Clinical Features and Treatment Strategies of Li-Fraumeni Syndrome Patients With Inherited TP53 Mutations

Sep 22, 2026

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Li-Fraumeni syndrome (LFS) is a rare autosomal dominant disorder caused by pathogenic TP53 mutations, with early onset and an association with multiple tumors. This study reports a retrospective analysis of clinicopathologic features, family history, treatments, and follow-up in five LFS patients carrying germline TP53 pathogenic/likely pathogenic variants. Immune checkpoint inhibitors show unexpected efficacy, while traditional chemotherapy has limited effectiveness. The work also adds a novel TP53 frameshift variant, supporting more targeted therapeutic strategies and diagnostic evaluation.

LanguageEnglish

CategoryHealthcare

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Abstract

Introduction

Clinical History

Case 1

Molecular Genetics & Genomic Medicine ORIGINAL ARTICLE OPEN ACCESS Clinical Features and Treatment Strategies of Li-Fraumeni Syndrome Patients With Inherited TP53 Mutations Keyu Chen1 | Yufen Xu1 | Binbin Song1 | Yuyang Gu1 | Xiaofang Xu1 | Jun Cao2 | Meiyu Fang2 1The First Hospital of Jiaxing & The Affiliated Hospital of Jiaxing University, Jiaxing, China | 2Key Laboratory of Head & Neck Cancer Translational Research of Zhejiang Province, Department of Head and Neck and Rare Oncology, Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, China Correspondence: Xiaofang Xu ([693657635@qq.com](693657635@qq.com)) | Jun Cao ([caojun@zjcc.org.cn](caojun@zjcc.org.cn)) | Meiyu Fang ([fangmy@zjcc.org.cn](fangmy@zjcc.org.cn)) Received: 25 June 2024 | Revised: 1 May 2025 | Accepted: 23 December 2025 Keywords: germline mutations | hereditary disease | immune checkpoint inhibitors | Li-Fraumeni syndrome | TP53 pathogenic/likely pathogenic variants ABSTRACT Background: Li-Fraumeni syndrome is a rare autosomal dominant disorder caused by a pathogenic mutation of the tumor suppressor gene TP53. This disease starts at an early age and has been shown to be associated with multiple tumors. The study aims to discuss the clinical and genetic characteristics of Li-Fraumeni syndrome (LFS) and to provide therapeutic experience of LFS. Materials and Methods: We conducted a retrospective analysis of the clinicopathologic features, family history, treatment and follow-up in five LFS patients with germline TP53 (NCBI Gene: 7157, HGNC: 11998 , OMIM: 191170) pathogenic/likely pathogenic (P/LP) variants. This research had been approved by the ethics committee and implemented. Results: Our study involved five LFS patients with germline TP53 P/LP variants, including thyroid cancer, ovarian melanoma, colon cancer, fibrosarcoma, and lung cancer. Among this group of patients, the age at which tumors first appeared was between 24 and 53 years old. Three patients had a family history of tumors, and the other two were probands in the family. Traditional chemotherapy has limited effectiveness in clinical practice and may increase the risk of tumor development. However, immune checkpoint inhibitors (ICIs) have shown unexpected efficacy in patients with high programmed cell death ligand-1 (PD-L1) expression. Next-generation sequencing (NGS) and PD-L1 detection may provide more potential targets for LFS patients to achieve better therapeutic outcomes. In addition, we have added a new TP53 frameshift mutation spectrum, namely c.642 _ 643delTA (p.H214Qfs*7), which belongs to the pathogenic variant. This mutant has not been described in the existing literature. Conclusion: Patients with LFS may be potential beneficiaries of immune checkpoint inhibitors and targeted therapies. 1 | Introduction TP53 (*191170) is the most commonly mutated gene in human cancers and coordinates the cellular response to DNA damage (Liu et al. 2019) . Mutations in this gene often lead to a loss of activity in the protein that codes for p53 (Liu et al. 2019) . Somatic mutations in the TP53 gene are present in more than 50% of tumors (Liu et al. 2019) . Germline TP53 pathogenic/ likely pathogenic (P/LP) variants are the basis for diagnosis of Li-Fraumeni syndrome (LFS) . According to the studies in the United States and European, the frequency of germline TP53 mutations is about 0.02% in the population, which tends to lead to early-onset of cancer (Lalloo et al. 2003) . 50% of patients are found to have malignant tumors before the age of 30. Here, we report five patients with germline TP53 pathogenic variants. Two of them have thyroid cancer, one has malignant melanoma, and the other two have two primary tumors. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. © 2

FAQs

What is the main clinical-genetic focus of this study on Li-Fraumeni syndrome?

The study analyzes clinical and genetic characteristics of Li-Fraumeni syndrome, focusing on germline TP53 pathogenic/likely pathogenic variants and their associated tumor presentation and management in five patients.

What treatment approach showed better performance than traditional chemotherapy in the study?

Immune checkpoint inhibitors (ICIs) showed unexpected efficacy, particularly in patients with high programmed cell death ligand-1 (PD-L1) expression.

What additional TP53 mutation finding did the authors report?

The authors added a new TP53 frameshift mutation spectrum, c.642_643delTA (p.H214Qfs*7), and noted that it had not been described in existing literature.

Sep 22, 2026

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