Prognostic Significance of p16 Protein Levels in Oropharyngeal Squamous Cell Cancer

Weinberger, Paul M.; Yang, Ziwei; Haffty, Bruce G.; Kowalski, Diane; Harigopal, Malini; Sasaki, Clarence T.; Rimm, David L.; Psyrri, Amanda

doi:10.1158/1078-0432.ccr-04-0448

Cited by 135 publications

(118 citation statements)

References 44 publications

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“…Interestingly, we found no correlation between p16 protein expression and outcome. In contrast to studies of p16 mRNA, previous studies have reported overexpression of p16 protein to be predictive of improved prognosis in oropharyngeal squamous-cell cancer (Weinberger et al, 2004), vulvar carcinoma (Knopp et al, 2004) and colorectal carcinoma (Zhao et al, 2003;Cui et al, 2004), whereas high levels of p16 protein expression have been associated with shorter event-free survival in prostate cancer (Lee et al, 1999). Whether these inconsistencies reflect tumourspecific roles of p16, or differences in the prognostic significance of mRNA and protein remain to be seen.…”

Section: Discussionmentioning

confidence: 90%

Chromosome 9p21 gene copy number and prognostic significance of p16 in ESFT

2007

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Chromosome 9p21 gene copy number in Ewing's sarcoma family of tumour (ESFT) cell lines and primary ESFT has been evaluated using Multiplex Ligation-dependent probe amplification, and the clinical significance of CDKN2A loss and p16/p14 ARF expression investigated. Homozygous deletion of CDKN2A was identified in 4/9 (44%) of ESFT cell lines and 4/42 (10%) primary ESFT; loss of one copy of CDKN2A was identified in a further 2/9 (22%) cell lines and 2/42 (5%) tumours. CDKN2B was co-deleted in three (33%) cell lines and two (5%) tumours. Co-deletion of the MTAP gene was observed in 1/9 (11%) cell lines and 3/42 (7%) tumours. No correlation was observed between CDKN2A deletion and clinical parameters. However, co-expression of high levels of p16/p14 ARF mRNA predicted a poor event-free survival (P ¼ 0.046, log-rank test). High levels of p16/p14 ARF mRNA did not correlate with high expression of p16 protein. Furthermore, p16 protein expression did not predict event-free or overall survival. Methylation is not a common mechanism of p16 gene silencing in ESFT. These studies demonstrate that loss (homozygous deletion or single copy) of CDKN2A was not prognostically significant in primary ESFT. However, high levels of p16/p14 ARF mRNA expression were predictive of a poor event-free survival and should be investigated further.

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Section: Discussionmentioning

confidence: 90%

Chromosome 9p21 gene copy number and prognostic significance of p16 in ESFT

2007

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“…This has been independent of treatment modality, either primary chemoradiation, induction chemotherapy followed by definitive radiotherapy, or primary surgery with or without postoperative chemo radiotherapy [2,5,9,12,19,20]. Hazard ratios for overall, progressionfree, disease-free, and disease-specific survival for p16 positive versus negative cases are consistently low (Table 2) [2,3,5,6,12,21]. Also, all major studies that performed multivariate survival analysis to control for other variables have found that positive p16 IHC independently correlates with better survival [2,5,6,9,12].…”

Section: Introductionmentioning

confidence: 93%

p16 Immunohistochemistry As a Standalone Test for Risk Stratification in Oropharyngeal Squamous Cell Carcinoma

Lewis

2012

Head and Neck Pathol

210

197

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It is widely acknowledged that human papillomavirus (HPV)-related oropharyngeal carcinoma is a biologically unique form of head and neck cancer that should be singled out and treated differently. It is now incumbent to find a test (or combination of tests) that accurately identifies cancers with the associated favorable prognosis for proper patient counseling and management and for placing patients in the correct treatment arms in the emerging clinical trials that are attempting to establish unique treatment types and approaches. The test (or combination of tests) that are utilized must be widely available, reliable, easy to interpret, and wellvalidated. While HPV-specific testing seems completely logical to use as a single test or one of a combination of tests, it turns out to be quite complicated in practice. Because of the different forms of the virus, the differing types of HPV-specific tests can give different information. HPV DNA, RNA, and protein assays have varying sensitivities for virus detection and also varying availability from formalin-fixed, paraffin-embedded tissue. Since p16 protein over expression is very sensitive for the presence of transcriptionally-active HPV and since it correlates strongly with patient outcomes, is widely available, and easy to interpret, it appears to currently be the single test that combines all of the desired attributes in a risk stratification marker for widespread implementation in clinical and research study settings. This article will review the literature on p16 immunohistochemistry and its relation to HPV-specific testing, discuss some practical issues related to its implementation, and present the case for why it should be the single test used for this purpose.

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“…Several studies have consistently shown HPV infection and p16 immunoexpression to be independent favorable prognostic factors in head and neck cancers, especially among the oropharyngeal cancers (Begum et al, 2003;Weinberger et al, 2004;Reimers et al, 2007;Ang et al, 2010). Some studies have shown no prognostic relevance pertaining to loss of p16 expression (Geisler et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

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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Prognostic Significance of p16 Protein Levels in Oropharyngeal Squamous Cell Cancer

Cited by 135 publications

References 44 publications

Chromosome 9p21 gene copy number and prognostic significance of p16 in ESFT

Chromosome 9p21 gene copy number and prognostic significance of p16 in ESFT

p16 Immunohistochemistry As a Standalone Test for Risk Stratification in Oropharyngeal Squamous Cell Carcinoma

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

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