TY - JOUR
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 Maurice
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.
N1 - Funding Information:
We would like to thank the patients from Cambridge University Hospital NHS Foundation Trust (CUHT) for volunteering clinical samples. We also thank David Allen, Dr. Naomi Guppy and Josep Linares from UCL Advanced Diagnostics for their invaluable help. We would also like to thank the teams at the Head and Neck Centre and the Department of Histopathology at CUHT for their support. The Human Research Tissue Bank of CUHT is supported by the Cambridge NIHR CBRC. The results shown here are in large part based upon data generated by the TCGA Research Network: http://cancergenome.nih.gov/. T.R.F was supported by Rosetrees Trust grant JS15/M229-CD1 and D.N.H. was supported by the National Cancer Institute Grant U10 CA181009.
Publisher Copyright:
© 2018 Elsevier Ltd
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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U2 - 10.1016/j.oraloncology.2018.06.006
DO - 10.1016/j.oraloncology.2018.06.006
M3 - Article
C2 - 30098776
AN - SCOPUS:85048543969
SN - 1368-8375
VL - 83
SP - 32
EP - 37
JO - Oral Oncology
JF - Oral Oncology
ER -