Differential Roles of <i>p16INK4A</i> and <i>p14ARF</i> Genes in Prognosis of Oral Carcinoma

Sailasree, R.; Abhilash, A.; Sathyan, Kizhakke Mattada; Nalinakumari, K.R.; Thomas, Shaji; Kannan, S.

doi:10.1158/1055-9965.epi-07-0284

Cited by 74 publications

(54 citation statements)

References 24 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…In the present study, we have examined the GO tissue samples that were identified to be carrying wild type p53 and H-ras genes in earlier study (Jayaraman et al, 2012), for the occurrence of mutations in the oncogene PIK3CA and tumor suppressors p14ARF, p16INK4a and p21 Waf1/Cip1 . Exons 9 and 20 of PIK3CA subunit of PI3K protein, exons 1α, 1β and 2 of p14ARF and p16INK4a and exon 2 of p21 Waf1/Cip1 were investigated as mutations in these regions were found to be highly prevalent in OSCCs (Murugan et al, 2008;Sailasree et al, 2008;Abbas et al, 2009). The finding that none of the analyzed GO samples carried mutation in the above four genes suggests non-neoplastic nature of this condition, which is in agreement with our earlier report.…”

Section: Discussionsupporting

confidence: 90%

“…Hence loss of function mutations in either one of them, p14ARF or p16INK4a is likely to promote carcinogenesis. Indeed deletions and mutations in both p14ARF and p16INK4a have been observed in several cancers including OSCCs (Kresty et al, 2002;Sailasree et al, 2008). p21 Waf1/Cip1 is an universal inhibitor of cyclin dependent kinases and is under transcriptional control of wild type p53.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Comprehensive Mutation Analysis of PIK3CA, p14ARF, p16INK4a and p21^Waf1/Cip1Genes is Suggestive of a Non- Neoplastic Nature of Phenytoin Induced Gingival Overgrowth

Swamikannu

Kumar²,

Jayesh³

et al. 2013

Asian Pacific Journal of Cancer Prevention

View full text Add to dashboard Cite

Background: Dilantin sodium (phenytoin) is an antiepileptic drug, which is routinely used to control generalized tonic clonic seizure and partial seizure episodes. A few case reports of oral squamous cell carcinomas arising from regions of phenytoin induced gingival overgrowth (GO), and overexpression of mitogenic factors and p53 have presented this condition as a pathology with potential to transform into malignancy. We recently investigated the genetic status of p53 and H-ras, which are known to be frequently mutated in Indian oral carcinomas in GO tissues and found them to only contain wild type sequences, which suggested a non-neoplastic nature of phenytoin induced GO. However, besides p53 and H-ras, other oncogenes and tumor suppressors such as PIK3CA, p14ARF, p16INK4a and p21 Waf1/Cip1 , are frequently altered in oral squamous cell carcinoma, and hence are required to be analyzed in phenytoin induced GO tissues to be affirmative of its non-neoplastic nature. Methods: 100ng of chromosomal DNA isolated from twenty gingival overgrowth tissues were amplified with primers for exons 9 and 20 of PIK3CA, exons 1α, 1β and 2 of p16INK4a and p14ARF, and exon 2 of p21 Waf1/Cip1 , in independent reactions. PCR amplicons were subsequently gel purified and eluted products were sequenced. Results: Sequencing analysis of the twenty samples of phenytoin induced gingival growth showed no mutations in the analyzed exons of PIK3CA, p14ARF, p16INK4a and p21 Waf1/Cip1 . Conclusion: The present data indicate that the mutational alterations of genes, PIK3CA, p14ARF, p16INK4a and p21 Waf1/Cip1 that are frequently mutated in oral squamous cell carcinomas are rare in phenytoin induced gingival growth. Thus the findings provide further evidence that phenytoin induced gingival overgrowth as a non-neoplastic lesion, which may be considered as clinically significant given the fact that the epileptic patients are routinely administered with phenytoin for the rest of their lives to control seizure episodes. Keywords:Cancer from gingival overgrowth -phenytoin induced gingival carcinoma -drug induced gingival carcinoma RESEARCH ARTICLEComprehensive Mutation Analysis of PIK3CA, p14ARF, p16INK4a and p21 Waf1/Cip1

show abstract

Section: Discussionsupporting

confidence: 90%

Section: Introductionmentioning

confidence: 99%

Comprehensive Mutation Analysis of PIK3CA, p14ARF, p16INK4a and p21^Waf1/Cip1Genes is Suggestive of a Non- Neoplastic Nature of Phenytoin Induced Gingival Overgrowth

