Evidence for a Causal Association Between Human Papillomavirus and a Subset of Head and Neck Cancers

Gillison, Maura L.; Koch, Wayne M.; Capone, Randolph B.; Spafford, Michael; Westra, William H.; Li, Wu; Zahurak, Marianna; Daniel, Richard; Viglione, Michael P.; Symer, David E.; Shah, Keerti V.; Sidransky, David

doi:10.1093/jnci/92.9.709

Cited by 2,675 publications

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“…In contrast and as observed in our study, p53 is frequently upregulated in HPVnegative tumors due to mutations in the TP53 gene as a result of exposure to tobacco and/or alcohol. 10,16,20,27,47 Although p21 Cip1/WAF1 is known to be a downstream effector of p53, 48,49 it was surprising to find overexpression in HPV-positive tumors harboring low or no detectable levels of p53. Such observations have also been reported by Milde-Langosch et al 50 in HPV-associated uterine cervical tumors and suggest that also p53-independent mechanisms may lead to p21 Cip1/WAF1 accumulation as described previously.…”

Section: Discussionmentioning

confidence: 99%

P21Cip1/WAF1 expression is strongly associated with HPV-positive tonsillar carcinoma and a favorable prognosis

et al. 2009

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Human papillomavirus is involved in the carcinogenesis of tonsillar squamous cell carcinomas. Here, we investigated the expression and the prognostic value of key cell cycle proteins in the pRb and p53 pathways in both human papillomavirus type 16-positive and -negative tonsillar squamous cell carcinomas. Using immunohistochemistry, 77 tonsillar squamous cell carcinomas with known human papillomavirus type 16 status and clinical outcome were analyzed for expression of Ki67, p16 INK4A, cyclin D1, pRb, p14 ARF , MDM2, p53, p21 Cip1/WAF1 , and p27 KIP1 . Results were correlated with each other and with clinical and demographic patient data. A total of 35% of tonsillar carcinomas harbored integrated human papillomavirus type 16 DNA and p16 INK4A overexpression, both being considered essential features for human papillomavirus association. These tumors also showed the overexpression of p14 ARF (Po0.0001) and p21 Cip1/WAF1 (P ¼ 0.001), and downregulation of pRb (Po0.0001) and cyclin D1 (P ¼ 0.027) compared with the human papillomavirus-negative cases. Univariate Cox regression analyses revealed a favorable survival rate for non-smokers (P ¼ 0.006), as well as for patients with T1-2 tumors (Po0.0001) or tumors showing low expression of cyclin D1 (P ¼ 0.028), presence of human papillomavirus and overexpression of p16 INK4A (P ¼ 0.01), p14 ARF (P ¼ 0.02) or p21 Cip1/WAF1 (P ¼ 0.004). In multivariate regression analyses, smoking and tumor size, as well as expression of cyclin D1 and p21 Cip1/WAF1 , were found to be independent prognostic markers. We conclude that human papillomavirus positivity in tonsillar squamous cell carcinomas strongly correlates with p21 Cip1/WAF1 and p14 ARF overexpression and downregulation of pRb and cyclin D1. In particular p21 Cip1/WAF1 overexpression is an excellent favorable prognosticator in tonsillar squamous cell carcinomas. Modern Pathology ( Head-and-neck squamous cell carcinoma is the sixth most prevalent malignancy in the world, contributing 6% of new cancer cases annually worldwide. 1,2 These tumors have a 5-year survival rate of approximately 50%, which has not improved in the last two decades. 3 Well-recognized risk factors in the etiology of head-and-neck squamous cell carcinomas are extensive tobacco and alcohol consumption in B90% of cases, as well as oncogenic human papillomaviruses (HPVs), predominantly HPV type 16. 3,4 Interestingly, the association of HPV is strongest for tonsillar squamous cell carcinoma with a prevalence up to 50%. [5][6][7][8]

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Section: Discussionmentioning

confidence: 99%

P21Cip1/WAF1 expression is strongly associated with HPV-positive tonsillar carcinoma and a favorable prognosis

et al. 2009

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“…The biological basis for this is provided by the fact that the HPV E6 oncoprotein specifically inactivates wild-type p53. In this way the high-risk HPV E6-mediated degradation of the p53 protein is probably an alternative pathway for a "classical" mutation to knock-out the p53 regulated pathways [15,16]. Analysis of TP53 mutational patterns has shown its usefulness in at least two main areas [17,18].…”

