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<p>Li-Fraumeni syndrome (LFS) has recently been redefined as a ‘spectrum’ cancer predisposition disorder to reflect its broad phenotypic heterogeneity. This variability is thought to stem in part from the diverse functional impacts of <i>TP53</i> variants, although the underlying mechanisms remain poorly understood and there is an unmet clinical need for effective risk stratification. Here, we apply unsupervised clustering to functional datasets and identify distinct <i>TP53</i> variant groups with clinical relevance, including a monomeric subgroup enriched in osteosarcoma cases. In cellular validation assays, dermal fibroblasts from carriers of more functionally impaired variants exhibit increased metabolic growth rates, mirroring trends observed in cluster-stratified clinical outcomes. These findings demonstrate the feasibility of developing diagnostic assays to guide personalized cancer risk assessment. More broadly, our results show that nuances in TP53 dysfunction shape the germline <i>TP53</i>-related cancer susceptibility spectrum and provide a framework for functionally delineating variant carriers.</p>

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TP53 variant clusters stratify phenotypic diversity in germline carriers and reveal an osteosarcoma-prone subgroup

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年9月29日

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  • Nicholas W. Fischer,
  • Noel Ong,
  • Brianne Laverty,
  • Pamela Psarianos,
  • Camilla Giovino,
  • Noa Alon,
  • Emilie Montellier,
  • Pierre Hainaut,
  • Kara N. Maxwell,
  • Christian P. Kratz,
  • Ran Kafri,
  • David Malkin

摘要

Li-Fraumeni syndrome (LFS) has recently been redefined as a ‘spectrum’ cancer predisposition disorder to reflect its broad phenotypic heterogeneity. This variability is thought to stem in part from the diverse functional impacts of TP53 variants, although the underlying mechanisms remain poorly understood and there is an unmet clinical need for effective risk stratification. Here, we apply unsupervised clustering to functional datasets and identify distinct TP53 variant groups with clinical relevance, including a monomeric subgroup enriched in osteosarcoma cases. In cellular validation assays, dermal fibroblasts from carriers of more functionally impaired variants exhibit increased metabolic growth rates, mirroring trends observed in cluster-stratified clinical outcomes. These findings demonstrate the feasibility of developing diagnostic assays to guide personalized cancer risk assessment. More broadly, our results show that nuances in TP53 dysfunction shape the germline TP53-related cancer susceptibility spectrum and provide a framework for functionally delineating variant carriers.