title: Genomic profiling of multiple sequentially acquired tumor metastatic sites from an "exceptional responder" lung adenocarcinoma patient reveals extensive genomic heterogeneity and novel somatic variants driving treatment response.
abstract: We used next-generation sequencing to identify somatic alterations in multiple metastatic sites from an "exceptional responder" lung adenocarcinoma patient during his 7-yr course of ERBB2-directed therapies. The degree of heterogeneity was unprecedented, with ∼1% similarity between somatic alterations of the lung and lymph nodes. One novel translocation,PLAG1-ACTA2, present in both sites, up-regulated ACTA2 expression.ERBB2, the predominant driver oncogene, was amplified in both sites, more pronounced in the lung, and harbored an L869R mutation in the lymph node. Functional studies showed increased proliferation, migration, metastasis, and resistance to ERBB2-directed therapy because of L869R mutation and increased migration because of ACTA2 overexpression. Within the lung, a nonfunctional CDK12, due to a novel G879V mutation, correlated with down-regulation of DNA damage response genes, causing genomic instability, and sensitivity to chemotherapy. We propose a model whereby a subclone metastasized early from the primary site and evolved independently in lymph nodes.
authors.affiliation: Thoracic and Gastrointestinal Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland 20892, USA.
authors.forename: Romi
authors.initials: R
authors.lastname: Biswas
authors.affiliation: Thoracic and Gastrointestinal Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland 20892, USA.
authors.forename: Shaojian
authors.initials: S
authors.lastname: Gao
authors.affiliation: Thoracic and Gastrointestinal Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland 20892, USA.
authors.forename: Constance M
authors.initials: CM
authors.lastname: Cultraro
authors.affiliation: Thoracic and Gastrointestinal Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland 20892, USA.
authors.forename: Tapan K
authors.initials: TK
authors.lastname: Maity
authors.affiliation: Thoracic and Gastrointestinal Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland 20892, USA.
authors.forename: Abhilash
authors.initials: A
authors.lastname: Venugopalan
authors.affiliation: Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland 20892, USA.
authors.forename: Zied
authors.initials: Z
authors.lastname: Abdullaev
authors.affiliation: National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health, Bethesda, Maryland 20894, USA.
authors.forename: Alexey K
authors.initials: AK
authors.lastname: Shaytan
authors.affiliation: Walter Reed National Military Medical Center, Bethesda, Maryland 20889, USA.
authors.forename: Corey A
authors.initials: CA
authors.lastname: Carter
authors.affiliation: Thoracic and Gastrointestinal Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland 20892, USA.
authors.forename: Anish
authors.initials: A
authors.lastname: Thomas
authors.affiliation: Thoracic and Gastrointestinal Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland 20892, USA.
authors.forename: Arun
authors.initials: A
authors.lastname: Rajan
authors.affiliation: Genetics Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland 20892, USA.
authors.forename: Young
authors.initials: Y
authors.lastname: Song
authors.affiliation: Thoracic and Gastrointestinal Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland 20892, USA.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Pitts
authors.affiliation: Thoracic and Gastrointestinal Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland 20892, USA.
authors.forename: Kevin
authors.initials: K
authors.lastname: Chen
authors.affiliation: Cancer Genomics Research Laboratory, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Gaithersburg, Maryland 20848, USA.
authors.forename: Sara
authors.initials: S
authors.lastname: Bass
authors.affiliation: Cancer Genomics Research Laboratory, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Gaithersburg, Maryland 20848, USA.
authors.forename: Joseph
authors.initials: J
authors.lastname: Boland
authors.affiliation: Surgery Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland 20892, USA.
authors.forename: Ken-Ichi
authors.initials: KI
authors.lastname: Hanada
authors.affiliation: Laboratory of Cell Biology, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland 20892, USA.
authors.forename: Jinqiu
authors.initials: J
authors.lastname: Chen
authors.affiliation: Genetics Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland 20892, USA.
authors.forename: Paul S
authors.initials: PS
authors.lastname: Meltzer
authors.affiliation: National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health, Bethesda, Maryland 20894, USA.
authors.forename: Anna R
authors.initials: AR
authors.lastname: Panchenko
authors.affiliation: Surgery Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland 20892, USA.
authors.forename: James C
authors.initials: JC
authors.lastname: Yang
authors.affiliation: Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland 20892, USA.
authors.forename: Svetlana
authors.initials: S
authors.lastname: Pack
authors.affiliation: Lombardi Comprehensive Cancer Center, Georgetown University, Washington, D.C. 20057, USA.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Giaccone
authors.affiliation: Thoracic and Gastrointestinal Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland 20892, USA.
authors.forename: David S
authors.initials: DS
authors.lastname: Schrump
authors.affiliation: Genetics Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland 20892, USA.
authors.forename: Javed
authors.initials: J
authors.lastname: Khan
authors.affiliation: Thoracic and Gastrointestinal Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland 20892, USA.
authors.forename: Udayan
authors.initials: U
authors.lastname: Guha
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics* / Q000378:metabolism; D000077192:Adenocarcinoma of Lung; D015536:Down-Regulation; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D018734:Genes, erbB-2 / Q000235:genetics; D023281:Genomics; D059014:High-Throughput Nucleotide Sequencing / Q000379:methods; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009362:Neoplasm Metastasis / Q000235:genetics; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics* / Q000378:metabolism; D016896:Treatment Outcome
chemical_list: D018719:Erb-b2 Receptor Tyrosine Kinases; C508053:ERBB2 protein, human
keywords: neoplasm of the lung