title: Both gene amplification and allelic loss occur at 14q13.3 in lung cancer.
abstract: OBJECTIVE
  Because loss of Nkx2-8 increases lung cancer in the mouse, we studied suppressive mechanisms in human lung cancer.
  
  
  METHODS
  NKX2-8 is located within 14q13.3, adjacent to its close relative TTF1/NKX2-1. We first analyzed LOH of 14q13.3 in forty-five matched human lung cancer and control specimens. DNA from tumors with LOH was then analyzed with high-density single-nucleotide polymorphism (SNP) arrays. For correlation with this genetic analysis, we quantified expression of Nkx2-8 and TTF1 mRNA in tumors. Finally, suppressive function of Nkx2-8 was assessed via colony formation assays in five lung cancer cell lines.
  
  
  RESULTS
  Thirteen of forty-five (29%) tumors had LOH. In six tumors, most adenocarcinomas, LOH was caused by gene amplification. The 0.8-Mb common region of amplification included MBIP, SFTA, TTF1, NKX2-8, and PAX9. In 4 squamous or adenosquamous cancers, LOH was caused by deletion. In three other tumors, LOH resulted from whole chromosome mechanisms (14(-), 14(+), or aneuploidy). The 1.2-Mb common region of deletion included MBIP, SFTA, TTF1, NKX2-8, PAX9, SLC25A21, and MIPOL1. Most tumors had low expression of Nkx2-8. Nevertheless, sequencing did not show NKX2-8 mutations that could explain the low expression. TTF1 overexpression, in contrast, was common and usually independent of Nkx2-8 expression. Finally, stable transfection of Nkx2-8 selectively inhibited growth of H522 lung cancer cells.
  
  
  CONCLUSIONS
  14q13.3, which contains NKX2-8, is subject to both amplification and deletion in lung cancer. Most tumors have low expression of Nkx2-8, and its expression can inhibit growth of some lung cancer cells.
authors.affiliation: Department of Pathology, Albert Einstein College of Medicine, Montefiore Medical Center, Bronx, New York 10461, USA.
authors.forename: Thomas
authors.initials: T
authors.lastname: Harris
authors.forename: Qiulu
authors.initials: Q
authors.lastname: Pan
authors.forename: Juan
authors.initials: J
authors.lastname: Sironi
authors.forename: Dionne
authors.initials: D
authors.lastname: Lutz
authors.forename: Jianmin
authors.initials: J
authors.lastname: Tian
authors.forename: Jana
authors.initials: J
authors.lastname: Sapkar
authors.forename: Roman
authors.initials: R
authors.lastname: Perez-Soler
authors.forename: Steven
authors.initials: S
authors.lastname: Keller
authors.forename: Joseph
authors.initials: J
authors.lastname: Locker
mesh_terms: D002282:Adenocarcinoma, Bronchiolo-Alveolar / Q000235:genetics* / Q000473:pathology; D001483:Base Sequence; D018196:Carcinoma, Adenosquamous / Q000235:genetics* / Q000473:pathology; D002294:Carcinoma, Squamous Cell / Q000235:genetics* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002883:Chromosomes, Human, Pair 14 / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics; D015536:Down-Regulation; D005784:Gene Amplification; D017353:Gene Deletion; D018628:Gene Dosage; D056726:Genetic Association Studies; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D019656:Loss of Heterozygosity; D008175:Lung Neoplasms / Q000235:genetics* / Q000473:pathology; D008969:Molecular Sequence Data; D017422:Sequence Analysis, DNA; D014157:Transcription Factors / Q000235:genetics*
chemical_list: D004268:DNA-Binding Proteins; D018398:Homeodomain Proteins; C108070:NKX2-8 protein, human; C504003:TTF1 protein, human; D014157:Transcription Factors