Differences in methylation profiles between HPV-positive and HPV-negative oropharynx squamous cell carcinoma

Kempen, Pauline M.W. van; Noorlag, Rob; Braunius, W.W.; Stegeman, Inge; Willems, Stefan M.; Grolman, Wilko

doi:10.4161/epi.26881

Cited by 80 publications

(67 citation statements)

References 66 publications

(241 reference statements)

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“…As p16 INK4A has been reported to be further regulated by epigenetic control and multiple transcription factors or gain of function in chromosome 11q, 48 it is likely that HPV-negative and HPV-positive anal cancers with low viral load share comparable genetic alterations or epigenetic methylation profiles that might result in reduced sensitivity to RT/CRT and worse prognosis. 32,49,50 We would like to acknowledge the limitations of our study. Although the patient number is relatively large (n 5 95), these data need to be validated prospectively in a larger patient cohort.…”

Section: Cancer Cell Biologymentioning

confidence: 99%

Human papillomavirus DNA load and p16^INK4aexpression predict for local control in patients with anal squamous cell carcinoma treated with chemoradiotherapy

et al. 2014

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As the detection rate of HPV-DNA in anal carcinoma commonly exceeds 90%, a comparison between sole HPV-positive and HPV-negative cancers with respect to treatment response following chemoradiotherapy (CRT) and long-term oncological outcome is challenging. Against this background, we aimed to assess HPV types and HPV DNA load in formalin-fixed paraffinembedded tissue (FFPE) of 95 patients treated with standard CRT for anal cancer to correlate viral load ( /> median) with local failure, distant metastases, cancer-specific (CSS) and overall survival (OS) rates. Various clinicopathologic parameters and the immunohistochemical marker p16 INK4a were evaluated for any correlation with HPV16 DNA load and were included in uni-and multivariate analyses. The overall prevalence of HPV DNA was 95.8% with HPV16 monoinfection being the most commonly encountered HPV type (78.9%), followed by HPV16 and 31,35,39,44, 58, 66 and 81 dual infection in 9 patients (9.5%). HPV16 DNA load was significantly associated with p16 INK4a expression (p 5 0.001). Patients with HPV16 DNA load median and low p16 INK4a expression showed significantly worse local control (HPV16 DNA load: univariate p 5 0.023, multivariate p 5 0.042; p16 INK4a : univariate p 5 0.021), and OS (HPV16 DNA load: univariate p 5 0.02, multivariate p 5 0.03). Moreover, a combined HPV16 DNA load and p16 INK4a variable revealed a significant correlation to decreased local failure, and increased CSS and OS (p 5 0.019, p 5 0.04 and p 5 0.031). In conclusion, these data indicate that HPV16 DNA load and p16 INK4a expression are significant prognostic factors for local tumor control and overall survival of patients with anal SCC following CRT.The majority of anal squamous cell carcinoma (SCC) is considered to originate from infection with human papilloma viruses (HPV). 1,2 Especially the role of high-risk oncogenic HPV types, most prominently HPV type 16 (HPV16), in the etiology of anal SCC is well established by a multitude of epidemiological and experimental investigations. 3,4 As a consequence, technologies for the detection of HPV DNA may constitute valuable screening tools for anal malignancies and are of important clinical relevance, especially after the development of a preventive vaccine for both men and women. 5 Depending on the method used, the prevalence of HPV DNA in anal carcinoma ranges from 75% to 100% with HPV16 (>75%) and less frequent HPV18 (<10%) detection in the majority of cases. 6,7 In clinical series of head and neck as well as cervical SCC, recent data indicate that treatment response to radiotherapy (RT) or chemoradiotherapy (CRT) is superior in HPV-positive tumors as compared with their HPV-negative counterparts. [8][9][10] An increased sensitivity of HPV-positive tumor cells towards irradiation and chemotherapeutic agents was also observed in vitro and in animal studies. [11][12][13] However, as the detection rate of HPV DNA in anal SCC commonly exceeds 90%, a comparison between sole HPV-positive and HPV-negative cancers with respect to treatment respon...

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Section: Cancer Cell Biologymentioning

confidence: 99%

Human papillomavirus DNA load and p16^INK4aexpression predict for local control in patients with anal squamous cell carcinoma treated with chemoradiotherapy

et al. 2014

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“…4,5,24 Despite advances in our knowledge on the pathogenesis and implementation of multimodal treatment the 5-year survival rate for advanced HNSCC remains discouraging. Moreover, multimodal therapy is characterized by high toxicity and treatmentrelated mortality resulting in severe loss of life quality for HNSCC patients.…”

Section: Discussionmentioning

confidence: 99%

“…22 The epigenetic plasticity makes DNA methylation patterns bona fide prognostic and therapeutic biomarkers for human cancer, including HNSCC. 5,23,24 In the past, we investigated differentially methylated regions (DMR) in proximal gene promoters of HPV-related and non-HPV-related OPSCC and established a methylation score (MS), which was based on DNA methylation patterns of 62 CpG units in DMR of 5 gene promoters (ALDH1A2, OSR2, GRIA4, GATA4 and IRX4). 25 Although a high MS was more common in HPV-related OPSCC, it served as a reliable prognostic biomarker for overall survival independent of the HPV status and initial therapy.…”

