Performance of LFSPRO prediction in TP53 mutation status for prospectively collected probands

Area of Science:

• Genetics
• Oncology
• Medical Informatics

Background:

• Germline TP53 mutations cause Li-Fraumeni syndrome (LFS), a cancer predisposition disorder.
• Current clinical guidelines (e.g., Chompret criteria) have limitations in identifying all at-risk individuals.
• Challenges exist in risk assessment and genetic testing decisions for individuals not meeting strict criteria.

Purpose of the Study:

• To evaluate the performance of LFSPRO, a family-history-based model, in identifying individuals with TP53 pathogenic/likely pathogenic (P/LP) variants.
• To compare LFSPRO's accuracy against existing Chompret criteria for LFS risk assessment.
• To determine if LFSPRO improves the identification of LFS in clinical settings.

Main Methods:

• A prospective cohort of 178 probands undergoing genetic counseling and TP53 testing was analyzed.
• LFSPRO model probabilities were compared with Chompret criteria for predicting TP53 P/LP variants.
• Performance metrics including sensitivity, specificity, PPV, NPV, and AUC were calculated.

Main Results:

• LFSPRO demonstrated superior discrimination compared to Chompret criteria.
• LFSPRO achieved higher sensitivity (81% vs. 33%) and specificity (88% vs. 65%).
• LFSPRO showed improved PPV (0.53 vs. 0.14) and NPV (0.96 vs. 0.85), with an AUC of 0.88.

Conclusions:

• LFSPRO significantly outperforms traditional guideline-based criteria for identifying TP53 mutations in clinical practice.
• The model provides quantitative, well-calibrated probabilities, enhancing genetic counseling and testing decisions.
• LFSPRO is particularly valuable for individuals with features suggestive of LFS who do not meet established criteria.