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The Virome of HPV-Positive Tonsil Squamous Cell Carcinoma and Neck Metastasis

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The Virome of HPV-Positive Tonsil Squamous Cell Carcinoma and Neck Metastasis www.oncotarget.com Oncotarget, 2020, Vol. 11, (No. 3), pp: 282-293 Research Paper The virome of HPV-positive tonsil squamous cell carcinoma and neck metastasis Ryan M. Carey1,*, Karthik Rajasekaran1,*, Tyler Seckar1, Xiang Lin2, Zhi Wei2, Charles C.L. Tong1, Viran J. Ranasinghe1, Jason G. Newman1, Bert W. O'Malley Jr.1, Gregory S. Weinstein1, Michael D. Feldman3 and Erle S. Robertson1 1Department of Otorhinolaryngology-Head and Neck Surgery, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA, USA 2Department of Computer Science, New Jersey Institute of Technology, Newark, NJ, USA 3Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, USA *Co-first authors Correspondence to: Erle S. Robertson, email: [email protected] Keywords: HPV; cancer; virus; virome; oropharyngeal squamous cell carcinoma Received: November 06, 2019 Accepted: December 29, 2019 Published: January 21, 2020 Copyright: Carey et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License 3.0 (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. ABSTRACT Oropharyngeal squamous cell carcinoma (OPSCC) represents the most common HPV-related malignancy in the United States with increasing incidence. There is heterogeneity between the behavior and response to treatment of HPV-positive oropharyngeal squamous cell carcinoma that may be linked to the tumor virome. In this prospective study, a pan-pathogen microarray (PathoChip) was used to determine the virome of early stage, p16-positive OPSCC and neck metastasis treated with transoral robotic surgery (TORS) and neck dissection. The virome findings of primary tumors and neck lymph nodes were correlated with clinical data to determine if specific organisms were associated with clinical outcomes. A total of 114 patients were enrolled in the study. Double-stranded DNA viruses, specifically Papillomaviridae, showed the highest hybridization signal (viral copies) across all viral families in the primary and positive lymph node samples. High hybridization signals were also detected for signatures of Baculoviridae, Reoviridae, Siphoviridae, Myoviridae, and Polydnaviridae in most of the cancer specimens, including the lymph nodes without cancer present. Across all HPV signatures, HPV16 and 18 had the highest average hybridization signal index and prevalence. To our knowledge, this is the first study that has identified the viral signatures of OPSCC tumors. This will serve as a foundation for future research investigating the role of the virome in OPSCC. Further investigation into the OPSCC microbiome and its variations may allow for improved appreciation of the impact of microbial dysbiosis on risk stratification, oncologic outcomes, and treatment response which has been shown in other cancer sites. INTRODUCTION the primary causes of carcinogenesis for the majority of OPSCCs in North America and Europe [2]. Important Head and neck squamous cell carcinomas clinical differences exist between HPV-positive and (HNSCCs), including oropharyngeal squamous cell HPV-negative OPSCC which ultimately impact treatment carcinoma (OPSCC), are classically associated with risk decisions. HPV-positive OPSCCs have a higher incidence factors such as tobacco and alcohol use [1]. However, amongst younger patients with higher performance status, human papillomavirus (HPV) has emerged as one of lower tobacco consumption, and higher socioeconomic www.oncotarget.com 282 Oncotarget status [3, 4]. Compared to HPV-negative OPSCCs, HPV- and 36%, p = 0.031). The average age for patients from positive OPSCCs have an improved overall survival the negative-node SCC, positive-node SCC, and control (OS) and disease-free survival (DFS) [5, 6], which is groups was significantly different (58.4, 57.0, and 46.4 at least partially related to the increased sensitivity to years, p < 0.001). chemotherapy and radiation therapy [7]. The survival Disease and treatment characteristics for patients advantage of HPV-positivity persists even after adjusting with SCC are listed in Table 2. There were no statistically for confounders [8], suggesting a difference in the tumor significant differences between pathologic factors between biology between HPV-positive and -negative OPSCCs. the negative-node and positive-node groups. Significantly An improved understanding of prognostic factors and more patients from the positive-node cohort received post- tumor biology is necessary to improve clinical outcomes operative radiation therapy (70% vs 33%, p = 0.01). There and maximize quality of life in long-term survivors of were no statistically significant differences