Section: Introductionmentioning

confidence: 99%

p53 in head and neck cancer: Functional consequences and environmental implications of TP53mutations

et al. 2010

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BackgroundAlthough TP53 mutations in human tumours generally have been extensively studied, the significance of p53 in the aetiology of head and neck cancers is still incompletely characterized. In recent years, considerable interest has been focused on mutant forms of p53, the abnormal protein product of TP53 alleles with missense mutation that often accumulate in cancer cells.MethodsWe compared the nature of TP53 mutations in primary 46 head and neck squamous cell carcinomas (HNSCC) analyzed by PCR-SSCP and sequencing, immunohistochemistry, and using structural information available at IARC p53 database.ResultsSequencing confirmed 36 TP53 mutations in 23 tumours of the 39 mutations in 26 tumours found by PCR-SSCP. Only half (17) putatively affect the function of p53 protein. Of these 8 were in the L2 domain, three affected the LSH motif and three the L3 domain. Three were in other domains. Codon 259 (GAC > GAA) which is a very rare mutation was found in 4 samples in our study. There were indications of p53 aberrations being associated with the combined effect of smoking, alcohol and work history. Patients with a negative family history of cancer had more often TP53 mutations than patients with a positive family history (71% vs. 46%).ConclusionsOur study contributes to the knowledge of cumulative chemical exposure and p53 aberrations in head and neck cancer, an area where literature is scarce.

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“…[5][6][7] Patients with HPV-positive OPSCC reportedly have a better prognosis than patients with HPV-negative OPSCC. [8][9][10][11] In a prospective clinical trial by Fakhry et al, it was reported that patients who had HPV-positive OPSCC had a 95% overall survival rate at 2 years compared with a rate of 62% for patients who had HPV-negative disease. 8 Numerous retrospective studies also have demonstrated improved disease-free survival rates (range, 32%-38%) and overall survival rates (range, 24%-34%) in HPV-positive versus HPV-negative OPSCC, respectively.…”

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confidence: 99%

“…The detection of HPV DNA usually is assayed directly by polymerase chain reaction (PCR) 11 or in situ hybridization 18 and is assayed indirectly by immunohistochemical staining for p16, 19 because p16 over expression reportedly is a surrogate marker for HPV-positive OPSCC and an independent favorable prognostic indicator. 5,20 With the increased importance in HPV-positive OPSCC, we sought to determine whether or not practicing radiation oncologists across the United States have instituted HPV DNA analysis or p16 immunohistochemical staining into their practices, because little is known regarding its status in clinical use.…”

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confidence: 99%

Survey on human papillomavirus/p16 screening use in oropharyngeal carcinoma patients in the United States

Shoushtari

Rahimi

Schlesinger

et al. 2009

Cancer

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BACKGROUND:Patients with human papillomavirus (HPV)-positive oropharyngeal carcinoma (OC) have better prognosis than patients with HPV-negative OC. The objective of the current study was to assess how different practices across the United States treat patients with OC with respect to screening for HPV DNA or p16. METHODS: Five hundred forty-two randomly selected radiation oncologists were sent an 11-question survey by email regarding the use of HPV/p16 screening in OC. The questionnaire addressed demographics of the practice, intensity-modulated radiotherapy (IMRT) use, screening practices for HPV DNA or p16, which year this began, the use of HPV or p16 data to direct patient care, and future plans for its use if it had not already been instituted. RESULTS: One hundred ninety-two responses (39.6%) were received. Thirty-five percent of respondents (67 of 188) reported screening for HPV DNA routinely, whereas 4.8% of respondents (9 of 188) reported screening for p16. Of the physicians who did not use screening techniques, 37.2% (44 of 118 respondents) reported future plans to institute these screening techniques, 20% (9 of 45 respondents) stated plans to institute these techniques in the next 6 months, 55.5% (25 of 45 respondents) stated plans to institute these techniques within 6 months to 1 year, and 22.2% (10 of 45 respondents) stated plans to institute these techniques within 1 to 2 years. Academic physicians were more likely to use screening techniques (62.7%; P < .001) compared with private practitioners (31.4%). Only 12.4% of respondents reported using HPV or p16 data to direct care. CONCLUSIONS: Approximately 40.4% of radiation oncology practices that responded to a survey in the United States screened for HPV DNA or p16 in OC, whereas only 12.4% used it to further direct care. This number appears to be growing rapidly. Clinical trials to further elucidate how HPV or p16 status should direct care in OC are warranted. Cancer 2010;116:514-9.

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Evidence for a Causal Association Between Human Papillomavirus and a Subset of Head and Neck Cancers

Abstract: These data extend recent molecular and epidemiologic studies and strongly suggest that HPV-positive oropharyngeal cancers comprise a distinct molecular, clinical, and pathologic disease entity that is likely causally associated with HPV infection and that has a markedly improved prognosis.

Cited by 2,675 publications

References 74 publications

P21Cip1/WAF1 expression is strongly associated with HPV-positive tonsillar carcinoma and a favorable prognosis

P21Cip1/WAF1 expression is strongly associated with HPV-positive tonsillar carcinoma and a favorable prognosis

p53 in head and neck cancer: Functional consequences and environmental implications of TP53mutations

Survey on human papillomavirus/p16 screening use in oropharyngeal carcinoma patients in the United States

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