Molecular mechanisms underlying oncogenic RET fusion in lung adenocarcinoma

J Thorac Oncol. 2014 May;9(5):622-30. doi: 10.1097/JTO.0000000000000135.

Abstract

Background: Oncogenic RET fusion, caused by an inversion in chromosome 10, was recently identified as a driver mutation for the development of lung adenocarcinoma (LADC). Nevertheless, the molecular mechanism(s) underlying the rearrangement of the RET locus during lung carcinogenesis are unknown.

Methods: Genomic segments containing breakpoint junctions for RET fusions were cloned and analyzed by genomic polymerase chain reaction and genome capture sequencing using a next-generation sequencer to identify the mechanisms involved in DNA strand breaks and illegitimate joining of DNA ends. Of the 18 cases studied, 16 were identified by screening 671 LADC cases and two were previously published.

Results: Almost all (17 of 18, 94%) of the breakpoints in RET were located within a 2.0-kb region spanning exon 11 to intron 11 and no breakpoint occurred within 4 bp of any other. This suggested that as in papillary thyroid carcinoma, DNA strand breaks formed at nonspecific sites within this region trigger RET fusion. Just over half of the RET fusions in LADC (10 of 18, 56%) were caused by simple reciprocal inversion, and two DNA-repair mechanisms, namely nonhomologous end joining and break-induced replication, were deduced to have contributed to the illegitimate joining of the DNA ends.

Conclusions: Oncogenic RET fusion in LADC occurs through multiple pathways and involves the illegitimate repair of DNA strand breaks through mechanisms different from those identified in papillary thyroid carcinoma, where RET fusion also functions as a driver mutation.

MeSH terms

  • Adenocarcinoma / genetics*
  • Adenocarcinoma / pathology
  • Carcinogenesis / genetics*
  • Chromosome Breakpoints*
  • Chromosome Inversion*
  • Cytoskeletal Proteins / genetics
  • DNA End-Joining Repair
  • DNA, Neoplasm / genetics
  • Exons
  • Genetic Variation
  • Humans
  • Introns
  • Kinesin / genetics
  • Lung Neoplasms / genetics*
  • Lung Neoplasms / pathology
  • Molecular Sequence Data
  • Oncogene Proteins, Fusion / genetics*
  • Proto-Oncogene Proteins c-ret / genetics*

Substances

  • CCDC6 protein, human
  • Cytoskeletal Proteins
  • DNA, Neoplasm
  • KIF5B protein, human
  • Oncogene Proteins, Fusion
  • Proto-Oncogene Proteins c-ret
  • RET protein, human
  • Kinesin