TP53 Mutation and LiFraumeni Syndrome

Sydney D. Finkelstein and Frank S. Lieberman

Preeminent among human tumor suppressor genes in functionality and importance is TP53, reflected by its well-recognized characterization as "guardian of the genome."1-5 TP53 is perhaps the most intensively studied human-cancer-associated oncoprotein, in keeping with its protean effects on critical cellular pathways, including transcriptional control of gene expression, cell cycle proliferation, DNA repair, apoptosis, and cellular maturation and differentiation.6-8 Mutational damage to TP53 is the single most common cancer DNA alteration, having been observed in more than 50% of all human cancers.9 Detection of TP53 mutation is now performed for several clinical indications including assessment of tumor biological aggressiveness, discrimination of tumor recurrence versus de novo cancer formation, determination of tumor anaplasia, and as part of a search for germline inherited mutational change associated with heightened cancer susceptibility.10,11 The emerging diagnostic and prognostic role attributed to TP53 mutation detection justifies testing in selected patients as part of the clinical molecular pathology workup of human cancer.

Soon after its initial molecular description, germline inheritance of TP53 mutations was sought and found in families exhibiting a high susceptibility to cancer forma-tion.12-15 Known as the Li-Fraumeni syndrome (LFS; Online Mendelian Inheritance in Man [OMIM; database online] #151623], constitutional transmission of TP53 mutations is a well-recognized, though relatively uncommon, form of inherited predisposition for cancer development.12-15 While much remains to be learned regarding the frequency of germline passage of TP53 mutations in the general population and the relationship between specific forms of muta-tional damage and phenotypic expression of cancer, a variety of methods exist for the detection of TP53-related genomic damage. These methods utilize different analytical techniques for molecular characterization and, when used in conjunction with one another, can provide accurate, detailed, and validated data to identify and follow patients at risk for subsequent cancer occurrence as well as to further characterize cancer growth and treatment responsiveness. This chapter briefly describes these analytical techniques and their current and potential future application. The discussion focuses mainly on practical testing for this gene and also comments on the LFS and its clinical detection.

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