and neck squamous cell carcinoma in the Netherlands between 1989 and 2011. Oral. Oncol. 50, 670–675 (2014).
Google ScholarÂ
Dahlstrom, K. R. et al. Squamous cell carcinoma of the head and neck in never smoker–never drinkers: A descriptive epidemiologic study. Head & Neck 30, 75–84.
Deneuve, S. et al. Oral tongue squamous cell carcinomas in young patients according to their smoking status: a GETTEC study. Eur. Arch. Otorhinolaryngol. https://doi.org/10.1007/s00405-021-06793-7 (2021).
Valero, C. et al. Young non-smokers with oral cancer: What are we missing and why?. Oral. Oncol. 127, 105803 (2022).
Google ScholarÂ
Volkova, N. V. et al. Mutational signatures are jointly shaped by DNA damage and repair. Nat. Commun. 11, 2169 (2020).
Google ScholarÂ
Islam, S. M. A. et al. Uncovering novel mutational signatures by de novo extraction with SigProfilerExtractor. Cell Genomics 100179 https://doi.org/10.1016/j.xgen.2022.100179 (2022).
Alexandrov, L. B. et al. The repertoire of mutational signatures in human cancer. Nature 578, 94–101 (2020).
Google ScholarÂ
Degasperi, A. et al. Substitution mutational signatures in whole-genome–sequenced cancers in the UK population. Science 376, abl9283 (2022).
Google ScholarÂ
Campbell, B. R. et al. The mutational landscape of early- and typical-onset oral tongue squamous cell carcinoma. Cancer 127, 544–553 (2021).
Google ScholarÂ
Gillison, M. L. et al. Human papillomavirus and the landscape of secondary genetic alterations in oral cancers. Genome Res. 29, 1–17 (2019).
Google ScholarÂ
Plath, M. et al. Unraveling most abundant mutational signatures in head and neck cancer. Int. J. Cancer 148, 115–127 (2021).
Google ScholarÂ
South, A. P. et al. Mutation signature analysis identifies increased mutation caused by tobacco smoke associated DNA adducts in larynx squamous cell carcinoma compared with oral cavity and oropharynx. Sci. Rep. 9, 19256 (2019).
Google ScholarÂ
Alexandrov, L. B. et al. Mutational signatures associated with tobacco smoking in human cancer. Science 354, 618–622 (2016).
Google ScholarÂ
Faden, D. L. et al. Multi-modality analysis supports APOBEC as a major source of mutations in head and neck squamous cell carcinoma. Oral. Oncol. 74, 8–14 (2017).
Google ScholarÂ
Bosetti, C. et al. Cancer of the larynx in non-smoking alcohol drinkers and in non-drinking tobacco smokers. Br. J. Cancer 87, 516–518 (2002).
Google ScholarÂ
Henderson, S., Chakravarthy, A., Su, X., Boshoff, C. & Fenton, T. R. APOBEC-Mediated Cytosine Deamination Links PIK3CA Helical Domain Mutations to Human Papillomavirus-Driven Tumor Development. Cell Rep. 7, 1833–1841 (2014).
Google ScholarÂ
Pickering, C. R. et al. Squamous cell carcinoma of the oral tongue in young non-smokers is genomically similar to tumors in older smokers. Clin. Cancer Res 20, 3842–3848 (2014).
Google ScholarÂ
Vossen, D. M. et al. Comparative genomic analysis of oral versus laryngeal and pharyngeal cancer. Oral. Oncol. 81, 35–44 (2018).
Google ScholarÂ
Jéhannin-Ligier, K. et al. Incidence trends for potentially human papillomavirus-related and -unrelated head and neck cancers in France using population-based cancer registries data: 1980-2012. Int J. Cancer 140, 2032–2039 (2017).
Google ScholarÂ
Chan, K. et al. An APOBEC3A hypermutation signature is distinguishable from the signature of background mutagenesis by APOBEC3B in human cancers. Nat. Genet. 47, 1067–1072 (2015).
Google ScholarÂ
Letouzé, E. et al. Mutational signatures reveal the dynamic interplay of risk factors and cellular processes during liver tumorigenesis. Nat. Commun. 8, 1315 (2017).
Google ScholarÂ
Ko, J. M.-Y. et al. Clonal relationship and alcohol consumption-associated mutational signature in synchronous hypopharyngeal tumours and oesophageal squamous cell carcinoma. Br. J. Cancer 127, 2166–2174 (2022).
Google ScholarÂ
Moody, S. et al. Mutational signatures in esophageal squamous cell carcinoma from eight countries with varying incidence. Nat. Genet. 53, 1553–1563 (2021).
Google ScholarÂ
Chang, J. et al. Genomic analysis of oesophageal squamous-cell carcinoma identifies alcohol drinking-related mutation signature and genomic alterations. Nat. Commun. 8, 15290 (2017).
