Matt Lechner1, Ankur R Chakravarthy2, Vonn Walter3, Liam Masterson4, Andrew Feber5, Amrita Jay6, Paul M Weinberger7, Richard A McIndoe7, Cillian T Forde8, Kerry Chester2, Nicholas Kalavrezos8, Paul O'Flynn8, Martin Forster1, Terry M Jones9, Francis M Vaz8, D Neil Hayes10, Tim R Fenton11. 1. UCL Cancer Institute, University College London, 72 Huntley Street, London WC1E 6DD, United Kingdom; Head and Neck Centre, University College London Hospitals NHS Trust, Euston Road, London NW1 2PG, United Kingdom. 2. UCL Cancer Institute, University College London, 72 Huntley Street, London WC1E 6DD, United Kingdom. 3. Department of Public Health Sciences, Penn State College of Medicine, Hershey, PA, United States; UNC Lineberger Comprehensive Cancer Center, School of Medicine, UNC-Chapel Hill, NC, United States. 4. Department of Pathology, University of Cambridge, Tennis Court Road, Cambridge CB2 1QP, United Kingdom. 5. Division of Surgery & Interventional Science, University College London,London, United Kingdom. 6. Department of Histopathology, University College London Hospitals NHS Trust, Euston Road, London NW1 2PG, United Kingdom. 7. Center for Biotechnology and Genomic Medicine, Department of Otolaryngology, and Georgia Regents Cancer Center, Georgia Regents University, Augusta, GA, United States. 8. Head and Neck Centre, University College London Hospitals NHS Trust, Euston Road, London NW1 2PG, United Kingdom. 9. Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool, United Kingdom. 10. Department of Public Health Sciences, Penn State College of Medicine, Hershey, PA, United States. Electronic address: hayes@med.unc.edu. 11. School of Biosciences, University of Kent, Canterbury CT2 7NJ, United Kingdom. Electronic address: t.fenton@kent.ac.uk.
Abstract
OBJECTIVES: p16INK4A (p16) is the most widely used clinical biomarker for Human Papillomavirus (HPV) in head and neck squamous cell cancer (HNSCC). HPV is a favourable prognostic marker in HNSCC and is used for patient stratification. While p16 is a relatively accurate marker for HPV within the oropharynx, recent reports suggest it may be unsuitable for use in other HNSCC subsites, where a smaller proportion of tumors are HPV-driven. MATERIALS AND METHODS: We integrated reverse phase protein array (RPPA) data for p16 with HPV status based on detection of viral transcripts by RNA-seq in a set of 210 HNSCCs profiled by The Cancer Genome Atlas project. Samples were queried for alterations in CDKN2A, and other pathway genes to investigate possible drivers of p16 expression. RESULTS: While p16 levels as measured by RPPA were significantly different by HPV status, there were multiple HPV (-) samples with similar expression levels of p16 to HPV (+) samples, particularly at non-oropharyngeal subsites. In many cases, p16 overexpression in HPV (-) tumors could not be explained by mutation or amplification of CDKN2A or by RB1 mutation. Instead, we observed enrichment for inactivating mutations in the histone H3 lysine 36 methyltransferase, NSD1 in HPV (-)/p16-high tumors. CONCLUSIONS: RPPA data suggest high p16 protein expression in many HPV (-) non-oropharyngeal HNSCCs, limiting its potential utility as an HPV biomarker outside of the oropharynx. HPV-independent overexpression of wild-type p16 in non-oropharyngeal HNSCC may be linked to global deregulation of chromatin state by inactivating mutations in NSD1.
OBJECTIVES: p16INK4A (p16) is the most widely used clinical biomarker for Human Papillomavirus (HPV) in head and neck squamous cell cancer (HNSCC). HPV is a favourable prognostic marker in HNSCC and is used for patient stratification. While p16 is a relatively accurate marker for HPV within the oropharynx, recent reports suggest it may be unsuitable for use in other HNSCC subsites, where a smaller proportion of tumors are HPV-driven. MATERIALS AND METHODS: We integrated reverse phase protein array (RPPA) data for p16 with HPV status based on detection of viral transcripts by RNA-seq in a set of 210 HNSCCs profiled by The Cancer Genome Atlas project. Samples were queried for alterations in CDKN2A, and other pathway genes to investigate possible drivers of p16 expression. RESULTS: While p16 levels as measured by RPPA were significantly different by HPV status, there were multiple HPV (-) samples with similar expression levels of p16 to HPV (+) samples, particularly at non-oropharyngeal subsites. In many cases, p16 overexpression in HPV (-) tumors could not be explained by mutation or amplification of CDKN2A or by RB1 mutation. Instead, we observed enrichment for inactivating mutations in the histone H3 lysine 36 methyltransferase, NSD1 in HPV (-)/p16-high tumors. CONCLUSIONS: RPPA data suggest high p16 protein expression in many HPV (-) non-oropharyngeal HNSCCs, limiting its potential utility as an HPV biomarker outside of the oropharynx. HPV-independent overexpression of wild-type p16 in non-oropharyngeal HNSCC may be linked to global deregulation of chromatin state by inactivating mutations in NSD1.
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