Ultra-Sensitive TP53 Sequencing for Cancer Detection Reveals Progressive Clonal Selection in Normal Tissue over a Century of Human Lifespan

Abstract : High-accuracy next-generation DNA sequencing promises a paradigm shift in early cancer detection by enabling the identification of mutant cancer molecules in minimally invasive body fluid samples. We demonstrate 80% sensitivity for ovarian cancer detection using ultra-accurate Duplex Sequencing to identify TP53 mutations in uterine lavage. However, in addition to tumor DNA, we also detect low-frequency TP53 mutations in nearly all lavages from women with and without cancer. These mutations increase with age and share the selection traits of clonal TP53 mutations commonly found in human tumors. We show that low-frequency TP53 mutations exist in multiple healthy tissues, from newborn to centenarian, and progressively increase in abundance and pathogenicity with older age across tissue types. Our results illustrate that subclonal cancer evolutionary processes are a ubiquitous part of normal human aging, and great care must be taken to distinguish tumor-derived from age-associated mutations in high-sensitivity clinical cancer diagnostics.
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https://hal.sorbonne-universite.fr/hal-02180268
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Soumis le : jeudi 11 juillet 2019 - 12:50:16
Dernière modification le : samedi 13 juillet 2019 - 01:30:46

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Jesse Salk, Kaitlyn Loubet-Senear, Elisabeth Maritschnegg, Charles Valentine, Lindsey Williams, et al.. Ultra-Sensitive TP53 Sequencing for Cancer Detection Reveals Progressive Clonal Selection in Normal Tissue over a Century of Human Lifespan. Cell Reports , Elsevier Inc, 2019, 28 (1), pp.132-144.e3. ⟨10.1016/j.celrep.2019.05.109⟩. ⟨hal-02180268⟩

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