Mutations of TP53 in cancers of the head and neck and of the oesophagus: implications for the identification of environmental factors of risk.

Pierre Hainaut, PhD

Group of Molecular Carcinogenesis, International Agency for Research on Cancer, World Health Organization, Lyon, France.

AIM: The TP53 tumor suppressor gene is often mutated in cancers of the upper aero-digestive tract. Mutations occur early in tumorigenesis and are sometimes detectable in exposed, normal mucosa of individuals at risk for these cancers. Mutation load and patterns vary with the degree of exposure to exogenous risk factors. Mutation patterns also show geographic variations that may reveal clues on the nature of environmental mutagens. Our aim is to analyze TP53 mutations to determine their significance for early detection and identification of the causes of cancers of the upper aero-digestive tract.. METHODS: TP53 mutations are analyzed in archived tumors or surrogate materials with various methods including sequencing and APEX, a micro-array method based on primer extension. All mutations are compiled in a database of TP53 mutations identified in human cancers, which contains 16399 mutations (IARC TP53 database, January 2002). RESULTS: Comparison of mutation patterns in squamous cell carcinomas (SCC) shows that, in Western countries, the mutation load increases with exposure to tobacco and alcohol. Specific “signatures” of polycyclic aromatic hydrocarbons, a class of tobacco carcinogens, are found in cancers of the larynx and of the hypopharynx, but their prevalence decreases in the proximal part of the oral cavity. SCC of the oesophagus often contains mutations that may be induced by metabolites of alcohol such as acetaldehyde. Distinct mutation patterns are observed in geographic areas of extreme incidence of oesophageal SCC (northern Iran, central China), consistent with epidemiological evidence of a role for region-specific risk factors. Adenocarcinoma (ADC) of the oesophagus shows a different mutation pattern than SCC. Mutations are often detectable in high-grade dysplasia of Barrett’s mucosa. Their nature is consistent with a mutagenic role for inflammation due to chronic reflux. We have recently shown that TP63, a TP53-related gene encoding several isoforms of the p63 protein, is overexpressed and sometimes amplified in SCC, but not in ADC of the upper aero-digestive tract. Deregulation of p63 function may be specifically related to the pathogenesis of SCC. The p63 protein plays a role in the control of squamous cell differentiation and we have observed that mutant p53 complexes with wild-type p63 protein in oesophageal cancer cells. These results suggest that mutation of TP53 is part of a set of events that deregulate both normal, cellular response to exogenous stress as well as normal differentiation patterns of the squamous mucosa. CONCLUSIONS: Tumors of the upper aero-digestive tract are clonal with respect to TP53 mutations. Presence of mutant TP53 in normal, exposed tissues and in non-involved mucosa adjacent to cancer is consistent with “field carcinogenesis” hypothesis. Further studies on carcinogen “signatures” in TP53 may help to define strategies for prevention. Moreover, detection of mutant TP53 in surrogate material such as exfoliated cells or plasma DNA, may provide an useful approach to monitor individual and populations at risk.

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Paper presented at the International Symposium on Predictive Oncology and Intervention Strategies; Paris, France; February 9 - 12, 2002; in the section on Molecular Genetics & Therapy - 2.