title: Whole exome sequencing identifies driver mutations in asymptomatic computed tomography-detected lung cancers with normal karyotype.
abstract: The efficacy of curative surgery for lung cancer could be largely improved by non-invasive screening programs, which can detect the disease at early stages. We previously showed that 18% of screening-identified lung cancers demonstrate a normal karyotype and, following high-density genome scanning, can be subdivided into samples with 1) numerous; 2) none; and 3) few copy number alterations. Whole exome sequencing was applied to the two normal karyotype, screening-detected lung cancers, constituting group 2, as well as normal controls. We identified mutations in both tumors, including KEAP1 (commonly mutated in lung cancers) in one, and TP53, PMS1, and MSH3 (well-characterized DNA-repair genes) in the other. The two normal karyotype screening-detected lung tumors displayed a typical lung cancer mutational profile that only next generation sequencing could reveal, which offered an additional contribution to the over-diagnosis bias concept hypothesized within lung cancer screening programs.
authors: Department of Experimental Oncology, European Institute of Oncology, Milan, Italy; Molecular Medicine for Care Program, European Institute of Oncology, Milan, Italy.
authors: Elena
authors: E
authors: Belloni
authors: Division of Thoracic Surgery, European Institute of Oncology, Milan, Italy.
authors: Giulia
authors: G
authors: Veronesi
authors: Genomic Unit, European Institute of Oncology, Milan, Italy.
authors: Luca
authors: L
authors: Rotta
authors: The Federazione Italiana per la Ricerca sul Cancro (FIRC) Institute of Molecular Oncology Foundation (IFOM), Milan, Italy; Consortium for Genomic Technologies (Cogentech), Milan, Italy.
authors: Sara
authors: S
authors: Volorio
authors: The Federazione Italiana per la Ricerca sul Cancro (FIRC) Institute of Molecular Oncology Foundation (IFOM), Milan, Italy; Consortium for Genomic Technologies (Cogentech), Milan, Italy.
authors: Domenico
authors: D
authors: Sardella
authors: Department of Experimental Oncology, European Institute of Oncology, Milan, Italy; Consortium for Genomic Technologies (Cogentech), Milan, Italy.
authors: Loris
authors: L
authors: Bernard
authors: Department of Experimental Oncology, European Institute of Oncology, Milan, Italy; Molecular Medicine for Care Program, European Institute of Oncology, Milan, Italy; Dipartimento di Scienze della salute, Università degli Studi di Milano, Milan, Italy.
authors: Salvatore
authors: S
authors: Pece
authors: Department of Experimental Oncology, European Institute of Oncology, Milan, Italy; Molecular Medicine for Care Program, European Institute of Oncology, Milan, Italy; The Federazione Italiana per la Ricerca sul Cancro (FIRC) Institute of Molecular Oncology Foundation (IFOM), Milan, Italy; Dipartimento di Scienze della salute, Università degli Studi di Milano, Milan, Italy.
authors: Pier Paolo
authors: PP
authors: Di Fiore
authors: Division of Pathology, European Institute of Oncology, Milan, Italy.
authors: Caterina
authors: C
authors: Fumagalli
authors: Division of Pathology, European Institute of Oncology, Milan, Italy.
authors: Massimo
authors: M
authors: Barberis
authors: Division of Thoracic Surgery, European Institute of Oncology, Milan, Italy; Dipartimento di Scienze della salute, Università degli Studi di Milano, Milan, Italy.
authors: Lorenzo
authors: L
authors: Spaggiari
authors: Department of Experimental Oncology, European Institute of Oncology, Milan, Italy; Molecular Medicine for Care Program, European Institute of Oncology, Milan, Italy; Dipartimento di Scienze della salute, Università degli Studi di Milano, Milan, Italy. Electronic address: piergiuseppe.pelicci@ieo.eu.
authors: Pier Giuseppe
authors: PG
authors: Pelicci
authors: Center for Genomic Science of IIT@SEMM, Fondazione Istituto Italiano di Tecnologia, Milan, Italy. Electronic address: laura.riva@iit.it.
authors: Laura
authors: L
authors: Riva
mesh_terms: D004268:DNA-Binding Proteins / Q000235:genetics; D059472:Exome; D020022:Genetic Predisposition to Disease; D059014:High-Throughput Nucleotide Sequencing / Q000379:methods*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics; D059785:Karyotype; D000072019:Kelch-Like ECH-Associated Protein 1; D008175:Lung Neoplasms / Q000235:genetics* / Q000473:pathology; D000070956:MutL Proteins; D000074081:MutS Homolog 3 Protein; D009154:Mutation; D009363:Neoplasm Proteins / Q000235:genetics; D017422:Sequence Analysis, DNA / Q000379:methods*; D014057:Tomography, X-Ray Computed; D016159:Tumor Suppressor Protein p53 / Q000235:genetics
chemical_list: D004268:DNA-Binding Proteins; D047908:Intracellular Signaling Peptides and Proteins; C431364:KEAP1 protein, human; D000072019:Kelch-Like ECH-Associated Protein 1; C078444:MSH3 protein, human; D000074081:MutS Homolog 3 Protein; D009363:Neoplasm Proteins; C088996:PMS1 protein, human; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D000070956:MutL Proteins
keywords: CT-screening; mutation instability in lung cancer; normal karyotype; over-diagnosis; whole-exome sequencing