Circulating tumor DNA (ctDNA) is emerging as a key potential biomarker for post-diagnosis surveillance but it may also play a crucial role in the detection of pre-clinical cancer. Small-cell lung cancer (SCLC) is an excellent candidate for early detection given there are no successful therapeutic options for late-stage disease, and it displays almost universal inactivation of TP53. We assessed the presence of TP53 mutations in the cell-free DNA (cfDNA) extracted from the plasma of 51 SCLC cases and 123 non-cancer controls. We identified mutations using a pipeline specifically designed to accurately detect variants at very low fractions. We detected TP53 mutations in the cfDNA of 49% SCLC patients and 11.4% of non-cancer controls. When stratifying the 51 initial SCLC cases by stage, TP53 mutations were detected in the cfDNA of 35.7% early-stage and 54.1% late-stage SCLC patients. The results in the controls were further replicated in 10.8% of an independent series of 102 non-cancer controls. The detection of TP53 mutations in 11% of the 225 non-cancer controls suggests that somatic mutations in cfDNA among individuals without any cancer diagnosis is a common occurrence, and poses serious challenges for the development of ctDNA screening tests.

1st Faculty of Medicine Charles University Prague Czech Republic

CHU Grenoble University Grenoble Alpes INSERM U823 Grenoble France

CRO Aviano National Cancer Institute Aviano Italy

Department of Molecular Medicine University of Padova Padova Italy

Instituto Angel Roffo Buenos Aires Argentina

International Agency for Research on Cancer 150 cours Albert Thomas 69008 Lyons France

International Agency for Research on Cancer 150 cours Albert Thomas 69008 Lyons France; Institute of Nutrition Genetics and Metabolism Research Universidad El Bosque Bogotá Colombia

Russian N N Blokhin Cancer Research Centre Moscow Russian Federation

University of Athens Medical School Greece

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