Google ScholarÂ
Li, X. C. et al. A mutational signature associated with alcohol consumption and prognostically significantly mutated driver genes in esophageal squamous cell carcinoma. Ann. Oncol. 29, 938–944 (2018).
Google ScholarÂ
Torrens, L. et al. The complexity of tobacco smoke-induced mutagenesis in head and neck cancer. Nat. Genet. 1–13 https://doi.org/10.1038/s41588-025-02134-0 (2025).
Pinyol, R. et al. Molecular characterisation of hepatocellular carcinoma in patients with non-alcoholic steatohepatitis. J. Hepatol. 75, 865–878 (2021).
Google ScholarÂ
Nguyen, L. et al. Precancerous liver diseases do not cause increased mutagenesis in liver stem cells. Commun. Biol. 4, 1301 (2021).
Google ScholarÂ
Ng, S. W. K. et al. Convergent somatic mutations in metabolism genes in chronic liver disease. Nature 598, 473–478 (2021).
Google ScholarÂ
Ma, H.-Y. et al. IL-17 signaling in steatotic hepatocytes and macrophages promotes hepatocellular carcinoma in alcohol-related liver disease. J. Hepatol. 72, 946–959 (2020).
Google ScholarÂ
Brunner, S. F. et al. Somatic mutations and clonal dynamics in healthy and cirrhotic human liver. Nature 574, 538–542 (2019).
Google ScholarÂ
Dal Maso, L. et al. Combined effect of tobacco smoking and alcohol drinking in the risk of head and neck cancers: a re-analysis of case-control studies using bi-dimensional spline models. Eur. J. Epidemiol. 31, 385–393 (2016).
Google ScholarÂ
Yoshida, K. et al. Tobacco smoking and somatic mutations in human bronchial epithelium. Nature 578, 266–272 (2020).
Google ScholarÂ
Wallenius, K. Experimental oral cancer in the rat. With special reference to the influence of saliva. Acta Pathol. Microbiol Scand. Suppl. 180, 1–91 (1966).
Ames, B. N., McCann, J. & Yamasaki, E. Methods for detecting carcinogens and mutagens with the salmonella/mammalian-microsome mutagenicity test. Mutat. Res./Environ. Mutagen. Relat. Subj. 31, 347–363 (1975).
Google ScholarÂ
Lekholm, U. & Wallenius, K. Experimental oral cancer in rats with xerostomia. Odontol. Rev. 27, 11–18 (1976).
Google ScholarÂ
Nishioka, H., Nishi, K. & Kyokane, K. Human saliva inactivates mutagenicity of carcinogens. Mutat. Res./Environ. Mutagen. Relat. Subj. 85, 323–333 (1981).
Google ScholarÂ
Dayar, D., Hirshberg, A., Kaplan, I., Rotem, N. & Bodner, L. Experimental tongue cancer in desalivated rats. Oral. Oncol. 33, 105–109 (1997).
Google ScholarÂ
Matsuo, K. & Palmer, J. B. Anatomy and physiology of feeding and swallowing – normal and abnormal. Phys. Med Rehabil. Clin. N. Am. 19, 691–707 (2008).
Google ScholarÂ
Roberts, S. A. et al. An APOBEC cytidine deaminase mutagenesis pattern is widespread in human cancers. Nat. Genet. 45, 970–976 (2013).
Google ScholarÂ
Burns, M. B., Temiz, N. A. & Harris, R. S. Evidence for APOBEC3B mutagenesis in multiple human cancers. Nat. Genet. 45, 977–983 (2013).
Google ScholarÂ
Pecori, R., Di Giorgio, S., Paulo Lorenzo, J. & Nina Papavasiliou, F. Functions and consequences of AID/APOBEC-mediated DNA and RNA deamination. Nat. Rev. Genet. 23, 505–518 (2022).
Google ScholarÂ
Alexandrov, L. B. et al. Clock-like mutational processes in human somatic cells. Nat. Genet. 47, 1402–1407 (2015).
Google ScholarÂ
Guo, Q. et al. The mutational signatures of formalin fixation on the human genome. Nat. Commun. 13, 4487 (2022).
Google ScholarÂ
Moore, L. et al. The mutational landscape of human somatic and germline cells. Nature 1–6 https://doi.org/10.1038/s41586-021-03822-7 (2021).
Abascal, F. et al. Somatic mutation landscapes at single-molecule resolution. Nature 593, 405–410 (2021).
Google ScholarÂ
Tomkova, M. et al. Human DNA polymerase ε is a source of C>T mutations at CpG dinucleotides. Nat. Genet 56, 2506–2516 (2024).
Google ScholarÂ
The Cancer Genome Atlas Network Comprehensive genomic characterization of head and neck squamous cell carcinomas. Nature 517, 576–582 (2015).
Google ScholarÂ
Papillon-Cavanagh, S. et al. Impaired H3K36 methylation defines a subset of head and neck squamous cell carcinomas. Nat. Genet. 49, 180–185 (2017).
