title: Common Oncogene Mutations and Novel SND1-BRAF Transcript Fusion in Lung Adenocarcinoma from Never Smokers.
abstract: Lung adenocarcinomas from never smokers account for approximately 15 to 20% of all lung cancers and these tumors often carry genetic alterations that are responsive to targeted therapy. Here we examined mutation status in 10 oncogenes among 89 lung adenocarcinomas from never smokers. We also screened for oncogene fusion transcripts in 20 of the 89 tumors by RNA-Seq. In total, 62 tumors had mutations in at least one of the 10 oncogenes, including EGFR (49 cases, 55%), K-ras (5 cases, 6%), BRAF (4 cases, 5%), PIK3CA (3 cases, 3%), and ERBB2 (4 cases, 5%). In addition to ALK fusions identified by IHC/FISH in four cases, two previously known fusions involving EZR- ROS1 and KIF5B-RET were identified by RNA-Seq as well as a third novel fusion transcript that was formed between exons 1-9 of SND1 and exons 2 to 3' end of BRAF. This in-frame fusion was observed in 3/89 tested tumors and 2/64 additional never smoker lung adenocarcinoma samples. Ectopic expression of SND1-BRAF in H1299 cells increased phosphorylation levels of MEK/ERK, cell proliferation, and spheroid formation compared to parental mock-transfected control. Jointly, our results suggest a potential role of the novel BRAF fusion in lung cancer development and therapy.
authors.affiliation: Departments of Medicine, Division of Pulmonary and Critical Care Medicine, Mayo Clinic, Rochester, MN.
authors.forename: Jin Sung
authors.initials: JS
authors.lastname: Jang
authors.affiliation: Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN.
authors.forename: Adam
authors.initials: A
authors.lastname: Lee
authors.affiliation: Departments of Medicine, Division of Pulmonary and Critical Care Medicine, Mayo Clinic, Rochester, MN.|Department of Oncology and Hematology, China-Japan Union Hospital of Jilin University, Jilin, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Li
authors.affiliation: Sequenom, Inc., San Diego, CA, USA.
authors.forename: Hema
authors.initials: H
authors.lastname: Liyanage
authors.affiliation: Departments of Medicine, Division of Pulmonary and Critical Care Medicine, Mayo Clinic, Rochester, MN.
authors.forename: Yanan
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Departments of Medicine, Division of Pulmonary and Critical Care Medicine, Mayo Clinic, Rochester, MN.
authors.forename: Lixia
authors.initials: L
authors.lastname: Guo
authors.affiliation: Health Science Research, Mayo Clinic, Rochester, MN.
authors.forename: Yan W
authors.initials: YW
authors.lastname: Asmann
authors.affiliation: Health Science Research, Mayo Clinic, Rochester, MN.
authors.forename: Peter W
authors.initials: PW
authors.lastname: Li
authors.affiliation: Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN.
authors.forename: Michele
authors.initials: M
authors.lastname: Erickson-Johnson
authors.affiliation: Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN.
authors.forename: Yuta
authors.initials: Y
authors.lastname: Sakai
authors.affiliation: Health Science Research, Mayo Clinic, Rochester, MN.
authors.forename: ZhiFu
authors.initials: Z
authors.lastname: Sun
authors.affiliation: Molecular Diagnostics and Imaging Center, School of Medicine, Kyungpook National University, Daegu, Korea.
authors.forename: Hyo-Sung
authors.initials: HS
authors.lastname: Jeon
authors.affiliation: New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation, Daegu, Korea.
authors.forename: Hayoung
authors.initials: H
authors.lastname: Hwang
authors.affiliation: Departments of Medicine, Division of Pulmonary and Critical Care Medicine, Mayo Clinic, Rochester, MN.
authors.forename: Aaron O
authors.initials: AO
authors.lastname: Bungum
authors.affiliation: Departments of Medicine, Division of Pulmonary and Critical Care Medicine, Mayo Clinic, Rochester, MN.
authors.forename: Eric S
authors.initials: ES
authors.lastname: Edell
authors.affiliation: Gene Expression Core, Mayo Clinic, Rochester, MN.
authors.forename: Vernadette A
authors.initials: VA
authors.lastname: Simon
authors.affiliation: Biospecimen Accessioning and Processing Core, Mayo Clinic, Rochester, MN.
authors.forename: Karla J
authors.initials: KJ
authors.lastname: Kopp
authors.affiliation: DNA Sequencing Core, Mayo Clinic, Rochester, MN.
authors.forename: Bruce
authors.initials: B
authors.lastname: Eckloff
authors.affiliation: Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN.
authors.forename: Andre M
authors.initials: AM
authors.lastname: Oliveira
authors.affiliation: DNA Sequencing Core, Mayo Clinic, Rochester, MN.
authors.forename: Eric
authors.initials: E
authors.lastname: Wieben
authors.affiliation: Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN.
authors.forename: Marie Christine
authors.initials: MC
authors.lastname: Aubry
authors.affiliation: Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN.
authors.forename: Eunhee
authors.initials: E
authors.lastname: Yi
authors.affiliation: Thoracic Surgery, Mayo Clinic, Rochester, MN.
authors.forename: Dennis
authors.initials: D
authors.lastname: Wigle
authors.affiliation: Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN.
authors.forename: Robert B
authors.initials: RB
authors.lastname: Diasio
authors.affiliation: Health Science Research, Mayo Clinic, Rochester, MN.
authors.forename: Ping
authors.initials: P
authors.lastname: Yang
authors.affiliation: Departments of Medicine, Division of Pulmonary and Critical Care Medicine, Mayo Clinic, Rochester, MN.|Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN.|Gene Expression Core, Mayo Clinic, Rochester, MN.
authors.forename: Jin
authors.initials: J
authors.lastname: Jen
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000077192:Adenocarcinoma of Lung; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor; D004720:Endonucleases; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D023061:Gene Order; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008875:Middle Aged; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009154:Mutation; D009367:Neoplasm Staging; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D015514:Oncogene Proteins, Fusion / Q000235:genetics* / Q000378:metabolism; D009857:Oncogenes; D010766:Phosphorylation; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics* / Q000378:metabolism; D015203:Reproducibility of Results; D014158:Transcription, Genetic
chemical_list: D014408:Biomarkers, Tumor; D009687:Nuclear Proteins; D015514:Oncogene Proteins, Fusion; D048493:Proto-Oncogene Proteins B-raf; D048049:Extracellular Signal-Regulated MAP Kinases; D020928:Mitogen-Activated Protein Kinases; D004720:Endonucleases; C095221:SND1 protein, human