ΔNp63 Overexpression, Alone and in Combination with Other Biomarkers, Predicts the Development of Oral Cancer in Patients with Leukoplakia

Purpose: The risk of malignant transformation of oral preneoplastic lesion (OPL) is difficult to assess. ΔNp63 is an early oncoprotein associated with mucosal tumorigenesis. The purpose of this study was to assess ΔNp63 expression in OPL and its role as a marker of oral cancer risk. Experimental Design: ΔNp63 expression was determined using immunohistochemistry in 152 OPL patients included in a clinical trial comparing retinyl palmitate alone or plus β-carotene with low-dose 13-cis-retinoic acid. The associations between ΔNp63 expression as well as ΔNp63 expression with other potential risk factors for oral cancer development were analyzed. Results: ΔNp63 expression was positive in 41 (27%) patients, clusters of intraepithelial inflammatory cells (EIC) were noted in 37 (26%) patients, and podoplanin (previously reported) was positive in 56 (37%) patients. Significantly more patients whose lesions were ΔNp63 positive or exhibited EIC developed oral cancers. In the multicovariate analysis including age, treatment, and histologic status as cofactors, positive ΔNp63 expression was associated with an increased hazard ratio of 3.308 (95% confidence interval, 1.663-6.580; P = 0.0007). Patients whose lesions showed positive ΔNp63, podoplanin, and EIC had the highest oral cancer risk with a hazard ratio of 4.372 (95% confidence interval, 1.912-9.992; P = 0.0005) and 61% oral cancer development rate at 5 years compared with 15% of other OPL patients (P < 0.0001). Conclusion: ΔNp63 overepression in OPL is associated with increased oral cancer risk. Together, ΔNp63, podoplanin, and EIC may be used as biomarkers to identify OPL patients with substantially high oral cancer risk. (Clin Cancer Res 2009;15(19):6284–91)

[1]  Ethan Lee,et al.  DeltaNp63 antagonizes p53 to regulate mesoderm induction in Xenopus laevis. , 2009, Developmental biology.

[2]  Jan-Kan Chen,et al.  Overexpression of ΔNp63 in a human nasopharyngeal carcinoma cell line downregulates CKIs and enhances cell proliferation , 2009, Journal of cellular physiology.

[3]  Edward S. Kim,et al.  Randomized trial of 13-cis retinoic acid compared with retinyl palmitate with or without beta-carotene in oral premalignancy. , 2009, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[4]  S. Zucoloto,et al.  Prognostic factors and survival analysis in a sample of oral squamous cell carcinoma patients. , 2008, Oral surgery, oral medicine, oral pathology, oral radiology, and endodontics.

[5]  D. Knight,et al.  Characterization of Side Population Cells from Human Airway Epithelium , 2008, Stem cells.

[6]  J. Mora,et al.  Vitamin effects on the immune system: vitamins A and D take centre stage , 2008, Nature Reviews Immunology.

[7]  R. Weinberg,et al.  Growth-Inhibitory and Tumor- Suppressive Functions of p53 Depend on Its Repression of CD44 Expression , 2008, Cell.

[8]  J. Bouquot,et al.  Oral epithelial dysplasia classification systems: predictive value, utility, weaknesses and scope for improvement. , 2008, Journal of oral pathology & medicine : official publication of the International Association of Oral Pathologists and the American Academy of Oral Pathology.

[9]  G. Giaccone,et al.  Biomarkers of response to epidermal growth factor receptor inhibitors in Non-Small-Cell Lung Cancer Working Group: standardization for use in the clinical trial setting. , 2008, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[10]  F. Khuri,et al.  Head and neck cancer chemoprevention gets a shot in the arm. , 2008, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[11]  Edward S. Kim,et al.  Podoplanin: a novel marker for oral cancer risk in patients with oral premalignancy. , 2008, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[12]  P. Coates,et al.  ΔNp63 isoforms regulate CD44 and keratins 4, 6, 14 and 19 in squamous cell carcinoma of head and neck , 2007, The Journal of pathology.

[13]  H. Ohtani,et al.  Differing phenotypes between intraepithelial and stromal lymphocytes in early-stage tongue cancer. , 2007, Cancer research.

[14]  S. Warnakulasuriya,et al.  Nomenclature and classification of potentially malignant disorders of the oral mucosa. , 2007, Journal of oral pathology & medicine : official publication of the International Association of Oral Pathologists and the American Academy of Oral Pathology.

[15]  K. E. King,et al.  p63: Defining roles in morphogenesis, homeostasis, and neoplasia of the epidermis , 2007, Molecular carcinogenesis.

[16]  S. Lippman,et al.  The Convergent Development of Molecular-Targeted Drugs for Cancer Treatment and Prevention , 2007, Clinical Cancer Research.

[17]  P. Speight,et al.  Natural history of potentially malignant oral lesions and conditions: an overview of the literature. , 2007, Journal of oral pathology & medicine : official publication of the International Association of Oral Pathologists and the American Academy of Oral Pathology.

