PURPOSE OF REVIEW: Germline TP53 (tumor protein 53) mutations are the molecular basis of a complex cancer predisposition syndrome, the Li-Fraumeni syndrome. The present review discusses the diversity of tumor patterns in TP53 mutation carriers, focusing on molecular factors that may explain familial and individual differences, such as genotype/phenotype correlations, genetic modifiers and genetic anticipation. RECENT FINDINGS: Initially identified 20 years ago, germline TP53 mutations appear to be associated with an extremely diverse range of cancers. Although no other gene has been found in Li-Fraumeni syndrome, recent results show that the functional effects of particular mutations, polymorphisms in TP53 or in regulators such as MDM2 (murine double minute 2), variations in DNA copy number and variations in telomere length, have a strong impact on individual risk and on tumor patterns. Furthermore, recent studies in large cohorts suggest that TP53 germline mutations may occur in up to 1: 5000 individuals. SUMMARY: Germline TP53 mutations may be responsible for a large fraction (15-20%) of all inherited cancers. Although mutations are detectable by sequencing, counseling and follow-up remain problematic due to the wide variations in disease presentation. Elucidating the molecular mechanisms underlying the predisposition caused by TP53 deficiency may help to develop better, evidence-based and personalized clinical protocols.
PURPOSE OF REVIEW: Germline TP53 (tumor protein 53) mutations are the molecular basis of a complex cancer predisposition syndrome, the Li-Fraumeni syndrome. The present review discusses the diversity of tumor patterns in TP53 mutation carriers, focusing on molecular factors that may explain familial and individual differences, such as genotype/phenotype correlations, genetic modifiers and genetic anticipation. RECENT FINDINGS: Initially identified 20 years ago, germline TP53 mutations appear to be associated with an extremely diverse range of cancers. Although no other gene has been found in Li-Fraumeni syndrome, recent results show that the functional effects of particular mutations, polymorphisms in TP53 or in regulators such as MDM2 (murine double minute 2), variations in DNA copy number and variations in telomere length, have a strong impact on individual risk and on tumor patterns. Furthermore, recent studies in large cohorts suggest that TP53 germline mutations may occur in up to 1: 5000 individuals. SUMMARY: Germline TP53 mutations may be responsible for a large fraction (15-20%) of all inherited cancers. Although mutations are detectable by sequencing, counseling and follow-up remain problematic due to the wide variations in disease presentation. Elucidating the molecular mechanisms underlying the predisposition caused by TP53 deficiency may help to develop better, evidence-based and personalized clinical protocols.
Authors: Simon N Stacey; Patrick Sulem; Aslaug Jonasdottir; Gisli Masson; Julius Gudmundsson; Daniel F Gudbjartsson; Olafur T Magnusson; Sigurjon A Gudjonsson; Bardur Sigurgeirsson; Kristin Thorisdottir; Rafn Ragnarsson; Kristrun R Benediktsdottir; Bjørn A Nexø; Anne Tjønneland; Kim Overvad; Peter Rudnai; Eugene Gurzau; Kvetoslava Koppova; Kari Hemminki; Cristina Corredera; Victoria Fuentelsaz; Pilar Grasa; Sebastian Navarrete; Fernando Fuertes; Maria D García-Prats; Enrique Sanambrosio; Angeles Panadero; Ana De Juan; Almudena Garcia; Fernando Rivera; Dolores Planelles; Virtudes Soriano; Celia Requena; Katja K Aben; Michelle M van Rossum; Ruben G H M Cremers; Inge M van Oort; Dick-Johan van Spronsen; Jack A Schalken; Wilbert H M Peters; Brian T Helfand; Jenny L Donovan; Freddie C Hamdy; Daniel Badescu; Ovidiu Codreanu; Mariana Jinga; Irma E Csiki; Vali Constantinescu; Paula Badea; Ioan N Mates; Daniela E Dinu; Adrian Constantin; Dana Mates; Sjofn Kristjansdottir; Bjarni A Agnarsson; Eirikur Jonsson; Rosa B Barkardottir; Gudmundur V Einarsson; Fridbjorn Sigurdsson; Pall H Moller; Tryggvi Stefansson; Trausti Valdimarsson; Oskar T Johannsson; Helgi Sigurdsson; Thorvaldur Jonsson; Jon G Jonasson; Laufey Tryggvadottir; Terri Rice; Helen M Hansen; Yuanyuan Xiao; Daniel H Lachance; Brian Patrick O Neill; Matthew L Kosel; Paul A Decker; Gudmar Thorleifsson; Hrefna Johannsdottir; Hafdis T Helgadottir; Asgeir Sigurdsson; Valgerdur Steinthorsdottir; Annika Lindblom; Robert S Sandler; Temitope O Keku; Karina Banasik; Torben Jørgensen; Daniel R Witte; Torben Hansen; Oluf Pedersen; Viorel Jinga; David E Neal; William J Catalona; Margaret Wrensch; John Wiencke; Robert B Jenkins; Eduardo Nagore; Ulla Vogel; Lambertus A Kiemeney; Rajiv Kumar; José I Mayordomo; Jon H Olafsson; Augustine Kong; Unnur Thorsteinsdottir; Thorunn Rafnar; Kari Stefansson Journal: Nat Genet Date: 2011-09-25 Impact factor: 38.330
Authors: Monica Gostissa; Julia M Bianco; Daniel J Malkin; Jeffery L Kutok; Scott J Rodig; Herbert C Morse; Craig H Bassing; Frederick W Alt Journal: Proc Natl Acad Sci U S A Date: 2013-02-04 Impact factor: 11.205