Swamikannu

Kumar²,

Jayesh³

et al. 2013

Asian Pacific Journal of Cancer Prevention

View full text Add to dashboard Cite

show abstract

“…28 There is a wide range in the reported frequencies of strong and diffuse p16 INK4a overexpression in oral cavity squamous cell carcinoma. [29][30][31][32][33][34][35][36][37][38] Here, in studying a large cohort of patients with oral cavity squamous cell carcinoma, we confirm that p16 INK4a overexpression is uncommon (15.5%). Furthermore, we demonstrate that p16 INK4a overexpression has a protective effect with respect to disease progression (hazard ratio 0.11, 95% CI 0.02-0.63).…”

Section: Discussionsupporting

confidence: 65%

The protective effect of p16INK4a in oral cavity carcinomas: p16Ink4A dampens tumor invasion—integrated analysis of expression and kinomics pathways

Isayeva

Ragin

et al. 2015

Modern Pathology

View full text Add to dashboard Cite

A large body of evidence shows that p16 INK4a overexpression predicts improved survival and increased radiosensitivity in HPV-mediated oropharyngeal squamous cell carcinomas.(OPSCC). Here we demonstrate that the presence of transcriptionally active HPV16 in oral cavity squamous cell carcinomas does not correlate with p16 INK4a overexpression, enhanced local tumor immunity, or improved outcome. It is interesting that HPVmediated oropharyngeal squamous cell carcinomas can be categorized as having a 'nonaggressive' invasion phenotype, whereas aggressive invasion phenotypes are more common in HPV-negative squamous cell carcinomas. We have developed primary cancer cell lines from resections with known pattern of invasion as determined by our validated risk model. Given that cell lines derived from HPV-mediated oropharyngeal squamous cell carcinomas are less invasive than their HPV-negative counterparts, we tested the hypothesis that viral oncoproteins E6, E7, and p16 INK4a can affect tumor invasion. Here we demonstrate that p16 INK4a overexpression in two cancer cell lines (UAB-3 and UAB-4), derived from oral cavity squamous cell carcinomas with the most aggressive invasive phenotype (worst pattern of invasion type 5 (WPOI-5)), dramatically decreases tumor invasiveness by altering expression of extracellular matrix remodeling genes. Pathway analysis integrating changes in RNA expression and kinase activities reveals different potential p16 INK4a -sensitive pathways. Overexpressing p16 INK4a in UAB-3 increases EGFR activity and increases MMP1 and MMP3 expression, possibly through STAT3 activation. Overexpressing p16 INK4a in UAB-4 decreases PDGFR gene expression and reduces MMP1 and MMP3, possibly through STAT3 inactivation. Alternatively, ZAP70/Syk might increase MUC1 phosphorylation, leading to the observed decreased MMP1 expression.

show abstract

“…We consider this conclusion to be drawn cautiously, as some publications summarized various RT modalities as primary RT, RCT and adjuvant RT after radical surgery in one and the same group. 15,24,34,35,38,39 A conclusion regarding radiosensitivity should be based on results of tumors treated with primary RT or RCT only, which are directed against the tumor volume as a whole. Primary RT normally differs from adjuvant RT in decreased dosage and single fractionation directed against possible microscopic tumor cell remains, utilized after primary radical surgery.…”

Section: Discussionmentioning

confidence: 99%

“…Reports on prognosis of HPV induced p16 positive OPSCC including tumor collectives treated by different treatment modalities such as surgery, 26,37 RT, 37 RCT 25,40 or OPSCC treated by various, but summarized modalities. 15,20,21,24,34,35,38,39 In addition, our single-institutional study requires validation in large prospective trials prior to implementation of p16 as a potential prognostic marker in OPSCC.…”

Section: Discussionmentioning

confidence: 99%

Is the improved prognosis of p16 positive oropharyngeal squamous cell carcinoma dependent of the treatment modality?

