Differential Mechanisms of CDKN2A (p16) Inactivation in Oral Tongue Squamous Cell Carcinomas and Correlation With Patient Outcome

Lim, Annette; Do, H.; Young, Richard J.; Wong, Stephen Q.; Angel, Christopher; Collins, Marnie; Corry, June; Rischin, Danny; Dobrovic, Alexander; Solomon, Benjamin

doi:10.1016/j.ijrobp.2013.11.155

Cited by 16 publications

(21 citation statements)

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“…Using both HPV DNA and RNA detection methods, we have shown that HPV may be a causative factor in OSCC, albeit at low prevalence (1 patient, 2.3%) in our small cohort. Our frequency of HPV‐positive tumours, using more precise laboratory methods, is concordant with the existing literature . We have shown that p16 overexpression is only rarely HPV‐related and p16 IHC expression cannot be used as a surrogate marker for the presence of HPV in oral cavity carcinomas.…”

Section: Discussionsupporting

confidence: 88%

“…However, we found that whilst all patients in the cohort with detectable HPV were p16 IHC‐positive, p16 expression was not a predictor of HPV status in OSCC. We also found no statistically significant association between p16 overexpression and survival in our study cohort, which is similar to studies involving non‐OPC patient cohorts, but is in contrast to the study by Chung et al …”

Section: Discussionsupporting

confidence: 85%

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The role of human papillomavirus in p16‐positive oral cancers

Belobrov

Cornall

Young

et al. 2017

J Oral Pathology Medicine

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Background The aim of this study was to identify the presence and frequency of human papillomavirus (HPV) nucleic acid in p16‐positive oral squamous cell carcinomas (OSCCs), to assess whether the virus was transcriptionally active and to assess the utility of p16 overexpression as a surrogate marker for HPV in OSCC. Methods Forty‐six OSCC patients treated between 2007 and 2011 with available formalin‐fixed paraffin‐embedded (FFPE) specimens were included. Twenty‐three patients were positive for p16 by immunohistochemistry (IHC) and these were matched with 23 patients with p16‐negative tumours. Laser capture microdissection of the FFPE OSCC tissues was undertaken to isolate invasive tumour tissue. DNA was extracted and tested for high‐risk HPV types using a PCR‐ELISA method based on the L1 SPF10 consensus primers, and a real‐time PCR method targeting HPV‐16 and HPV‐18 E6 region. Genotyping of HPV‐positive cases was performed using a reverse line blot hybridization assay (Inno‐LiPA). RNAScope® (a chromogenic RNA in situ hybridization assay) was utilized to detect E6/E7 mRNA of known high‐risk HPV types for detection of transcriptionally active virus. Results HPV DNA was found in 3 OSCC cases, all of which were p16 IHC‐positive. Two cases were genotyped as HPV‐16 and one as HPV‐33. Only one of the HPV‐16 cases was confirmed to harbour transcriptionally active virus via HPV RNA ISH. Conclusion We have shown that the presence of transcriptionally active HPV rarely occurs in OSCC and that p16 is not an appropriate surrogate marker for HPV in OSCC cases. We propose that non‐viral mechanisms are responsible for the majority of IHC p16 overexpression in OSCC.

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Section: Discussionsupporting

confidence: 88%

Section: Discussionsupporting

confidence: 85%

The role of human papillomavirus in p16‐positive oral cancers

Belobrov

Cornall

Young

et al. 2017

J Oral Pathology Medicine

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“…HPV 16 and p16 concordance: In our study cohort, a majority of OTSCCs did not express p16 (84.6%) as was also the case in previously reported studies (Lim et al, 2014). Our study showed a very poor concordance between HPV 16 DNA and p16 IHC with a kappa less than 0.2.…”

Section: Discussionsupporting

confidence: 69%

Risk Stratification of Early Stage Oral Tongue Cancers Based on HPV Status and p16 Immunoexpression

