Key Points
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There are major molecular differences between human papillomavirus (HPV)-positive and HPV-negative oropharyngeal cancers, and these underlie the major clinical differences. HPV-positive oropharyngeal cancers are associated with a favourable prognosis.
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The lack of HPV-positive mucosal precursor changes has hampered investigation of the natural history of HPV-driven oropharyngeal cancers. Current data suggest that the productive infections take place in the oral cavity and transforming infections in a subgroup of epithelial cells mostly found in the tonsils, which are characterized by specific molecular markers.
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Assessing HPV status in oropharyngeal cancer with the use of immunostaining for the surrogate marker p16INK4A is appropriate for staging, but additional HPV DNA or RNA testing will be required for treatment de-escalation.
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Detailed molecular characterization of head and neck cancer revealed that the major cancer genes causing the disease are tumour suppressor genes.
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Many head and neck cancer genes are involved in cell proliferation and cell cycle control, WNT–β-catenin signalling, cell survival and epigenetic regulation.
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Head and neck cancer is an unexpectedly heterogeneous disease with at least three genetically defined major subgroups: HPV-positive tumours; HPV-negative tumours with many copy number changes; and copy number alteration-silent, HPV-negative tumours.
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Besides the classification into three distinct genetic subgroups, both HPV-positive and HPV-negative tumours can be subclassified on the basis of genomic profiling.
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The many genetic changes in head and neck cancer present an opportunity for immunotherapy with immune checkpoint inhibitors.
Abstract
Head and neck squamous cell carcinomas (HNSCCs) arise in the mucosal linings of the upper aerodigestive tract and are unexpectedly heterogeneous in nature. Classical risk factors are smoking and excessive alcohol consumption, and in recent years, the role of human papillomavirus (HPV) has emerged, particularly in oropharyngeal tumours. HPV-induced oropharyngeal tumours are considered a separate disease entity, which recently has manifested in an adapted prognostic staging system while the results of de-intensified treatment trials are awaited. Carcinogenesis caused by HPV in the mucosal linings of the upper aerodigestive tract remains an enigma, but with some recent observations, a model can be proposed. In 2015, The Cancer Genome Atlas (TCGA) consortium published a comprehensive molecular catalogue on HNSCC. Frequent mutations of novel druggable oncogenes were not demonstrated, but the existence of a subgroup of genetically distinct HPV-negative head and neck tumours with favourable prognoses was confirmed. Tumours can be further subclassified based on genomic profiling. However, the amount of molecular data is currently overwhelming and requires detailed biological interpretation. It also became apparent that HNSCC is a disease characterized by frequent mutations that create neoantigens, indicating that immunotherapies might be effective. In 2016, the first results of immunotherapy trials with immune checkpoint inhibitors were published, and these may be considered as a paradigm shift in head and neck oncology.
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Acknowledgements
The authors' research summarized here is supported by Cancer Center Amsterdam, the Dutch Cancer Society, the European Commission, The Netherlands Organization for Scientific Research (NWO), The Fanconi Anaemia Research Fund and The German Fanconi Support Group.
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C.R.L, P.J.F.S and R.H.B contributed to the design, concepts and writing of the manuscript.
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R.H.B has a longstanding collaboration with and receives support from InteRNA Technologies BV and received support from Agilent Technologies Netherlands BV and AbbVie. C.R.L has a collaboration with and receives support from Genmab and InteRNA Technologies BV. C.R.L. also participates in the advisory boards of Merck and MSD. P.J.F.S. is a minority stakeholder and the Chief Science Officer of Self-Screen BV, a spin-off company of VU University Medical Center. P.J.F.S. has been on the Speaker Bureau of Roche Diagnostics, Gen-Probe, Abbott, Qiagen and Seegene and has been a consultant for Crucell BV.
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Glossary
- Leukoplakia
-
A macroscopic white change in the mucosal linings of the upper aerodigestive tract, which is defined by the World Health Organization (WHO) as “a white plaque of questionable risk having excluded (other) known diseases or disorders that carry no increased risk for cancer”.
- Erythroplakia
-
A macroscopic red change in the mucosal linings of the upper aerodigestive tract, which is defined by the World Health Organization (WHO) as “a fiery red patch that cannot be characterized either clinically or pathologically as any other definable lesion”.
- Kabuki syndrome
-
A dominant autosomal disease caused by inactivating germline mutations in the histone-lysine N-methyltransferase 2D (KMT2D) gene and characterized by anatomical abnormalities and mental retardation.
- Sotos syndrome
-
A neurological autosomal dominant disorder caused by the loss of one active copy of the nuclear receptor-binding SET domain-containing protein 1 (NSD1) gene and characterized by an unusual face with a large skull, acromegalic features and mental retardation.
- MicroRNAs
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(miRNAs). Small, 22–24 nucleotide single-stranded RNAs that bind to the 3′ untranslated region of genes and cause degradation of the transcript or a stop in translation.
- HPV attributable fraction
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The percentage of head and neck squamous cell carcinomas in any defined subsite that are assumingly caused by human papillomavirus (HPV).
- Productive HPV infections
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A type of human papillomavirus (HPV) infection that supports the normal viral life cycle and leads to viral progeny.
- Transforming HPV infections
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A type of human papillomavirus (HPV) infection that does not result in virus production but may instead cause malignant transformation of the infected cell.
- Apolipoprotein B mRNA-editing enzyme catalytic subunit
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(APOBEC). A class of cytidine deaminases that function in innate immunity as well as in RNA editing. Viral infections may induce high expression of these genes, causing specific mutation patterns that have also been identified in human papillomavirus (HPV)-induced head and neck cancers.
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Leemans, C., Snijders, P. & Brakenhoff, R. The molecular landscape of head and neck cancer. Nat Rev Cancer 18, 269–282 (2018). https://doi.org/10.1038/nrc.2018.11
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DOI: https://doi.org/10.1038/nrc.2018.11
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