[18]  Carole Fakhry,et al.  Case-control study of human papillomavirus and oropharyngeal cancer. , 2007, The New England journal of medicine.

[19]  S. Zucoloto,et al.  Prognostic impact of p53 and p63 immunoexpression in oral squamous cell carcinoma. , 2007, Journal of oral pathology & medicine : official publication of the International Association of Oral Pathologists and the American Academy of Oral Pathology.

[20]  I. Weissman,et al.  Identification of a subpopulation of cells with cancer stem cell properties in head and neck squamous cell carcinoma , 2007, Proceedings of the National Academy of Sciences.

[21]  F. Carinci,et al.  Effect of p63 Expression on Survival in Oral Squamous Cell Carcinoma , 2007, Cancer investigation.

[22]  G. Christofori,et al.  The potential role of podoplanin in tumour invasion , 2006, British Journal of Cancer.

[23]  Kevin Struhl,et al.  Relationships between p63 binding, DNA sequence, transcription activity, and biological function in human cells. , 2006, Molecular cell.

[24]  G. Lodi,et al.  Interventions for treating oral leukoplakia. , 2006, The Cochrane database of systematic reviews.

[25]  Diane D. Liu,et al.  Overexpression of podoplanin in oral cancer and its association with poor clinical outcome , 2006, Cancer.

[26]  K. Sugihara,et al.  Immunohistological evaluation of Ki-67, p63, CK19 and p53 expression in oral epithelial dysplasias. , 2006, Journal of oral pathology & medicine : official publication of the International Association of Oral Pathologists and the American Academy of Oral Pathology.

[27]  G. Christofori,et al.  Tumor invasion in the absence of epithelial-mesenchymal transition: podoplanin-mediated remodeling of the actin cytoskeleton. , 2006, Cancer cell.

[28]  C. Perou,et al.  Phenotypic evaluation of the basal-like subtype of invasive breast carcinoma , 2006, Modern Pathology.

[29]  E. Tartour,et al.  Prognostic Value of Tumor-Infiltrating CD4+ T-Cell Subpopulations in Head and Neck Cancers , 2006, Clinical Cancer Research.

[30]  Yuk-Kwan Chen,et al.  Expression of p63 protein and mRNA in oral epithelial dysplasia. , 2005, Journal of oral pathology & medicine : official publication of the International Association of Oral Pathologists and the American Academy of Oral Pathology.

[31]  F. Carinci,et al.  p63 overexpression associates with poor prognosis in head and neck squamous cell carcinoma. , 2005, Human pathology.

[32]  R. Jordan,et al.  Assessment of p63 expression in oral squamous cell carcinomas and dysplasias. , 2004, Oral surgery, oral medicine, oral pathology, oral radiology, and endodontics.

[33]  B. Sjöström,et al.  Complex p63 mRNA isoform expression patterns in squamous cell carcinoma of the head and neck. , 2004, International journal of oncology.

[34]  I. Gannot,et al.  Increase in immune cell infiltration with progression of oral epithelium from hyperkeratosis to dysplasia and carcinoma , 2002, British Journal of Cancer.

[35]  S. Nomoto,et al.  ΔNp63 induces β-catenin nuclear accumulation and signaling , 2002 .

[36]  E. Sturgis,et al.  Differential expression of p53 gene family members p63 and p73 in head and neck squamous tumorigenesis. , 2002, Human pathology.

[37]  C Scully,et al.  Oral cancer , 2000, BMJ : British Medical Journal.

[38]  S. Lippman,et al.  Predicting cancer development in oral leukoplakia: ten years of translational research. , 2000, Clinical cancer research : an official journal of the American Association for Cancer Research.

[39]  N D Le,et al.  Use of allelic loss to predict malignant risk for low-grade oral epithelial dysplasia. , 2000, Clinical cancer research : an official journal of the American Association for Cancer Research.

[40]  R. A’Hern,et al.  Allelic imbalance at chromosomal loci implicated in the pathogenesis of oral precancer, cumulative loss and its relationship with progression to cancer. , 1998, Oral oncology.

[41]  S. Lippman,et al.  Low-dose isotretinoin versus beta-carotene to prevent oral carcinogenesis: long-term follow-up. , 1997, Journal of the National Cancer Institute.

[42]  S. Lippman,et al.  Frequent microsatellite alterations at chromosomes 9p21 and 3p14 in oral premalignant lesions and their value in cancer risk assessment , 1996, Nature Medicine.

[43]  M. Gorsky,et al.  Oral leukoplakia and malignant transformation. A follow‐up study of 257 patients , 1984, Cancer.

[44]  L. Ellisen,et al.  p63 mediates survival in squamous cell carcinoma by suppression of p73-dependent apoptosis. , 2006, Cancer cell.

[45]  R. Nenutil,et al.  Function and importance of p63 in normal oral mucosa and squamous cell carcinoma of the head and neck. , 2005, Advances in oto-rhino-laryngology.

[46]  Nigel P. Hunt,et al.  ABC of oral health , 2000 .