Section: Introductionmentioning

confidence: 99%

Gene promoter methylation signature predicts survival of head and neck squamous cell carcinoma patients

et al. 2016

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Infection with high-risk types of human papilloma virus (HPV) is currently the best-established prognostic marker for head and neck squamous cell carcinoma (HNSCC), one of the most common and lethal human malignancies worldwide. Clinical trials have been launched to address the concept of treatment de-escalation for HPV-positive HNSCC with the final aim to reduce treatment related toxicity and debilitating long-term impacts on the quality of life. However, HPV-related tumors are mainly restricted to oropharyngeal SCC (OPSCC) and there is an urgent need to establish reliable biomarkers for all patients at high risk for treatment failure. A patient cohort (n D 295) with mainly non-OPSCC (72.9%) and a low prevalence of HPV16-related tumors (8.8%) was analyzed by MassARRAY to determine a previously established prognostic methylation score (MS). Kaplan-Meier revealed a highly significant correlation between a high MS and a favorable survival for OPSCC (P D 0.0004) and for non-OPSCC (P<0.0001), which was confirmed for all HNSCC by multivariate Cox regression models (HR: 9.67, 95% ], P<0.0001). Next, we established a minimal methylation signature score (MMSS), which consists of ten most informative of the originally 62 CpG units used for the MS. The prognostic value of the MMSS was confirmed by Kaplan-Meier analysis for all HNSCC (P<0.0001) and non-OPSCC (P D 0.0002), and was supported by multivariate Cox regression models for all HNSCC (HR: 2.15, 95% CI [1.36-3.41], P D 0.001). In summary, the MS and the MMSS exhibit an excellent performance as prognosticators for survival, which is not limited by the anatomical site, and both could be implemented in future clinical trials.

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“…Each subsite in the head and neck region displays a diverse biological and clinical behavior based on divergent etiological pathways [23]. This heterogeneity has previously been shown on epigenetic, genetic and transcriptomic levels [24,25,26]. It has been proposed that different tumor types have their own TP53 mutational pattern that represents the agent responsible for this mutation [27].…”

Section: Discussionmentioning

confidence: 99%

<b><i>TP53</i></b> Y220C Is a Hotspot Mutation in Oropharyngeal Squamous Cell Carcinoma

Kempen¹,

Verdam²,

Poel³

et al. 2015

Pathobiology

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Objectives: Although TP53 mutations in head and neck squamous cell carcinoma (HNSCC) have been extensively studied, their association with the different subsites in the head and neck region has never been described. Methods: Sanger sequence analysis evaluating exons 4-9 in the TP53 gene was performed on 116 HNSCC patients. The exon location, exact codon and corresponding substitution in relation to the anatomical site (subsite) of the HNSCC were evaluated. Results: We found nonsynonymous TP53 mutations in 70% (81/116) of the patients. In oral cavity carcinomas, most mutations occurred in exon 7 (37%). In oropharyngeal and laryngeal tumors, mutations were mainly found in exons 6 and 7. The most common mutation was located in codon 220, and all of these were an Y220C mutation. Five out of nine (56%) Y220C mutations occurred in oropharyngeal tumors. Additionally, 22% of all mutations observed in oropharyngeal squamous cell carcinoma (OPSCC) consisted of Y220C mutations. Conclusion: In this study, the subsite-related distribution of TP53 mutations underlines the biological diversity between tumors arising from different anatomical regions in the head and neck region. Moreover, the Y220C mutation was by far the most prevalent TP53 mutation in HNSCC and a relative hotspot mutation in the oropharynx.

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Differences in methylation profiles between HPV-positive and HPV-negative oropharynx squamous cell carcinoma

Cited by 80 publications

References 66 publications

Human papillomavirus DNA load and p16^INK4aexpression predict for local control in patients with anal squamous cell carcinoma treated with chemoradiotherapy

Human papillomavirus DNA load and p16^INK4aexpression predict for local control in patients with anal squamous cell carcinoma treated with chemoradiotherapy

Gene promoter methylation signature predicts survival of head and neck squamous cell carcinoma patients

<b><i>TP53</i></b> Y220C Is a Hotspot Mutation in Oropharyngeal Squamous Cell Carcinoma

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Differences in methylation profiles between HPV-positive and HPV-negative oropharynx squamous cell carcinoma

Cited by 80 publications

References 66 publications

Human papillomavirus DNA load and p16INK4aexpression predict for local control in patients with anal squamous cell carcinoma treated with chemoradiotherapy

Human papillomavirus DNA load and p16INK4aexpression predict for local control in patients with anal squamous cell carcinoma treated with chemoradiotherapy

Gene promoter methylation signature predicts survival of head and neck squamous cell carcinoma patients

<b><i>TP53</i></b> Y220C Is a Hotspot Mutation in Oropharyngeal Squamous Cell Carcinoma

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Human papillomavirus DNA load and p16^INK4aexpression predict for local control in patients with anal squamous cell carcinoma treated with chemoradiotherapy

Human papillomavirus DNA load and p16^INK4aexpression predict for local control in patients with anal squamous cell carcinoma treated with chemoradiotherapy