LFSPRO

LFSPRO estimates TP53 germline carrier probability and cancer-specific penetrance for Li-Fraumeni syndrome from pedigree data as an R package.

Key Features:

• TP53 Germline Mutation Carrier Estimation: Estimates the probability that an individual carries germline TP53 mutations using family pedigree information.
• Cancer-Specific Penetrance Estimation: Implements a competing risk-based statistical model that integrates pedigree structure to estimate cancer-specific penetrance and corrects for ascertainment bias.
• Penetrance Validation Across Multiple Cohorts: Validated using combined datasets from two clinically ascertained family cohorts comprising 668 families to mitigate cohort-specific biases.
• Age-Dependent Onset Probability Distributions: Models age-dependent onset probability distributions for breast (BR), sarcoma (SA), and other cancers (OT), noting earlier TP53-associated breast cancer penetrance compared to BRCA1/2-associated penetrance.
• Performance Metrics: Demonstrates independent-cohort AUCs of 0.92 for breast cancer, 0.75 for sarcoma, and 0.81 for other cancers.

Scientific Applications:

• Penetrance Estimation for LFS-Associated Cancers: Provides cancer-specific TP53 penetrance estimates for Li-Fraumeni syndrome to inform familial risk assessment.
• Clinical Risk Assessment and Management: Supports clinical risk assessment for breast, sarcoma, and other cancers to inform surveillance strategies and preventive measures.

Methodology:

LFSPRO employs a competing risk-based statistical model that leverages pedigree structure to estimate cancer-specific TP53 penetrance while correcting for ascertainment bias and increasing effective sample size.