Fischer

Zlobec

Green

et al. 2009

Intl Journal of Cancer

167

132

View full text Add to dashboard Cite

The incidence of human papilloma virus (HPV) induced oropharyngeal squamous cell carcinoma (OPSCC) increases in the western countries. These OPSCC show distinct molecular characteristics and are characterized by an overexpression of p16, considered a surrogate marker for HPV infection. When compared to patients with p16 negative OPSCC, patients with HPV induced p16 positive OPSCC show a significantly better prognosis, which is reported to be caused by increased radiosensitivity. The objective of the present study was to analyze the impact of p16 expression status on the prognosis of OPSCC treated by either radiotherapy (RT) or primary surgery. Results are based upon a tissue microarray (TMA) of 365 head neck squamous cell carcinomas (HNSCC) including 85 OPSCC with clinico-pathological and follow-up data. p16 positivity correlated significantly with oropharyngeal tumor localization (p < 0.001). Patients with p16 positive OPSCC exhibited a significantly better overall survival than those with p16 negative tumors (p 5 0.007). In a multivariate analysis, survival benefit of patients with p16 positive OPSCC was independent of clinico-pathological parameters such as cT and cN classification and treatment modality. The improved prognosis of p16 positive OPSCC is found after RT as well as after surgery.Although incidence of head and neck squamous cell carcinoma (HNSCC) in general has decreased progressively during the last two decades, 1 an increased incidence of oral and oropharyngeal squamous cell carcinoma (OPSCC) was reported in the United States as well as in Europe. [2][3][4] As already suggested in 1983, these OPSCC are characterized by human papilloma virus (HPV) infection. 5 Viral DNA of high risk HPV 16 can be detected in nuclei of tonsillar cancer cells, 6 and is responsible for the vast majority of HPV positive tumors. 7 These tumors arise mainly in the lingual and palatal tonsils and are characterized as being a type of HNSCC with different distinct epidemiological, molecular, and clinical characteristics. 8 The main risk factor for these HPV positive OPSCC is sexual behavior with a high number of vaginal or oral sex partners. 8,9 HPV-induced OPSCC show distinct molecular characteristics suggesting a different pathway in carcinogenesis compared to HPV negative HNSCC. 10 One particular molecular difference among others concerns p16 expression. p16 functions as a cell-cycle checkpoint regulator, a tumor suppressor gene located on chromosome 9p21.In HPV negative HNSCC p16 is frequently inactivated by deletions, mutations or promoter methylation. 11 In HPV positive OPSCC, overexpressed viral oncoprotein E7 degrades pRb, 12 which otherwise inhibits p16 transcription. 13 The resulting nuclear and cytoplasmic p16 overexpression correlates precisely to HPV positivity and is suggested to be specific for HPV positive OPSCC. 14,15 As p16 overexpression is very rarely seen in HPV negative HNSCC it is considered a surrogate marker for HPV positive OPSCC. Direct diagnosis of HPV in HNSCC is only reliably possible by in s...

show abstract

Differential Roles of p16INK4A and p14ARF Genes in Prognosis of Oral Carcinoma

Cited by 74 publications

References 24 publications

Comprehensive Mutation Analysis of PIK3CA, p14ARF, p16INK4a and p21^Waf1/Cip1Genes is Suggestive of a Non- Neoplastic Nature of Phenytoin Induced Gingival Overgrowth

Comprehensive Mutation Analysis of PIK3CA, p14ARF, p16INK4a and p21^Waf1/Cip1Genes is Suggestive of a Non- Neoplastic Nature of Phenytoin Induced Gingival Overgrowth

The protective effect of p16INK4a in oral cavity carcinomas: p16Ink4A dampens tumor invasion—integrated analysis of expression and kinomics pathways

Is the improved prognosis of p16 positive oropharyngeal squamous cell carcinoma dependent of the treatment modality?

Contact Info

Product

Resources

About

Differential Roles of p16INK4A and p14ARF Genes in Prognosis of Oral Carcinoma

Cited by 74 publications

References 24 publications

Comprehensive Mutation Analysis of PIK3CA, p14ARF, p16INK4a and p21Waf1/Cip1Genes is Suggestive of a Non- Neoplastic Nature of Phenytoin Induced Gingival Overgrowth

Comprehensive Mutation Analysis of PIK3CA, p14ARF, p16INK4a and p21Waf1/Cip1Genes is Suggestive of a Non- Neoplastic Nature of Phenytoin Induced Gingival Overgrowth

The protective effect of p16INK4a in oral cavity carcinomas: p16Ink4A dampens tumor invasion—integrated analysis of expression and kinomics pathways

Is the improved prognosis of p16 positive oropharyngeal squamous cell carcinoma dependent of the treatment modality?

Contact Info

Product

Resources

About

Comprehensive Mutation Analysis of PIK3CA, p14ARF, p16INK4a and p21^Waf1/Cip1Genes is Suggestive of a Non- Neoplastic Nature of Phenytoin Induced Gingival Overgrowth

Comprehensive Mutation Analysis of PIK3CA, p14ARF, p16INK4a and p21^Waf1/Cip1Genes is Suggestive of a Non- Neoplastic Nature of Phenytoin Induced Gingival Overgrowth