Novel tool more accurately predicts risk of Li-Fraumeni Syndrome

MD Anderson Research News April 23, 2026

In a prospective validation study, researchers at The University of Texas MD Anderson Cancer Center demonstrated that a new mathematical model, called LFSPRO, was effective in supporting genetic counselor decision-making and more accurately predicted individuals at higher risk of Li-Fraumeni Syndrome (LFS), a hereditary condition that carries a higher risk of developing multiple cancers.

LFSPRO provided risk scores that significantly outperformed current criteria for genetic testing and provided valuable insights and quantifiable data for genetic counselors that more closely aligned with their clinical judgment.

The study, published in The American Journal of Human Genetics, was led by Wenyi Wang, Ph.D., professor of Bioinformatics and Computational Biology, and Banu Arun, M.D., professor of Breast Medical Oncology.

“Most risk prediction models are validated only in research-based cohorts, but our study demonstrates LFSPRO's performance in a real-world genetic counseling setting, where limited family history information is provided within 30 minutes and most counselees test negative,” Wang said. “Our model demonstrated substantially higher accuracy than current clinical guidelines and had strong concordance with genetic counselors' judgment.”

What is Li-Fraumeni Syndrome and how is it currently detected?

LFS is a rare hereditary predisposition to cancer mainly caused by mutations in the TP53 tumor suppressor gene. Individuals who have LFS carry a much higher risk of developing multiple early-onset cancers – including sarcomas, breast cancer, brain tumors and leukemias – as well as secondary cancers, highlighting a need to accurately identify patients with LFS as early as possible.

Current guidelines for genetic testing endorsed by the National Comprehensive Cancer Network (NCCN), known as Chompret criteria, rely on individuals meeting certain yes or no criteria to determine who should receive TP53 genetic testing. However, these guidelines can miss individuals who might have atypical or limited family histories. Most referred individuals also end up testing negative for TP53 mutations, meaning this process often brings unnecessary worry.

How does this new model help genetic counselors determine who should be tested?

LFSPRO is a comprehensive statistical model that uses complete family history to calculate the probability of having a TP53 mutation and predict subsequent risk of developing LFS-related cancers. The model was previously developed as a way to help genetic counselors more accurately determine at-risk individuals.

The goal of LFSPRO is to provide a more quantitative risk estimate to address the gap for individuals who would benefit from testing but would not meet the established Chompret criteria. However, while LFSPRO performed strongly in research and retrospective cohorts, it had never been evaluated for prospective use by genetic counselors in clinical decision-making.

The researchers invited four genetic counselors to prospectively use LFSPRO in their standard genetic counseling sessions with 178 individuals who also received germline TP53 testing.

How did LFSPRO improve clinical accuracy and personalized risk?

LFSPRO demonstrated strong predictive performance for individual TP53 mutation probability estimates and significantly outperformed the current Chompret criteria on every metric, including sensitivity, specificity, and positive and negative predictive values. This led to fewer missed cases and fewer cases referred for unnecessary testing.

In addition to diagnostic accuracy, LFSPRO also aligned well with the clinical judgment of genetic counselors, with most counselors reporting they were comfortable sharing the results of LFSPRO with their patients and their families. They found it to be a helpful, numbers-based second opinion that could improve their confidence and clinical decision-making in determining patients likely to benefit from genetic testing, especially when those patients did not meet the current criteria due to atypical or limited family histories.

Accurate identification of individuals with LFS has major clinical implications for the screening and prevention of life-threating cancers. With the expansion of clinical germline testing in community settings, having access to a user-friendly tool that can be easily utilized by genetic counselors and other health care providers should increase the identification of at-risk individuals and facilitate timely implementation of appropriate surveillance and preventive strategies, the researchers explained.

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The study was funded by the National Institutes of Health (NIH) and the Cancer Prevention and Research Institute of Texas (CPRIT). A full list of collaborating authors and their disclosures can be found with the paper in The American Journal of Human Genetics.