title: Elucidating Genomic Characteristics of Lung Cancer Progression from In Situ to Invasive Adenocarcinoma.
abstract: To examine the diversity of somatic alterations and clonal evolution according to aggressiveness of disease, nineteen tumor-blood pairs of 'formerly bronchiolo-alveolar carcinoma (BAC)' which had been reclassified into preinvasive lesion (adenocarcinoma in situ; AIS), focal invasive lesion (minimally invasive adenocarcinoma; MIA), and invasive lesion (lepidic predominant adenocarcinoma; LPA and non-lepidic predominant adenocarcinoma; non-LPA) according to IASLC/ATS/ERS 2011 classification were explored by whole exome sequencing. Several distinct somatic alterations were observed compare to the lung adenocarcinoma study from the Cancer Genome Atlas (TCGA). There were higher numbers of tumors with significant APOBEC mutation fold enrichment (73% vs. 58% TCGA). The frequency of KRAS mutations was lower in our study (5% vs. 32% TCGA), while a higher number of mutations of RNA-splicing genes, RBM10 and U2AF1, were found (37% vs. 11% TCGA). We found neither mutational pattern nor somatic copy number alterations that were specific to AIS/MIA. We demonstrated that clonal cell fraction was the only distinctive feature that discriminated LPA/non-LPA from AIS/MIA. The broad range of clonal frequency signified a more branched clonal evolution at the time of diagnosis. Assessment of tumor clonal cell fraction might provide critical information for individualized therapy as a prognostic factor, however this needs further study.
authors.affiliation: International Agency for Research on Cancer, Lyon, France.|Division of Medical Oncology, Department of Medicine, Faculty of Medicine, Chulalongkorn University and The King Chulalongkorn Memorial Hospital, Bangkok, Thailand.
authors.forename: Chanida
authors.initials: C
authors.lastname: Vinayanuwattikun
authors.affiliation: International Agency for Research on Cancer, Lyon, France.
authors.forename: Florence
authors.initials: F
authors.lastname: Le Calvez-Kelm
authors.affiliation: International Agency for Research on Cancer, Lyon, France.
authors.forename: Behnoush
authors.initials: B
authors.lastname: Abedi-Ardekani
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: International Agency for Research on Cancer, Lyon, France.
authors.forename: Catherine
authors.initials: C
authors.lastname: Voegele
authors.affiliation: International Agency for Research on Cancer, Lyon, France.|Department of Molecular Medicine, CHUQ Research Center, Laval University, Quebec, Canada.
authors.forename: Maxime
authors.initials: M
authors.lastname: Vallée
authors.affiliation: International Agency for Research on Cancer, Lyon, France.|Department of Histology and Cell Biology and Molecular Biology Laboratory, Faculty of Medicine, Gadjah Mada University, Yogyakarta, Indonesia.
authors.forename: Dewajani
authors.initials: D
authors.lastname: Purnomosari
authors.affiliation: International Agency for Research on Cancer, Lyon, France.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Forey
authors.affiliation: International Agency for Research on Cancer, Lyon, France.
authors.forename: Geoffroy
authors.initials: G
authors.lastname: Durand
authors.affiliation: International Agency for Research on Cancer, Lyon, France.
authors.forename: Graham
authors.initials: G
authors.lastname: Byrnes
authors.affiliation: International Agency for Research on Cancer, Lyon, France.
authors.forename: James
authors.initials: J
authors.lastname: Mckay
authors.affiliation: International Agency for Research on Cancer, Lyon, France.
authors.forename: Paul
authors.initials: P
authors.lastname: Brennan
authors.affiliation: International Agency for Research on Cancer, Lyon, France.
authors.forename: Ghislaine
authors.initials: G
authors.lastname: Scelo
mesh_terms: D000071478:APOBEC Deaminases / Q000235:genetics*; D000230:Adenocarcinoma / Q000235:genetics* / Q000473:pathology / Q000628:therapy; D000368:Aged; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000473:pathology / Q000628:therapy; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009361:Neoplasm Invasiveness; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics*
chemical_list: C117307:KRAS protein, human; D000071478:APOBEC Deaminases; D016283:Proto-Oncogene Proteins p21(ras)