Frequent HPV-independent p16/INK4A overexpression in head and neck cancer

Matt Lechner, Ankur R. Chakravarthy, Vonn Walter, Liam Masterson, Andrew Feber, Amrita Jay, Paul M. Weinberger, Richard A. McIndoe, Cillian T. Forde, Kerry Chester, Nicholas Kalavrezos, Paul O'Flynn, Martin Forster, Terry M. Jones, Francis M. Vaz, D. Neil Hayes, Tim R. Fenton

Research output: Contribution to journalArticle

4 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)32-37
Number of pages6
JournalOral Oncology
Volume83
DOIs
StatePublished - Aug 2018

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Head and Neck Neoplasms
Squamous Cell Neoplasms
Protein Array Analysis
Head
Mutation
Oropharynx
Neoplasms
Biomarkers
Cyclin-Dependent Kinase Inhibitor p16
Atlases
Viral RNA
Methyltransferases
Histones
Lysine
Chromatin
Genome

ASJC Scopus subject areas

  • Oral Surgery
  • Oncology
  • Cancer Research

Cite this

Lechner, M., Chakravarthy, A. R., Walter, V., Masterson, L., Feber, A., Jay, A., ... Fenton, T. R. (2018). Frequent HPV-independent p16/INK4A overexpression in head and neck cancer. Oral Oncology, 83, 32-37. https://doi.org/10.1016/j.oraloncology.2018.06.006

Frequent HPV-independent p16/INK4A overexpression in head and neck cancer. / Lechner, Matt; Chakravarthy, Ankur R.; Walter, Vonn; Masterson, Liam; Feber, Andrew; Jay, Amrita; Weinberger, Paul M.; McIndoe, Richard A.; Forde, Cillian T.; Chester, Kerry; Kalavrezos, Nicholas; O'Flynn, Paul; Forster, Martin; Jones, Terry M.; Vaz, Francis M.; Hayes, D. Neil; Fenton, Tim R.

In: Oral Oncology, Vol. 83, 08.2018, p. 32-37.

Research output: Contribution to journalArticle

Lechner, M, Chakravarthy, AR, Walter, V, Masterson, L, Feber, A, Jay, A, Weinberger, PM, McIndoe, RA, Forde, CT, Chester, K, Kalavrezos, N, O'Flynn, P, Forster, M, Jones, TM, Vaz, FM, Hayes, DN & Fenton, TR 2018, 'Frequent HPV-independent p16/INK4A overexpression in head and neck cancer', Oral Oncology, vol. 83, pp. 32-37. https://doi.org/10.1016/j.oraloncology.2018.06.006
Lechner M, Chakravarthy AR, Walter V, Masterson L, Feber A, Jay A et al. Frequent HPV-independent p16/INK4A overexpression in head and neck cancer. Oral Oncology. 2018 Aug;83:32-37. https://doi.org/10.1016/j.oraloncology.2018.06.006
Lechner, Matt ; Chakravarthy, Ankur R. ; Walter, Vonn ; Masterson, Liam ; Feber, Andrew ; Jay, Amrita ; Weinberger, Paul M. ; McIndoe, Richard A. ; Forde, Cillian T. ; Chester, Kerry ; Kalavrezos, Nicholas ; O'Flynn, Paul ; Forster, Martin ; Jones, Terry M. ; Vaz, Francis M. ; Hayes, D. Neil ; Fenton, Tim R. / Frequent HPV-independent p16/INK4A overexpression in head and neck cancer. In: Oral Oncology. 2018 ; Vol. 83. pp. 32-37.
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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.",
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T1 - Frequent HPV-independent p16/INK4A overexpression in head and neck cancer

AU - Lechner, Matt

AU - Chakravarthy, Ankur R.

AU - Walter, Vonn

AU - Masterson, Liam

AU - Feber, Andrew

AU - Jay, Amrita

AU - Weinberger, Paul M.

AU - McIndoe, Richard A.

AU - Forde, Cillian T.

AU - Chester, Kerry

AU - Kalavrezos, Nicholas

AU - O'Flynn, Paul

AU - Forster, Martin

AU - Jones, Terry M.

AU - Vaz, Francis M.

AU - Hayes, D. Neil

AU - Fenton, Tim R.

PY - 2018/8

Y1 - 2018/8

N2 - 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.

AB - 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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