title: Identification of Circulating Tumor DNA for the Early Detection of Small-cell Lung Cancer.
abstract: 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.
authors.affiliation: International Agency for Research on Cancer (IARC-WHO), 150 cours Albert Thomas, 69008 Lyons, France.
authors.forename: Lynnette
authors.initials: L
authors.lastname: Fernandez-Cuesta
authors.affiliation: International Agency for Research on Cancer (IARC-WHO), 150 cours Albert Thomas, 69008 Lyons, France; Institute of Nutrition, Genetics and Metabolism Research, Universidad El Bosque, Bogotá, Colombia.
authors.forename: Sandra
authors.initials: S
authors.lastname: Perdomo
authors.affiliation: International Agency for Research on Cancer (IARC-WHO), 150 cours Albert Thomas, 69008 Lyons, France.
authors.forename: Patrice H
authors.initials: PH
authors.lastname: Avogbe
authors.affiliation: International Agency for Research on Cancer (IARC-WHO), 150 cours Albert Thomas, 69008 Lyons, France.
authors.forename: Noemie
authors.initials: N
authors.lastname: Leblay
authors.affiliation: International Agency for Research on Cancer (IARC-WHO), 150 cours Albert Thomas, 69008 Lyons, France.
authors.forename: Tiffany M
authors.initials: TM
authors.lastname: Delhomme
authors.affiliation: International Agency for Research on Cancer (IARC-WHO), 150 cours Albert Thomas, 69008 Lyons, France.
authors.forename: Valerie
authors.initials: V
authors.lastname: Gaborieau
authors.affiliation: International Agency for Research on Cancer (IARC-WHO), 150 cours Albert Thomas, 69008 Lyons, France.
authors.forename: Behnoush
authors.initials: B
authors.lastname: Abedi-Ardekani
authors.affiliation: International Agency for Research on Cancer (IARC-WHO), 150 cours Albert Thomas, 69008 Lyons, France.
authors.forename: Estelle
authors.initials: E
authors.lastname: Chanudet
authors.affiliation: International Agency for Research on Cancer (IARC-WHO), 150 cours Albert Thomas, 69008 Lyons, France.
authors.forename: Magali
authors.initials: M
authors.lastname: Olivier
authors.affiliation: Russian N.N. Blokhin Cancer Research Centre, Moscow, Russian Federation.
authors.forename: David
authors.initials: D
authors.lastname: Zaridze
authors.affiliation: Russian N.N. Blokhin Cancer Research Centre, Moscow, Russian Federation.
authors.forename: Anush
authors.initials: A
authors.lastname: Mukeria
authors.affiliation: Instituto Angel Roffo, Buenos Aires, Argentina.
authors.forename: Marta
authors.initials: M
authors.lastname: Vilensky
authors.affiliation: 1st Faculty of Medicine, Charles University, Prague, Czech Republic.
authors.forename: Ivana
authors.initials: I
authors.lastname: Holcatova
authors.affiliation: CRO Aviano National Cancer Institute, Aviano, Italy.
authors.forename: Jerry
authors.initials: J
authors.lastname: Polesel
authors.affiliation: Department of Molecular Medicine, University of Padova, Padova, Italy.
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Simonato
authors.affiliation: Department of Molecular Medicine, University of Padova, Padova, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Canova
authors.affiliation: University of Athens Medical School, Greece.
authors.forename: Pagona
authors.initials: P
authors.lastname: Lagiou
authors.affiliation: CHU Grenoble, University Grenoble- Alpes, INSERM U823, Grenoble, France.
authors.forename: Christian
authors.initials: C
authors.lastname: Brambilla
authors.affiliation: CHU Grenoble, University Grenoble- Alpes, INSERM U823, Grenoble, France.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Brambilla
authors.affiliation: International Agency for Research on Cancer (IARC-WHO), 150 cours Albert Thomas, 69008 Lyons, France.
authors.forename: Graham
authors.initials: G
authors.lastname: Byrnes
authors.affiliation: International Agency for Research on Cancer (IARC-WHO), 150 cours Albert Thomas, 69008 Lyons, France.
authors.forename: Ghislaine
authors.initials: G
authors.lastname: Scelo
authors.affiliation: International Agency for Research on Cancer (IARC-WHO), 150 cours Albert Thomas, 69008 Lyons, France.
authors.forename: Florence
authors.initials: F
authors.lastname: Le Calvez-Kelm
authors.affiliation: International Agency for Research on Cancer (IARC-WHO), 150 cours Albert Thomas, 69008 Lyons, France.
authors.forename: Matthieu
authors.initials: M
authors.lastname: Foll
authors.affiliation: International Agency for Research on Cancer (IARC-WHO), 150 cours Albert Thomas, 69008 Lyons, France. Electronic address: MckayJ@iarc.fr.
authors.forename: James D
authors.initials: JD
authors.lastname: McKay
authors.affiliation: International Agency for Research on Cancer (IARC-WHO), 150 cours Albert Thomas, 69008 Lyons, France. Electronic address: BrennanP@iarc.fr.
authors.forename: Paul
authors.initials: P
authors.lastname: Brennan
mesh_terms: D014408:Biomarkers, Tumor; D016022:Case-Control Studies; D004273:DNA, Neoplasm / Q000097:blood; D055088:Early Detection of Cancer; D005260:Female; D006801:Humans; D007962:Leukocytes / Q000378:metabolism; D008175:Lung Neoplasms / Q000097:blood / Q000175:diagnosis* / Q000235:genetics*; D008297:Male; D009154:Mutation; D009367:Neoplasm Staging; D055752:Small Cell Lung Carcinoma / Q000097:blood / Q000175:diagnosis* / Q000235:genetics*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics
chemical_list: D014408:Biomarkers, Tumor; D004273:DNA, Neoplasm; D016159:Tumor Suppressor Protein p53
keywords: Early detection; Screening; Small-cell lung cancer; TP53 mutations; cfDNA; ctDNA