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Molecular mechanisms underlying oncogenic RET fusion in lung adenocarcinoma

Tatsuji Mizukami1, Kouya Shiraishi, Yoko Shimada

  • 1*Division of Genome Biology, National Cancer Center Research Institute, Tokyo, Japan; †Department of Radiation Oncology, Gunma University Graduate School of Medicine, Gunma, Japan; ‡Division of Pathology and Clinical Laboratories, National Cancer Center Hospital, Tokyo, Japan; §Division of Genetics, National Cancer Center Research Institute, Tokyo, Japan; and ¶Division of Cancer Genomics, National Cancer Center Research Institute, Tokyo, Japan.

Journal of Thoracic Oncology : Official Publication of the International Association for the Study of Lung Cancer
|April 12, 2014
PubMed
Abstract

Insights

Oncogenic RET fusions in lung adenocarcinoma are driven by illegitimate DNA repair mechanisms, distinct from those in thyroid cancer. These fusions arise from non-specific DNA breaks and various repair pathways.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Oncogenic RET fusion is a driver mutation in lung adenocarcinoma (LADC).
  • The molecular mechanisms behind RET gene rearrangement in lung cancer remain unclear.

Purpose of the Study:

  • To investigate the molecular mechanisms of RET gene rearrangement in lung adenocarcinoma.
  • To identify the DNA repair pathways involved in oncogenic RET fusion formation.

Main Methods:

  • Cloning and analysis of genomic segments containing RET fusion breakpoint junctions.
  • Utilizing genomic polymerase chain reaction and next-generation sequencing.
  • Studied 18 LADC cases, with 16 identified from 671 LADC cases.

Main Results:

  • RET fusion breakpoints predominantly occurred within a specific 2.0-kb region (exon 11 to intron 11).
  • DNA strand breaks at non-specific sites within this region appear to trigger RET fusion.
  • Nonhomologous end joining and break-induced replication were identified as key DNA repair mechanisms contributing to RET fusion.

Conclusions:

  • Oncogenic RET fusion in LADC involves multiple pathways.
  • Illegitimate repair of DNA strand breaks contributes to RET fusion in LADC.
  • The mechanisms differ from those observed in papillary thyroid carcinoma, despite RET fusion also being a driver mutation there.

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