Significance of p16 in site-specific HPV positive and HPV negative HNSCC

Stephen, Josena K.; Divine, George; Chen, Kang Mei; Chitale, Dhananajay; Havard, Shaleta; Worsham, Maria J.

doi:10.5539/cco.v2n1p51

Cited by 94 publications

(125 citation statements)

References 29 publications

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“…p16 immunoexpression has in fact been used as a surrogate marker for HPV infection in both oropharyngeal as well as non-oropharyngeal squamous cell carcinomas. However, it has also been indicated that p16 expression without HPV could be a distinct entity showing HPV presence does not always guarantee p16 overexpression as shown earlier and clinical behavior of p16 positive tumours lacking HPV is therefore not clear (Smeets et al, 2007;Fakhry et al, 2008;Stephen et al, 2013;Salazar et al, 2014).…”

Section: Introductionmentioning

confidence: 98%

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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Section: Introductionmentioning

confidence: 98%

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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“…Interestingly, in paper III, 7% of the tumor samples were positive for p16. The significance of p16 in non-oropharyngeal HNSCC is disputed, but there are studies that have shown a prognostic value of p16 in other sites (120). In terms of prognosis, survival outcome did not differ between p16-positive and -negative samples in our study.…”

Section: The Role Of P16 In Papers I -Iiisupporting

confidence: 44%

The impact of Survivin, WRAP53β, and Hypoxia on treatment response in Head and Neck Cancer

Tiefenböck-Hansson¹

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v ABSTRACTSquamous cell carcinoma (SCC) is the most common histological type of cancer in the head and neck region and arises in the epithelial mucosa of the upper aerodigestive tract.Approximately one and a half million people are living with the diagnosis. Despite efforts in prevention and advances in treatment, the 5-year survival rate still lies around 60%, and recurrences and second primary tumors remain a problem. Moreover, treatment responses vary from patient to patient, highlighting the need for individually tailored treatments. To make this possible, biomarkers predicting treatment outcome are needed to better guide treatment decisions.The aim of this thesis was to evaluate the expression of certain proteins and the frequency of certain SNPs (Single nucleotide polymorphisms) in tumor biopsies and cell cultures of head and neck squamous cell carcinomas (HNSCC), and to explore their potential as biomarkers for treatment outcome. Furthermore, we aimed to study the impact of hypoxia on treatment response, epithelial-to-mesenchymal transition (EMT), and induction of cancer stem cells (CSC).In papers I and II, we investigated two proteins, survivin and WRAP53β, using immunohistochemistry (IHC) in tumor biopsies from 40 patients categorized as Nonresponders or Responders to radiotherapy. High expression of survivin and nuclear expression of WRAP53β were significantly more prevalent in the Responder group. The combination of these two factors correlated strongest to overall survival, but not to a significantly higher extent compared to survivin alone. Moreover, when examined separately, a high percentage of p53-stained cells and the presence of the SNP FGFR4 Gln388Arg correlated to improved overall survival, whereas the SNP XPD Lys751Gln was associated with worse overall survival. The latter three showed no significant correlations to radiotherapy response. In paper III, the two ABSTRACT vi most promising proteins identified in papers I and II were analyzed in a study cohort of 149 tumor biopsies of glottic laryngeal SCC, categorized as T2N0-T3N0. In this patient group, no significant associations between survivin expression and survival could be found. However, expression of cytoplasmic WRAP53β was significantly linked to worse disease-free-survival (DSF) compared to nuclear WRAP53β or negative staining for WRAP53β. Positive expression of p16INK4a was found in 7% of the tumors. The prevalence of p16 INK4a was higher in younger patients (<60) and associated with absence of recurrence and longer DSF.In paper IV, five HNSCC cell lines were cultured in normoxic (20% O 2 ) and hypoxic (1% O 2 )conditions and changes in treatment response, EMT profile, and expression of CSC markers were examined. As expected, hypoxia induced EMT and to a certain extent expression of CSC markers. Silencing of the hypoxia-inducible-factor-1α (HIF-1α) only partly reversed these effects, suggesting that other mechanisms are involved. Whereas most cell lines became more resistant to treatment in hypoxia, one cell line (LK0412) ...

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“…From this study, it can be concluded that the current treatment options are still suboptimal for both groups of HNSCC patients due to high resistance and recurrence (HPV´) and high toxicity (HPV´ and HPV+) issues 11 . It should be kept in mind that the slopes of clinical doseresponse curves indicate that enhancement of dose of RT by just 10% will increase tumor control rates by 5%-30% depending on tumor sites and current control rates.…”

Section: Resultsmentioning

confidence: 99%

Evaluation of Toxicity Profile and Prognosis of Treatment of Hpv Associated Head and Neck Squamous Cell Carcinoma (HNSCC), with Chemoradiotherapy

Yadav¹,

Singh²,

Tiwari³

et al. 2018

MEDRECH

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Abstract:Head and Neck cancer is generally referred as squamous cell carcinoma of Head and Neck and are located at the oral or nasal cavity. It has been one of the leading cause of death around the globe and has significantly increased epidemiological growth and rate of mortality over the last three decades. A significant subset of the 600,000 annual cases of HNSCC includes approximately 85,000 HPV associated (oropharyngeal) tumors, which means that the head and neck region is the second most common HPV+ tumor site. In 90% of the HPV associated tumors, HPV16 detection can be seen. The objective of the proposed study is to evaluate the effects of chemoradiotherapy and its toxicity profile for the treatment of HPV negative and HPV positive carcinomas. In a case-control study, 100 patients were enrolled and grouped into two groups with HPV negative and HPV positive carcinogenic tumor in the ratio of 50:50. All the patients are exposed to the treatment with concurrent chemoradiotherapy and radiotherapy. From the study, it can be concluded that HPV-positive tumors have less cumulative exposure to multiple risk factors (tobacco chewing, alcohol, smoking). The association of tumor HPV status with treatment response observed in our study showed a trend of better treatment outcome, consistent in the design and analysis of current and future clinical trials of treatments for head and neck cancer patients.

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Significance of p16 in site-specific HPV positive and HPV negative HNSCC

Cited by 94 publications

References 29 publications

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

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

The impact of Survivin, WRAP53β, and Hypoxia on treatment response in Head and Neck Cancer

Evaluation of Toxicity Profile and Prognosis of Treatment of Hpv Associated Head and Neck Squamous Cell Carcinoma (HNSCC), with Chemoradiotherapy

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