TP53 germline mutations: Genetics of li-fraumeni syndrome

Abstract

Li-Fraumeni syndrome (LFS) is a rare autosomal dominantly inherited cancer predisposition disorder commonly associated with germline TP53 mutations. The syndrome classically presents with a wide spectrum of childhood and adult-onset cancers. Penetrance of the cancer phenotype is high with a lifetime risk of >75 % to develop cancer in TP53 mutation carriers. The spectrum of germline TP53 mutations is similar to that observed for somatic TP53 mutations in sporadic cancers. Studies to explore the genetic and epigenetic events that modify the cancer phenotype in LFS families have identified several polymorphisms in TP53, as well as in other genes that regulate TP53 function. In addition, other global genetic/genomic features including excessive DNA copy number variation and accelerated telomere attrition have been implicated in modifying phenotype conferred by the primary TP53 defect. Genetic testing for TP53 mutations in LFS family members is now commonly used to identify at-risk individuals. Based on this information, and in the context of multidisciplinary genetic counseling teams, novel approaches to clinical surveillance for early cancer detection are being implemented. In the 20 years from discovery of the link between germline TP53 mutations and etiology of LFS, translation of basic discoveries in TP53 biology to clinical application in terms of tumor prognosis, therapy, and early detection has made significant impact on the lives of patients in these families.