Prevalence and penetrance of Li-Fraumeni cancer predisposition syndrome

Li-Fraumeni syndrome is associated with having a germline mutation in the tumor suppressor gene TP53, and carriers are predisposed to a wide spectrum of cancers over their lifetimes. How prevalent are germline mutations in TP53 and what determines penetrance of cancer types for such individuals? Screening of pediatric cancer patients for pathogenic germline mutations in cancer-associated genes identified TP53 to be the most frequently mutated gene and hypodiploid acute lymphoblastic leukemia to be another rare childhood cancer associated with Li-Fraumeni syndrome. Screening of early on-set colorectal cancer identified individuals with pathogenic germline mutations in TP53 who would not fit classic Li-Fraumeni syndrome. Penetrance for cancer in Li-Fraumeni syndrome is highly dependent on tissue type with sex being a strong genetic modifier. The increased relative risk for cancer is much higher for mesodermal and ectodermal tissues, but only moderately higher for endodermal tissues. The penetrance for most cancer types is below 20%, suggesting that stochasticity contributes to phenotype. Indeed, a pair of human identical twins and inbred mice with germline TP53 mutations, both exhibit discordant cancer types, even when genetics and environment are the same. The prevalence of TP53 mutation carriers may be larger and their clinical phenotype more diverse than what is known.