Ramshankar¹,

Soundara²,

Shyamsundar³

et al. 2014

Asian Pacific Journal of Cancer Prevention

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Background: Recent epidemiological data have implicated human papilloma virus (HPV) infection in the pathogenesis of head and neck cancers, especially oropharyngeal cancers. Although, HPV has been detected in varied amounts in persons with oral dysplasia, leukoplakias and malignancies, its involvement in oral tongue carcinogenesis remains ambiguous. Materials and Methods: HPV DNA prevalence was assessed by PCR with formalin fixed paraffin embedded sections (n=167) of oral tongue squamous cell carcinoma patients and the physical status of the HPV16 DNA was assessed by qPCR. Immunohistochemistry was conducted for p16 evaluation. Results: We found the HPV prevalence in tongue cancers to be 51.2%, HPV 16 being present in 85.2% of the positive cases. A notable finding was a very poor concordance between HPV 16 DNA and p16 IHC findings (kappa<0.2). Further molecular classification of patients based on HPV16 DNA prevalence and p16 overexpression showed that patients with tumours showing p16 overexpression had increased hazard of death (HR=2.395; p=0.005) and disease recurrence (HR=2.581; p=0.002) irrespective of their HPV 16 DNA status. Conclusions: Our study has brought out several key facets which can potentially redefine our understanding of tongue cancer tumorigenesis. It has emphatically shown p16 overexpression to be a single important prognostic variable in defining a high risk group and depicting a poorer prognosis, thus highlighting the need for its routine assessment in tongue cancers. Another significant finding was a very poor concordance between p16 expression and HPV infection suggesting that p16 expression should possibly not be used as a surrogate marker for HPV infection in tongue cancers. Interestingly, the prognostic significance of p16 overexpression is different from that reported in oropharyngeal cancers. The mechanism of HPV independent p16 over expression in oral tongue cancers is possibly a distinct entity and needs to be further studied.

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“…Evaluation of HPV and p16 expression in OCC has failed to show any survival benefit, including in advanced OCC, where HPV-positive tumors were associated with worse survival and distant control in some studies. 74,75,77 One area of interest has been low-risk patients with oral tongue cancer. Harris et al 78 retrospectively examined patients younger than 40 years with OCC.…”

Section: Hpv In Occmentioning

confidence: 99%

Oral Cavity Carcinoma: Current Management, Controversies, and Future Directions

Chinn

Myers

2015

JCO

319

282

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Oral cavity carcinoma (OCC) remains a major cause of morbidity and mortality in patients with head and neck cancer. Although the incidence has decreased over the last decade, outcomes remain stagnant with only a 5% improvement in overall survival in the last 20 years. Although surgical resection remains the primary treatment modality, several areas of controversy exist with regard to work-up, management of the primary and neck tumors, and adjuvant therapy. As surgical techniques evolve, so has the delivery of radiotherapy and systemic treatment, which have helped to improve the outcomes for patients with advanced disease. Recently, the addition of cetuximab has shown promise as a way to improve outcomes while minimizing toxicity, and this remains an active area of study in the adjuvant setting. Advances in microvascular free-flap reconstruction have extended the limits of resection and enabled enhanced restoration of function and cosmesis. While these advances have led to limited survival benefit, evaluation of alternative modalities has gained interest on the basis of success in other head and neck subsites. Organ preservation with definitive chemoradiotherapy, though proven in the larynx and pharynx, remains controversial in OCC. Likewise, although the association of human papillomavirus is well established in oropharyngeal carcinoma, it has not been proven in the pathogenesis or survival of OCC. Future study of the molecular biology and pathogenesis of OCC should offer additional insight into screening, treatment selection, and novel therapeutic approaches.

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Differential Mechanisms of CDKN2A (p16) Inactivation in Oral Tongue Squamous Cell Carcinomas and Correlation With Patient Outcome

Cited by 16 publications

References 0 publications

The role of human papillomavirus in p16‐positive oral cancers

The role of human papillomavirus in p16‐positive oral cancers

Risk Stratification of Early Stage Oral Tongue Cancers Based on HPV Status and p16 Immunoexpression

Oral Cavity Carcinoma: Current Management, Controversies, and Future Directions

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