in the 2-year HPV-positive OPSCC. Various studies have demonstrated OS or DFS between the negative-node and positive-node that there are unique microbiomes associated with certain groups. cancer types [9–14], including in oral and oropharyngeal squamous cell carcinomas [15]. These specific microbiomes Viral signatures in p16-positive tonsil squamous may create a microenvironment conducive to oncogenesis, cell carcinoma or it may be that the microenvironment in malignancy may promote specific microbiomes. Regardless, the interplay Various DNA and RNA viral signatures were between the host and microbiome impacts the immune associated with the tonsil cancer groups (Figure 2). system on a local and systemic level that contributes Double-stranded DNA viruses had the highest ratio to oncologic outcomes [16, 17]. Our previous work on amongst the viral signatures for all cohorts (p < 0.001), the mixed group of p16-negative and -positive oral and followed by single-stranded RNA (Figure 2A). There oropharyngeal squamous cell carcinomas demonstrated were 101 virus families with signatures. A hybridization that there were distinct viral and other microbial signature signal index of > 5 was used to select virus families with patterns associated with this type of malignancy [15]. relatively higher intensity signatures, of which there Amongst the viruses, HPV, specifically HPV16 was the were 43. High hybridization signals were detected from most detected molecular signature which is consistent with Siphoviridae, Myoviridae, Reoviridae, Polydnaviridae, the fact that approximately 95% of HPV-positive OPSCCs and Baculoviridae in most of the cancer specimens, are caused by HPV16 [18]. Additional viral signatures including NLN (Figure 2B, Supplementary Table 1). detected in our study included other HPVs, Herpesviridae, Viral sequences belonging to the double-stranded DNA Poxviridae, Retroviridae and Polyomaviridae, and host virus Papillomaviridae showed the highest hybridization integration hotspots were identified for HPV16 and JC signal across all viral families in the PPR, PLN, and polyomavirus [15]. NPR samples (Figure 2B, Supplementary Table 1). In the present study, we utilized a pan-pathogen HPV detection by PathoChip was 95.7%, 100%, 100%, microarray (PathoChip [19]) to determine the viral 86.4%, and 20.8% of PPR, NPR, PLN, NLN, and control microbiome of p16-positive, T1 or T2 tonsil squamous specimens, respectively. cell carcinomas with no positive nodes or a single <6 Fourteen HPV subtype signatures were detected cm lymph node metastasis treated with transoral robotic with high hybridization signals amongst all cohorts, with surgery (TORS) and neck dissection. The virome findings the two high-risk subtypes HPV16 and HPV18, detected were then correlated with clinical data to determine (Figure 2C). Across all HPV signatures, HPV16 had prognostic and diagnostic markers. the highest average hybridization signal intensity and prevalence (Figure 2C). HPV16 was present in 73.9%, RESULTS 95.7%, 95.5%, 0.00%, and 16.7% of PPR, NPR, PLN, NLN, and control specimens, respectively. Additionally, Clinical characteristics and outcomes HPV18 maintained a high prevalence amongst the cohorts and was present in 65.2%, 69.6%, 95.5%, 45.5%, and After excluding inadequate tissue samples, a total 0.00% of PPR, NPR, PLN, NLN, and control specimens, of 114 patients were enrolled in the study. There were respectively. Low-risk HPV6b had a prevalence of 34.8%, 23, 22, 23, 22, and 24 samples in the NPR (“negative- 34.8%, 31.8%, 0.00%, and 0.00% in PPR, NPR, PLN, node primary”), NLN (“negative lymph node”), PPR NLN, and control specimens, respectively. (“positive-node primary”), PLN (“positive lymph node”), Due to the low number of deaths in each cohort, and control groups, respectively (Figure 1). Table 1 lists no significant probes were identified on Kaplan–Meier the demographic characteristics for patients included in analysis of OS and DFS. Specifically, we could only the study. The difference in the proportions of patients perform survival analysis in the NPR group because of who smoked from the negative-node SCC, positive-node the limited number of deaths in the other cohorts. HPV16 SCC, and control groups was significant (71%, 74%, probes had the highest hybridization signal indexes, www.oncotarget.com 283 Oncotarget prevalence, and number of probes within the NPR and negative lymph node specimens in addition to group. Comparisons of overall survival for high and low primary tumors was to improve our understanding of the hybridization signal indexes for HPV16 probes in the microenvironment necessary for or induced by regional NPR group were not significant (p = 0.082). There were metastasis. Furthermore, we attempted to determine no significant
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