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Estimating TP53 mutation carrier probability in families with Li-Fraumeni syndrome using LFSPRO

Abstract

BACKGROUND: Li-Fraumeni syndrome (LFS) is associated with germline TP53 mutations 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 for TP53 mutation testing and LFS management. METHODS: Based on a Mendelian model, LFSPRO estimates TP53 mutation 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 predicted TP53 mutation carriers in a pediatric sarcoma cohort from MD Anderson Cancer Center (MDACC) in the US, the observed to expected ratio (OE) = 1.35 (95%CI, 0.99 to 1.80); area under the receiver operating characteristic curve (AUC) = 0.85 (0.75 to 0.93); a population-based sarcoma cohort from the International Sarcoma Kindred Study (ISKS) in Australia, OE = 1.62 (1.03 to 2.55); AUC = 0.67 (0.54 to 0.79); and the NCI LFS study cohort, OE = 1.28 (1.17 to 1.39); AUC = 0.82 (0.78 to 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 predicting TP53 mutations 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.

Type Journal
ISBN 1538-7755 (Electronic) 1055-9965 (Linking)
Authors Peng, G.; Bojadzieva, J.; Ballinger, M. L.; Li, J.; Blackford, A. L.; Mai, P. L.; Savage, S. A.; Thomas, D. M.; Strong, L. C.; Wang, W.
Responsible Garvan Author Dr Mandy Ballinger
Publisher Name CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION
Published Date 2017-06-30 00:00:00
Published Volume 26
Published Issue 6
Published Pages 837-844
Status Published in-print
URL link to publisher's version https://www.ncbi.nlm.nih.gov/pubmed/28137790