Google ScholarÂ
Brennan, K., Koenig, J. L., Gentles, A. J., Sunwoo, J. B. & Gevaert, O. Identification of an atypical etiological head and neck squamous carcinoma subtype featuring the CpG island methylator phenotype. EBioMedicine 17, 223–236 (2017).
Google ScholarÂ
Li, Y. et al. Histone methylation antagonism drives tumor immune evasion in squamous cell carcinomas. Mol. Cell 82, 3901–3918.e7 (2022).
Google ScholarÂ
Brennan, K. et al. NSD1 inactivation defines an immune cold, DNA hypomethylated subtype in squamous cell carcinoma. Sci. Rep. 7, 17064 (2017).
Google ScholarÂ
Farhangdoost, N. et al. Chromatin dysregulation associated with NSD1 mutation in head and neck squamous cell carcinoma. Cell Rep. 34, 108769 (2021).
Google ScholarÂ
Peng, P. et al. Epigenetic remodeling under oxidative stress: Mechanisms driving tumor metastasis. MedComm. – Oncol. 3, e70000 (2024).
Google ScholarÂ
Zhu, Z., Zhou, Q., Guan, P., Sun, Y. & Li, G. Novel DNA methylation biomarkers in enhancer regions with chromatin interactions for diagnosis of non-small-cell lung cancer. MedComm. – Oncol. 2, e51 (2023).
Google ScholarÂ
Rooney, M. S., Shukla, S. A., Wu, C. J., Getz, G. & Hacohen, N. Molecular and genetic properties of tumors associated with local immune cytolytic activity. Cell 160, 48–61 (2015).
Google ScholarÂ
Poore, G. D. et al. Microbiome analyses of blood and tissues suggest cancer diagnostic approach. Nature 579, 567–574 (2020).
Google ScholarÂ
Nejman, D. et al. The human tumor microbiome is composed of tumor-type-specific intracellular bacteria. Science 368, 973–980 (2020).
Google ScholarÂ
Narunsky-Haziza, L. et al. Pan-cancer analyses reveal cancer-type-specific fungal ecologies and bacteriome interactions. Cell 185, 3789–3806.e17 (2022).
Google ScholarÂ
Galeano Niño, J. L. et al. Effect of the intratumoral microbiota on spatial and cellular heterogeneity in cancer. Nature 611, 810–817 (2022).
Google ScholarÂ
Gettinger, S. et al. Impaired HLA Class I antigen processing and presentation as a mechanism of acquired resistance to immune checkpoint inhibitors in lung cancer. Cancer Discov. 7, 1420–1435 (2017).
Google ScholarÂ
Buisson, R., Lawrence, M. S., Benes, C. H. & Zou, L. APOBEC3A and APOBEC3B activities render cancer cells susceptible to ATR inhibition. Cancer Res 77, 4567–4578 (2017).
Google ScholarÂ
Warren, C. J., Santiago, M. L. & Pyeon, D. APOBEC3: Friend or Foe in Human Papillomavirus Infection and Oncogenesis?. Annu Rev. Virol. 9, 375–395 (2022).
Google ScholarÂ
Foy, J.-P. et al. Arguments to support a viral origin of oral squamous cell carcinoma in non-smoker and non-drinker patients. Front Oncol. 10, 822 (2020).
Google ScholarÂ
Bullman, S. The intratumoral microbiota: From microniches to single cells. Cell 186, 1532–1534 (2023).
Google ScholarÂ
Cai, L. et al. Integrative analysis reveals associations between oral microbiota dysbiosis and host genetic and epigenetic aberrations in oral cavity squamous cell carcinoma. NPJ Biofilms Microbiomes 10, 39 (2024).
Google ScholarÂ
Xue, C. et al. Current understanding of the intratumoral microbiome in various tumors. Cell Rep. Med. 4, 100884 (2023).
Google ScholarÂ
Gihawi, A. et al. The landscape of microbial associations in human cancer. Sci. Transl. Med. 17, eads6166 (2025).
Google ScholarÂ
Ge, Y., Lu, J., Puiu, D., Revsine, M. & Salzberg, S. L. Comprehensive analysis of microbial content in whole-genome sequencing samples from The Cancer Genome Atlas project. Sci. Transl. Med. 17, eads6335 (2025).
Google ScholarÂ
Campbell, J. D. et al. Genomic, pathway network, and immunologic features distinguishing squamous carcinomas. Cell Rep. 23, 194–212.e6 (2018).
Google ScholarÂ
Senkin, S. MSA: reproducible mutational signature attribution with confidence based on simulations. BMC Bioinforma. 22, 540 (2021).
Google ScholarÂ
Martincorena, I. et al. Universal patterns of selection in cancer and somatic tissues. Cell 171, 1029–1041.e21 (2017).
Google ScholarÂ
Wu, T. et al. clusterProfiler 4.0: A universal enrichment tool for interpreting omics data. Innovation 2, 100141 (2021).
Google ScholarÂ

