title: Genomic rearrangements define lineage relationships between adjacent lepidic and invasive components in lung adenocarcinoma.
abstract: The development of adenocarcinoma of the lung is believed to proceed from in situ disease (adenocarcinoma in situ, AIS) to minimally invasive disease with prominent lepidic growth (minimally invasive adenocarcinoma, MIA), then to fully invasive adenocarcinoma (AD), but direct evidence for this model has been lacking. Because some lung adenocarcinomas show prominent lepidic growth (AD-L), we designed a study to address the lineage relationship between the lepidic (noninvasive) component (L) and the adjacent nonlepidic growth component representing invasive disease within individual tumors. Lineage relationships were evaluated by next-generation DNA sequencing to define large genomic rearrangements in microdissected tissue specimens collected by laser capture. We found a strong lineage relationship between the majority of adjacent lepidic and invasive components, supporting a putative AIS-AD transition. Notably, many rearrangements were detected in the less aggressive lepidic component, although the invasive component exhibited an overall higher rate of genomic rearrangement. Furthermore, a significant number of genomic rearrangements were present in histologically normal lung adjacent to tumor, but not in host germline DNA, suggesting field defects restricted to zonal regions near a tumor. Our results offer a perspective on the genetic pathogenesis underlying adenocarcinoma development and its clinical management.
authors.affiliation: Authors' Affiliations: Departments of Molecular Medicine, General Thoracic Surgery, Pulmonary and Critical Care Medicine, Health Sciences Research, and Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Murphy
authors.affiliation: Authors' Affiliations: Departments of Molecular Medicine, General Thoracic Surgery, Pulmonary and Critical Care Medicine, Health Sciences Research, and Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota.
authors.forename: Dennis A
authors.initials: DA
authors.lastname: Wigle
authors.affiliation: Authors' Affiliations: Departments of Molecular Medicine, General Thoracic Surgery, Pulmonary and Critical Care Medicine, Health Sciences Research, and Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota.
authors.forename: Joema Felipe
authors.initials: JF
authors.lastname: Lima
authors.affiliation: Authors' Affiliations: Departments of Molecular Medicine, General Thoracic Surgery, Pulmonary and Critical Care Medicine, Health Sciences Research, and Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota.
authors.forename: Faye R
authors.initials: FR
authors.lastname: Harris
authors.affiliation: Authors' Affiliations: Departments of Molecular Medicine, General Thoracic Surgery, Pulmonary and Critical Care Medicine, Health Sciences Research, and Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota.
authors.forename: Sarah H
authors.initials: SH
authors.lastname: Johnson
authors.affiliation: Authors' Affiliations: Departments of Molecular Medicine, General Thoracic Surgery, Pulmonary and Critical Care Medicine, Health Sciences Research, and Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota.
authors.forename: Geoffrey
authors.initials: G
authors.lastname: Halling
authors.affiliation: Authors' Affiliations: Departments of Molecular Medicine, General Thoracic Surgery, Pulmonary and Critical Care Medicine, Health Sciences Research, and Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota.
authors.forename: Michael K
authors.initials: MK
authors.lastname: Asiedu
authors.affiliation: Authors' Affiliations: Departments of Molecular Medicine, General Thoracic Surgery, Pulmonary and Critical Care Medicine, Health Sciences Research, and Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota.
authors.forename: Charlie T
authors.initials: CT
authors.lastname: Seto
authors.affiliation: Authors' Affiliations: Departments of Molecular Medicine, General Thoracic Surgery, Pulmonary and Critical Care Medicine, Health Sciences Research, and Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota.
authors.forename: Simone
authors.initials: S
authors.lastname: Terra
authors.affiliation: Authors' Affiliations: Departments of Molecular Medicine, General Thoracic Surgery, Pulmonary and Critical Care Medicine, Health Sciences Research, and Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota.
authors.forename: Farhad
authors.initials: F
authors.lastname: Kosari
authors.affiliation: Authors' Affiliations: Departments of Molecular Medicine, General Thoracic Surgery, Pulmonary and Critical Care Medicine, Health Sciences Research, and Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota.
authors.forename: Tobias
authors.initials: T
authors.lastname: Peikert
authors.affiliation: Authors' Affiliations: Departments of Molecular Medicine, General Thoracic Surgery, Pulmonary and Critical Care Medicine, Health Sciences Research, and Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MinnesotaAuthors' Affiliations: Departments of Molecular Medicine, General Thoracic Surgery, Pulmonary and Critical Care Medicine, Health Sciences Research, and Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota.
authors.forename: Ping
authors.initials: P
authors.lastname: Yang
authors.affiliation: Authors' Affiliations: Departments of Molecular Medicine, General Thoracic Surgery, Pulmonary and Critical Care Medicine, Health Sciences Research, and Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota vasmatzis.george@mayo.edu aubry.mariechristine@mayo.edu.
authors.forename: Marie-Christine
authors.initials: MC
authors.lastname: Aubry
authors.affiliation: Authors' Affiliations: Departments of Molecular Medicine, General Thoracic Surgery, Pulmonary and Critical Care Medicine, Health Sciences Research, and Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota vasmatzis.george@mayo.edu aubry.mariechristine@mayo.edu.
authors.forename: George
authors.initials: G
authors.lastname: Vasmatzis
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics* / Q000473:pathology*; D000077192:Adenocarcinoma of Lung; D019070:Cell Lineage; D015321:Gene Rearrangement; D006801:Humans; D008168:Lung / Q000473:pathology; D008175:Lung Neoplasms / Q000235:genetics* / Q000473:pathology*