RET, ROS1 and ALK Fusions in Lung Cancer

Nat Med. 2012 Feb 12;18(3):378-81. doi: 10.1038/nm.2658.

Abstract

Through an integrated molecular- and histopathology-based screening system, we performed a screening for fusions of anaplastic lymphoma kinase (ALK) and c-ros oncogene 1, receptor tyrosine kinase (ROS1) in 1,529 lung cancers and identified 44 ALK-fusion-positive and 13 ROS1-fusion-positive adenocarcinomas, including for unidentified fusion partners for ROS1. In addition, we discovered previously unidentified kinase fusions that may be promising for molecular-targeted therapy, kinesin family member 5B (KIF5B)-ret proto-oncogene (RET) and coiled-coil domain containing 6 (CCDC6)-RET, in 14 adenocarcinomas. A multivariate analysis of 1,116 adenocarcinomas containing these 71 kinase-fusion-positive adenocarcinomas identified four independent factors that are indicators of poor prognosis: age ≥ 50 years, male sex, high pathological stage and negative kinase-fusion status.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3T3 Cells
  • Adenocarcinoma / genetics*
  • Adenocarcinoma / pathology
  • Adenocarcinoma of Lung
  • Adult
  • Age Factors
  • Aged
  • Aged, 80 and over
  • Anaplastic Lymphoma Kinase
  • Animals
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cell Transformation, Neoplastic / genetics
  • Cytoskeletal Proteins / genetics
  • Female
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Lung Neoplasms / genetics*
  • Lung Neoplasms / pathology
  • Male
  • Mice
  • Middle Aged
  • Neoplasm Staging
  • Oncogene Proteins, Fusion / genetics*
  • Piperidines / pharmacology
  • Prognosis
  • Protein-Tyrosine Kinases / genetics*
  • Proto-Oncogene Proteins / genetics*
  • Proto-Oncogene Proteins c-ret / genetics*
  • Quinazolines / pharmacology
  • Receptor Protein-Tyrosine Kinases / genetics*
  • Sex Factors

Substances

  • CCDC6 protein, human
  • Cytoskeletal Proteins
  • Oncogene Proteins, Fusion
  • Piperidines
  • Proto-Oncogene Proteins
  • Quinazolines
  • ALK protein, human
  • Alk protein, mouse
  • Anaplastic Lymphoma Kinase
  • Protein-Tyrosine Kinases
  • Proto-Oncogene Proteins c-ret
  • RET protein, human
  • ROS1 protein, human
  • Receptor Protein-Tyrosine Kinases
  • N-(4-bromo-2-fluorophenyl)-6-methoxy-7-((1-methylpiperidin-4-yl)methoxy)quinazolin-4-amine