Abstract
Deregulation of miRNAs is associated with almost all human malignancies. Human papillomavirus (HPV)-associated oropharyngeal carcinoma (OPC) has a significantly more favorable outcome compared with HPV-negative OPCs; however, the underlying mechanisms are not well understood. Hence, the objectives of this study were to determine whether miRNA expression differed as a function of HPV status and to assess whether such miRNAs provide prognostic value beyond HPV status. Global miRNA profilings were conducted on 88 formalin-fixed and paraffin-embedded (FFPE) OPC biopsies (p16-positive: 56; p16-negative: 32), wherein the expression levels of 365 miRNAs plus 3 endogenous controls were simultaneously measured using quantitative real-time (qRT)-PCR. Seven FFPE specimens of histologically normal tonsils were used as controls. Overall, 224 miRNAs were expressed in more than 80% of the investigated samples, with 128 (57%) being significantly differentially expressed between tumor versus normal tissues (P < 0.05). Upregulated miR-20b, miR-9, and miR-9* were significantly associated with HPV/p16-status. Three miRNA sets were significantly associated with overall survival (miR-107, miR-151, miR-492; P = 0.0002), disease-free survival (miR-20b, miR-107, miR-151, miR-182, miR-361; P = 0.0001), and distant metastasis (miR-151, miR-152, miR-324-5p, miR-361, miR492; P = 0.0087), which retained significance even after adjusting for p16 status. The associated biologic functions of these miRNAs include immune surveillance, treatment resistance, invasion, and metastasis. We have identified several miRNAs, which associate with HPV status in OPC; furthermore, three candidate prognostic sets of miRNAs seem to correlate with clinical outcome, independent of p16 status. Furthermore, evaluations will offer biologic insights into the mechanisms underlying the differences between HPV-positive versus HPV-negative OPC.
Highlights
Over the past 2 decades, the incidence of human papilloma virus (HPV)-associated head and neck squamous cell carcinomas (HNSCC) involving the oropharynx has been increasing, nowadays comprising the majority of oropharyngeal carcinoma (OPC) cases seen in North AmericaAuthors' Affiliations: 1Ontario Cancer Institute, University Health Network; 2Division of Biostatistics, 3Division of Surgical Oncology, 4Division of Medical Oncology, and 5Department of Radiation Oncology, Princess Margaret Cancer Center; 6Division of Signaling Biology, Ontario Cancer Institute; 7Department of Pathology, University Health Network; and 8Department of Radiation Oncology; University of Toronto, Toronto, Ontario, CanadaNote: Supplementary data for this article are available at Clinical Cancer Research Online.Ó2013 American Association for Cancer Research.(1–3)
We have previously reported that approximately 60% of patients with OPC seen at the Princess Margaret Cancer Center were HPV-positive, with 3-year overall survival (OS) rates of 88% versus 67% in favor of HPV-positive versus negative patients [4]
We evaluated the miRNA profiles of archival formalin-fixed and paraffin-embedded diagnostic biopsy specimens from 88 nonmetastatic OPC samples (p16þve:58; p16Àve:34)
Summary
Over the past 2 decades, the incidence of human papilloma virus (HPV)-associated head and neck squamous cell carcinomas (HNSCC) involving the oropharynx has been increasing, nowadays comprising the majority of oropharyngeal carcinoma (OPC) cases seen in North AmericaAuthors' Affiliations: 1Ontario Cancer Institute, University Health Network; 2Division of Biostatistics, 3Division of Surgical Oncology, 4Division of Medical Oncology, and 5Department of Radiation Oncology, Princess Margaret Cancer Center; 6Division of Signaling Biology, Ontario Cancer Institute; 7Department of Pathology, University Health Network; and 8Department of Radiation Oncology; University of Toronto, Toronto, Ontario, CanadaNote: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/).Ó2013 American Association for Cancer Research.(1–3). Over the past 2 decades, the incidence of human papilloma virus (HPV)-associated head and neck squamous cell carcinomas (HNSCC) involving the oropharynx has been increasing, nowadays comprising the majority of oropharyngeal carcinoma (OPC) cases seen in North America. There are several unique clinical characteristics of HPV-positive OPC, such as younger age at diagnosis, lower likelihood of heavy smoking or alcohol, and greater degree of sexual activity, compared with patients with HPV-negative OPC [1, 2]. We have previously reported that approximately 60% of patients with OPC seen at the Princess Margaret Cancer Center were HPV-positive, with 3-year overall survival (OS) rates of 88% versus 67% in favor of HPV-positive versus negative patients [4]. The biologic mechanisms behind this unique clinical entity of HPV-associated OPC remain to be elucidated
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