Dataset Information

Early Cancer Detection in Li-Fraumeni Syndrome with Cell-Free DNA.

ABSTRACT: People with Li-Fraumeni syndrome (LFS) harbor a germline pathogenic variant in the TP53 tumor suppressor gene, face a near 100% lifetime risk of cancer, and routinely undergo intensive surveillance protocols. Liquid biopsy has become an attractive tool for a range of clinical applications, including early cancer detection. Here, we provide a proof-of-principle for a multimodal liquid biopsy assay that integrates a targeted gene panel, shallow whole-genome, and cell-free methylated DNA immunoprecipitation sequencing for the early detection of cancer in a longitudinal cohort of 89 LFS patients. Multimodal analysis increased our detection rate in patients with an active cancer diagnosis over uni-modal analysis and was able to detect cancer-associated signal(s) in carriers prior to diagnosis with conventional screening (positive predictive value = 67.6%, negative predictive value = 96.5%). Although adoption of liquid biopsy into current surveillance will require further clinical validation, this study provides a framework for individuals with LFS.

Significance

By utilizing an integrated cell-free DNA approach, liquid biopsy shows earlier detection of cancer in patients with LFS compared with current clinical surveillance methods such as imaging. Liquid biopsy provides improved accessibility and sensitivity, complementing current clinical surveillance methods to provide better care for these patients. See related commentary by Latham et al., p. 23. This article is featured in Selected Articles from This Issue, p. 5.

SUBMITTER: Wong D

PROVIDER: S-EPMC10784744 | biostudies-literature | 2024 Jan

REPOSITORIES: biostudies-literature

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Early Cancer Detection in Li-Fraumeni Syndrome with Cell-Free DNA.

Wong Derek D Luo Ping P Oldfield Leslie E LE Gong Haifan H Brunga Ledia L Rabinowicz Ron R Subasri Vallijah V Chan Clarissa C Downs Tiana T Farncombe Kirsten M KM Luu Beatrice B Norman Maia M Sobotka Julia A JA Uju Precious P Eagles Jenna J Pedersen Stephanie S Wellum Johanna J Danesh Arnavaz A Prokopec Stephenie D SD Stutheit-Zhao Eric Y EY Znassi Nadia N Heisler Lawrence E LE Jovelin Richard R Lam Bernard B Lujan Toro Beatriz E BE Marsh Kayla K Sundaravadanam Yogi Y Torti Dax D Man Carina C Goldenberg Anna A Xu Wei W Veit-Haibach Patrick P Doria Andrea S AS Malkin David D Kim Raymond H RH Pugh Trevor J TJ

Cancer discovery 20240101 1

People with Li-Fraumeni syndrome (LFS) harbor a germline pathogenic variant in the TP53 tumor suppressor gene, face a near 100% lifetime risk of cancer, and routinely undergo intensive surveillance protocols. Liquid biopsy has become an attractive tool for a range of clinical applications, including early cancer detection. Here, we provide a proof-of-principle for a multimodal liquid biopsy assay that integrates a targeted gene panel, shallow whole-genome, and cell-free methylated DNA immunoprec ...[more]

PMID: 37874259

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Project description:Germline mutations of TP53, which cause the cancer predisposition disorder Li-Fraumeni syndrome (LFS), can increase mitochondrial activity as well as fatty acid β-oxidation (FAO) in mice. Increased fatty acid metabolism can promote cancer malignancy, but its specific contribution to tumorigenesis in LFS remains unclear. To investigate this, we crossed LFS mice carrying the p53 R172H knock-in mutation (p53172H/H , homolog of the human TP53 R175H LFS mutation) with myoglobin-knockout (MB-/- ) mice known to have decreased FAO. MB-/- p53172H/H double-mutant mice also showed mildly reduced FAO in thymus, a common site of T lymphoma development in LFS mice, in association with an approximately 40% improvement in cancer-free survival time. RNA sequencing profiling revealed that the p53 R172H mutation promotes mitochondrial metabolism and ribosome biogenesis, both of which are suppressed by the disruption of MB. The activation of ribosomal protein S6, involved in protein translation and implicated in cancer promotion, was also inhibited in the absence of MB. To further confirm the role of FAO in lymphomagenesis, mitochondrial FAO enzyme, carnitine palmitoyltransferase 2 (CPT2), was specifically disrupted in T cells of p53172H/H mice using a Cre-loxP-mediated strategy. The heterozygous knockout of CPT2 resulted in thymus FAO haploinsufficiency and an approximately 30% improvement in survival time, paralleling the antiproliferative signaling observed with MB disruption. Thus, this study demonstrates that moderating FAO in LFS can suppress tumorigenesis and improve cancer-free survival with potential implications for cancer prevention. PREVENTION RELEVANCE: Mildly inhibiting the increased fatty acid oxidation observed in a mouse model of Li-Fraumeni syndrome, a cancer predisposition disorder caused by inherited mutations of TP53, dampens aberrant pro-tumorigenic cell signaling and improves the survival time of these mice, thereby revealing a potential strategy for cancer prevention in patients.

Dataset Information

Early Cancer Detection in Li-Fraumeni Syndrome with Cell-Free DNA.

Significance

Publications

Early Cancer Detection in Li-Fraumeni Syndrome with Cell-Free DNA.

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