Penetrance Estimates Over Time to First and Second Primary Cancer Diagnosis in Families with Li-Fraumeni Syndrome: A Single Institution Perspective
Year: 2019
Type: article
Study design: Observational Study
Abstract: Li-Fraumeni syndrome (LFS) is a rare autosomal dominant disorder associated with TP53 germline mutations and an increased lifetime risk of multiple primary cancers (MPC). Penetrance estimation of time to first and second primary cancer within LFS remains challenging due to limited data availability and the difficulty of accounting for the characteristic effects of a primary cancer on the penetrance of a second primary cancer. Using a recurrent events survival modeling approach, we estimated penetrance for both first and second primary cancer diagnosis from a pediatric sarcoma cohort (number families=189; Single primary cancer, or SPC=771; MPC=87). We then validated the risk prediction performance using an independent clinical cohort of TP53 tested individuals from MD Anderson (SPC=102; MPC=58). Our penetrance estimates are dependent on TP53 genotype, sex, and, importantly, age of diagnosis (AoD) for the first PC. We observed the later the AoD is, the shorter the gap time is for this person to be diagnosed with a second PC. We achieved an Area under the ROC curve (AUC) of 0.77 for predicting individual outcomes of MPC vs. SPC. In summary, we have provided the first set of penetrance estimates for SPC and MPC for TP53 mutation carriers, and demonstrated its accuracy for cancer risk assessment. Our open-source R package, LFSPRO, provides future risk estimates for SPC and MPC among TP53 germline mutation carriers. Significance Our tool can be used to support clinical counseling of LFS cancer survivors for better health management.
Source: Cancer Research
Language: English
Subfield: Epidemiology
Field: Medicine
Domain: Health Sciences
Open Access status: green
Awards: G1081030536, G111615301, Recruitment of Established Investigators, Personalized risk assessment for families with Li-Fraumeni Syndrome, G201133769, G204786143, G2299749020, G2592907185, Consistent variable selection in p>>n settings, Comparative Effectiveness of Cancer Research: Use Data from Multiple Sources, G2928171368, Integrative Analysis of Lung Cancer Etiology and Risk, A Mutational Model for Childhood Cancer, G4111184626, G4276892241, Bioinformatics Tools for Genomic Analysis of Tumor and Stromal Pathways in Cancer, G4553610997, G6230222439, G6341696546, G7510423959, G8139520674, G9000034222, G9000292079
OpenAlex ID: W2988868150