Authors
Derek Wong; Ping Luo; Leslie E. Oldfield; Haifan Gong; Ledia Brunga; Ron Rabinowicz; Vallijah Subasri; Clarissa Chan; Tiana Downs; Kirsten M. Farncombe; Beatrice Luu; Maia Norman; Julia A. Sobotka; Precious Uju; Jenna Eagles; Stephanie Pedersen; Johanna Wellum; Arnavaz Danesh; Stephenie D. Prokopec; Eric Y. Stutheit-Zhao; Nadia Znassi; Lawrence E. Heisler; Richard Jovelin; Bernard Lam; Beatriz E. Lujan Toro; Kayla Marsh; Yogi Sundaravadanam; Dax Torti; Carina Man; Anna Goldenberg; Wei Xu; Patrick Veit-Haibach; Andrea S. Doria; David Malkin; Raymond H. Kim; Trevor J. Pugh
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.
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