title: EstimatingTP53Mutation Carrier Probability in Families with Li-Fraumeni Syndrome Using LFSPRO.
abstract: Background:Li-Fraumeni syndrome (LFS) is associated with germlineTP53mutations and a very high lifetime cancer risk. Algorithms that assess a patient's risk of inherited cancer predisposition are often used in clinical counseling. The existing LFS criteria have limitations, suggesting the need for an advanced prediction tool to support clinical decision making forTP53mutation testing and LFS management.Methods:Based on a Mendelian model, LFSPRO estimatesTP53mutation probability through the Elston-Stewart algorithm and consequently estimates future risk of cancer. With independent datasets of 1,353 tested individuals from 867 families, we evaluated the prediction performance of LFSPRO.Results:LFSPRO accurately predictedTP53mutation carriers in a pediatric sarcoma cohort from MD Anderson Cancer Center in the United States, the observed to expected ratio (OE) = 1.35 (95% confidence interval, 0.99-1.80); area under the receiver operating characteristic curve (AUC) = 0.85 (0.75-0.93); a population-based sarcoma cohort from the International Sarcoma Kindred Study in Australia, OE = 1.62 (1.03-2.55); AUC = 0.67 (0.54-0.79); and the NCI LFS study cohort, OE = 1.28 (1.17-1.39); AUC = 0.82 (0.78-0.86). LFSPRO also showed higher sensitivity and specificity than the classic LFS and Chompret criteria. LFSPRO is freely available through the R packages LFSPRO and BayesMendel.Conclusions:LFSPRO shows good performance in predictingTP53mutations in individuals and families in varied situations.Impact:LFSPRO is more broadly applicable than the current clinical criteria and may improve clinical management for individuals and families with LFS.Cancer Epidemiol Biomarkers Prev; 26(6); 837-44. ©2017 AACR.
authors.affiliation: Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Gang
authors.initials: G
authors.lastname: Peng
authors.affiliation: Department of Genetics, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Jasmina
authors.initials: J
authors.lastname: Bojadzieva
authors.affiliation: The Kinghorn Cancer Center and Garvan Institute of Medical Research, Darlinghurst, New South Wales, Australia.
authors.forename: Mandy L
authors.initials: ML
authors.lastname: Ballinger
authors.affiliation: Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Jialu
authors.initials: J
authors.lastname: Li
authors.affiliation: Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland.
authors.forename: Amanda L
authors.initials: AL
authors.lastname: Blackford
authors.affiliation: Clinical Genetics Branch, Division of Cancer Genetic and Epidemiology, National Cancer Institute, Bethesda, Maryland.
authors.forename: Phuong L
authors.initials: PL
authors.lastname: Mai
authors.affiliation: Clinical Genetics Branch, Division of Cancer Genetic and Epidemiology, National Cancer Institute, Bethesda, Maryland.
authors.forename: Sharon A
authors.initials: SA
authors.lastname: Savage
authors.affiliation: The Kinghorn Cancer Center and Garvan Institute of Medical Research, Darlinghurst, New South Wales, Australia.
authors.forename: David M
authors.initials: DM
authors.lastname: Thomas
authors.affiliation: Department of Genetics, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Louise C
authors.initials: LC
authors.lastname: Strong
authors.affiliation: Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas. wwang7@mdanderson.org.
authors.forename: Wenyi
authors.initials: W
authors.lastname: Wang
mesh_terms: D005260:Female; D020022:Genetic Predisposition to Disease; D018095:Germ-Line Mutation; D006801:Humans; D016864:Li-Fraumeni Syndrome / Q000235:genetics*; D008297:Male; D012307:Risk Factors; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*
chemical_list: D016159:Tumor Suppressor Protein p53