Alterations in p53 and pRb pathways and their prognostic significance in oesophageal cancer
Introduction
Despite advances in therapeutic strategies and postoperative management, prognosis for oesophageal cancer patients remains poor. Improvements in the prognosis and surveillance await a more comprehensive understanding of the molecular alterations and clinicopathological characteristics as predictors of a parsimonious model in tumour control. The clinical characterisation of oesophageal carcinoma remains inadequate using the conventional histological staging system. The TNM staging for oesophageal cancer [1] considered as the most important prognostic indicator does not differentiate between tumours confined to the mucosa and those involving the submucosa, a distinction that has been shown to be of considerable prognostic significance [2]. Several studies have demonstrated considerable heterogeneity in prognosis among oesophageal squamous cell carcinomas (ESCC) of various histological types. Submucosal oesophageal cancer has been shown to be associated with a significant risk of vascular invasion and lymph node metastasis [3]. Current inadequacy of clinicopathological parameters as prognosticators warrants a clearer understanding of the molecular alterations in predicting prognosis of the disease. Various molecular biological factors have been proposed as prognostic indicators of oesophageal cancer [4]. Cell cycle regulators of prognostic relevance in oesophageal cancer include, mutations in the tumour suppressor gene TP53, allelic loss at chromosomal loci encoding p16 and pRb and altered expression of p21, cyclin D1 and MDM2 5, 6, 7. Nevertheless, nearly all of these studies have examined these markers in isolation or in dual combinations and therefore the overall conclusions from these studies are discordant and a composite picture of the interactions between p53-MDM2-p21 and p16-pRb-cyclin D1 pathways is currently lacking.
The aetiological factors implicated in the pathogenesis of ESCCs are markedly different in the Western population compared with that of developing countries such as India. In Western countries, alcohol consumption and tobacco smoking are the major predisposing factors for ESCCs while, in the developing countries such as India and China, tobacco chewing and a variety of dietary factors confounded by nutritional deficiency are causally associated with the disease 8, 9, 10. The exposure of the gastric mucosa to a plethora of carcinogens present in betel and tobacco may provide a favourable milieu for neoplastic transformation. In light of the unique aetiological predisposition, it is worthwhile to investigate the prognostic profile of ESCC in the Indian population.
In a comprehensive analysis of molecular prognostic factors, Shimada and colleagues [4] reported that cyclin D1, E-cadherin, epidermal growth factor receptor (EGFR), pN, gender and cell growth capability are important predictors of patient survival and recurrence in the Japanese population. However, the relevance of the pRb protein, the central cog of the cell cycle regulation machinery as a molecular marker remains to be investigated. p53, MDM2, p21, p16, pRb and cyclin D1 constitute the most important proteins orchestrating the cell cycle regulation. To elucidate the prognostic significance of various cell cycle regulators, we examined the expression of six putative molecular markers: p53, MDM2, p21, p16, pRb and cyclin D1 by immunohistochemistry. The data were subjected to multivariate logistic regression analysis and the Kaplan–Meier method to identify predictors of prognosis for various clinicopathological parameters related to tumour progression.
Section snippets
Tumour specimens
Tumour and matched normal oesophageal tissue specimens from a distal site were collected from 100 ESCC patients who underwent curative oesophagectomy in the Surgical Oncology Unit of the Institute Rotary Cancer Hospital, All India Institute of Medical Sciences, New Delhi, India, with the prior consent of the patients. Tissue samples were fixed in formalin and embedded in paraffin for immunohistochemical analysis. The clinical and pathological data were recorded in a predesigned proforma
Alterations in the p53-MDM2-p21 pathway in human oesophageal squamous cell carcinoma
The results of the immunohistochemical analysis of the cell cycle regulatory proteins, p53, mdm2, p21, p16, pRb and cyclin D1 in 100 ESCC patients in relation to clinicopathological parameters are summarised in Table 1. The photomicrographs in Fig. 1 illustrate representative immunostaining patterns for p53, MDM2 and p21 proteins in normal oesophageal tissues (Fig. 1a, c and e, respectively). In ESCCs, p53 protein was localised predominantly in the nuclei of tumour cells (Fig. 1b).
Discussion
To the best of our knowledge, this is the first composite report demonstrating frequent alterations in the expression of major cell cycle regulatory proteins of the p53-MDM2-p21 and p16-pRb-cyclin D1 pathways and their association with various clinicopathological parameters of oesophageal squamous cell carcinoma and disease prognosis in the Indian subcontinent. Mutations in both of these regulatory pathways have been reported in several human tumours [18]. Interestingly, all the ESCC cases
Acknowledgements
The contract grant sponsor was the Council of Scientific and Industrial Research, India.
References (35)
- et al.
Prognostic significance of MDM2/p53 coexpression oral premalignant and malignant lesions
Eur. J. Cancer Oral Oncol.
(1999) - et al.
Induction of MDM2-P2 transcripts correlates with stabilized wild type p53 in betel- and tobacco related human oral cancer
American Journal of Pathology
(2000) p53, the cellular gatekeeper for growth and division
Cell
(1997)- et al.
RB regulates the stability and the apoptotic function of p53 via MDM2
Mol. Cell.
(1999) - et al.
Combined analysis of p53 and retino blastoma protein expressions in esophageal cancer
Ann. Thorac. Surg.
(2000) Guidelines for handling oesophageal biopsies and resected specimens and the reporting
J. Clin. Pathol.
(2000)- et al.
Oesophageal squamous cell carcinomapathology and prognosis
World J. Surg.
(1994) - et al.
Prognostic factors of oesophageal squamous cell carcinoma from the perspective of molecular biology
Br. J. Cancer
(1999) - et al.
High incidence of amplification of the epidermal growth factor receptor gene in human squamous carcinoma cell lines
Cancer Res.
(1986)
Amplification and expression of the human cyclin D gene in oesophageal cancer
Cancer Res.
p53 tumour supressor gene mutation in early oesophageal precancerous lesions and carcinoma among the high risk populations in Henan
China Cancer Res.
Oesophagus
High prevelance of p53 gene alterations and protein overexpression in human oesophageal cancercorrelation with dietary risk factors in India
Clin. Cancer Res.
Ethnic variations in the occurrence of gastrooesophageal cancers
Clin. Gastroenterol.
p53 overexpression in laryngeal squamous cell carcinoma and sysplasia
J. Clin. Pathol.
Altered p16/MTS1/CDKN2 and cyclin D1/PRAD-1 gene expression is associated with the prognosis of squamous cell carcinoma of the esophagus
Clin. Cancer Res.
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