title: RET mutation and expression in small-cell lung cancer.
abstract: BACKGROUND
  There is growing interest in defining the somatic mutations associated with small-cell lung cancer (SCLC). Unfortunately, a serious blockade to genomic analyses of this disease is a limited access to tumors because surgery is rarely performed. We used our clinical/pathologic database of SCLC patients to determine the availability of biopsy specimens that could be used for genomic studies and to identify tumors for initial oncogene analysis.
  
  
  METHODS
  DNA was extracted from six tumors, three primary and three metastatic, and analyzed by SEQUENOM platform technology.
  
  
  RESULTS
  Primary-resected tumor tissue represents less than 3% of all diagnostic specimens in this disease, highlighting the limited access to tissue sufficient for comprehensive genomic analyses. We identified an activating M918T RET somatic mutation in a metastatic SCLC tumor specimen. Bioinformatic search identified RET mutations in other SCLC studies. Stable overexpression of both mutant M918T and wild-type RET in two SCLC cell lines, H1048 and SW1271, activated ERK signaling, MYC expression, and increased cell proliferation, particularly by mutant RET. Stable cells became sensitized to the RET tyrosine kinase inhibitors, vandetanib and ponatinib. Further analysis of RET mRNA expression in SCLC revealed wide variability in both cells and tumors, and SCLC cells demonstrated significantly higher RET expression compared with adenocarcinoma lung cells.
  
  
  CONCLUSIONS
  Our data suggest that a subpopulation of SCLC patients may derive benefit from tyrosine kinase inhibitors targeting RET. Coupled with the presence of RET fusion proteins in non-small-cell lung cancer, our data indicate an emerging role for RET in SCLC.
authors.affiliation: *Division of Hematology and Oncology, Case Western Reserve University and University Hospitals Case Medical Center, Cleveland, Ohio; †Department of Medicine, MedStar Good Samaritan Hospital, Baltimore, Maryland; ‡Genetics and Genome Sciences, Case Western Reserve University, Cleveland, Ohio; §Division of Pathology, Case Western Reserve University and University Hospitals Case Medical Center, Cleveland, Ohio; and ‖Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, Washington.
authors.forename: Snehal
authors.initials: S
authors.lastname: Dabir
authors.forename: Shahab
authors.initials: S
authors.lastname: Babakoohi
authors.forename: Amy
authors.initials: A
authors.lastname: Kluge
authors.forename: James J
authors.initials: JJ
authors.lastname: Morrow
authors.forename: Adam
authors.initials: A
authors.lastname: Kresak
authors.forename: Michael
authors.initials: M
authors.lastname: Yang
authors.forename: David
authors.initials: D
authors.lastname: MacPherson
authors.forename: Gary
authors.initials: G
authors.lastname: Wildey
authors.forename: Afshin
authors.initials: A
authors.lastname: Dowlati
mesh_terms: D000368:Aged; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004252:DNA Mutational Analysis; D005500:Follow-Up Studies; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D008175:Lung Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D009154:Mutation; D051096:Proto-Oncogene Proteins c-ret / Q000235:genetics* / Q000378:metabolism; D012334:RNA, Neoplasm / Q000235:genetics*; D060888:Real-Time Polymerase Chain Reaction; D012189:Retrospective Studies; D015398:Signal Transduction; D055752:Small Cell Lung Carcinoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology
chemical_list: D012334:RNA, Neoplasm; D051096:Proto-Oncogene Proteins c-ret; C099282:RET protein, human