Prognostic factors in betel and tobacco related oral cancer.

Paucity of well-defined prognostic molecular markers severely hampers prediction of the clinical course of squamous cell carcinoma (SCC) of oral cavity. The aim of the study was to evaluate the prognostic significance of impairments in the expression of proteins involved in cell cycle regulation and locoregional spread in oral SCC of habitual betel and tobacco chewers. A prospective study was performed in 105 betel and tobacco consumers with oral SCCs during the period 1988-1999, to evaluate the prognostic relevance of impairments in the expression of proteins involved in cell cycle regulation and locoregional spread. Alterations in the expression of p53, pRb, p16, MDM2, p21, and Ets-1 proteins were determined by immunohistochemical analysis in formalin fixed, paraffin embedded tissue sections from oral SCCs. Analysis of multiple molecular biological factors showed overexpression of p53 in 69/105 (66%) cases, MDM2 in 72/105 (69%) cases, p21 in 57/105 (54%) cases and Ets-1 in 64/105 (61%) cases. Loss of pRb was observed in 58/105 (55%) cases and p16 loss was observed in 72/105 (69%) cases. Interestingly, multivariate analysis revealed loss of pRb as the most significant predictor of advanced tumour stage [P=0.001; Odd's Ratio (OR)=3.5] and overexpression of Ets-1 protein was an independent risk factor for lymph node metastasis (OR: 10.1; P<10(-6)). Multiple logistic regression models showed that pRb loss [Hazard's Ratio (HR): 3.93] and p53 overexpression (HR: 2.97) may serve as adverse prognosticators for disease free survival of the patients. The data demonstrate multiple impairments in p53/MDM2/p21/Ets-1 and p16/pRb pathways in betel and tobacco related oral tumourigenesis.

[1]  Joseph R. Nevins,et al.  The E2F transcription factor is a cellular target for the RB protein , 1991, Cell.

[2]  S. Groshen,et al.  Elevated and absent pRb expression is associated with bladder cancer progression and has cooperative effects with p53. , 1998, Cancer research.

[3]  T. Saito,et al.  Immunohistochemical analysis of cell cycle-associated proteins p16, pRb, p53, p27 and Ki-67 in oral cancer and precancer with special reference to verrucous carcinomas. , 2007, Journal of oral pathology & medicine : official publication of the International Association of Oral Pathologists and the American Academy of Oral Pathology.

[4]  W. Benedict,et al.  Altered retinoblastoma protein expression in nonsmall cell lung cancer , 1997, Cancer.

[5]  H. Harada,et al.  Prognostic factors of oesophageal squamous cell carcinoma from the perspective of molecular biology , 1999, British Journal of Cancer.

[6]  C. Cordon-Cardo,et al.  Cooperative effects of p53 and pRB alterations in primary superficial bladder tumors. , 1997, Cancer research.

[7]  B. Wasylyk,et al.  MDM2 induces hyperplasia and premalignant lesions when expressed in the basal layer of the epidermis , 2000, The EMBO journal.

[8]  R. Ralhan,et al.  Prognostic significance of p53 protein overexpression in betel‐ and tobacco‐related oral oncogenesis , 1998, International journal of cancer.

[9]  J. Varley,et al.  Frequent alterations of cell cycle regulators in early-stage breast lesions as detected by immunohistochemistry. , 1998, British Journal of Cancer.

[10]  K. Warnakulasuriya,et al.  Relationship of p53 overexpression to other cell cycle regulatory proteins 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.

[11]  W. Benedict,et al.  Altered retinoblastoma protein expression and prognosis in early-stage non-small-cell lung carcinoma. , 1994, Journal of the National Cancer Institute.

[12]  S. Shibata,et al.  Expression of the Ets-1 proto-oncogene correlates with malignant potential in human astrocytic tumors. , 1999, Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc.

[13]  G. Hannon,et al.  p53-Independent Role of MDM2 in TGF-β1 Resistance , 1998 .

[14]  Taylor Murray,et al.  Cancer statistics, 1999 , 1999, CA: a cancer journal for clinicians.

[15]  H. Dosaka-akita,et al.  Altered p16INK4 and retinoblastoma protein status in non-small cell lung cancer: potential synergistic effect with altered p53 protein on proliferative activity. , 1996, Cancer research.

[16]  Y. Eizuru,et al.  Retinoblastoma protein expression and prognosis in laryngeal cancer. , 1998, Acta oto-laryngologica.

[17]  R. Ralhan,et al.  Overexpression of p53 protein in betel‐ and tobacco‐related human oral dysplasia and squamous‐cell carcinoma in India , 1994, International journal of cancer.

[18]  R. Ralhan,et al.  Expression of cyclin dependent kinase inhibitor p21waf1/cip1 in premalignant and malignant oral lesions: relationship with p53 status. , 1998, Oral oncology.

[19]  R. Ralhan,et al.  Induction of MDM2-P2 transcripts correlates with stabilized wild-type p53 in betel- and tobacco-related human oral cancer. , 2000, The American journal of pathology.

[20]  S. Girod,et al.  Proliferative activity and loss of function of tumour suppressor genes as 'biomarkers' in diagnosis and prognosis of benign and preneoplastic oral lesions and oral squamous cell carcinoma. , 1998, The British journal of oral & maxillofacial surgery.

[21]  J. D. Weber,et al.  The ARF/p53 pathway. , 2000, Current opinion in genetics & development.

[22]  M. S. Burger,et al.  Different combinations of genetic/epigenetic alterations inactivate the p53 and pRb pathways in invasive human bladder cancers. , 2000, Cancer research.

[23]  M. Partridge,et al.  Role of p16/MTS1, cyclin D1 and RB in primary oral cancer and oral cancer cell lines , 1999, British Journal of Cancer.

[24]  R. Kratzke,et al.  Immunohistochemical detection of the cyclin-dependent kinase inhibitor 2/multiple tumor suppressor gene 1 (CDKN2/MTS1) product p16INK4A in archival human solid tumors: correlation with retinoblastoma protein expression. , 1995, Cancer research.

[25]  R. Ralhan,et al.  pRb and p16 protein alterations in human oral tumorigenesis. , 1998, Oral oncology.

[26]  Stephen N. Jones,et al.  Regulation of p53 stability by Mdm2 , 1997, Nature.

[27]  R. Ralhan,et al.  Ets‐1: a plausible marker of invasive potential and lymph node metastasis in human oral squamous cell carcinomas , 1999 .

[28]  S. Ishiguro,et al.  MDM2 gene amplification and expression in non-small-cell lung cancer: immunohistochemical expression of its protein is a favourable prognostic marker in patients without p53 protein accumulation. , 1997, British Journal of Cancer.

[29]  W. Benedict,et al.  Altered retinoblastoma and p53 protein status in non-small cell carcinoma of the lung: potential synergistic effects on prognosis. , 1996, Clinical cancer research : an official journal of the American Association for Cancer Research.

[30]  A. Børresen-Dale,et al.  Interaction between bcl‐2 and p21 (WAF1/CIP1) in breast carcinomas with wild‐type p53 , 1997, International journal of cancer.

[31]  B. Vandenbunder,et al.  Expression of the transcription factor c-Ets1 correlates with the occurrence of invasive processes during normal and pathological development. , 1994, Invasion & metastasis.

[32]  R. Ralhan,et al.  MDM2/p53 co-expression in oral premalignant and malignant lesions: potential prognostic implications. , 1999, Oral oncology.