Study Clarifies Molecular Mechanisms of RET Rearrangement
Contact: Rob Mansheim
IASLC Director of Communications
DENVER – Investigators have identified the molecular mechanisms underlying RET rearrangement, a genetic alteration recognized as a driver mutation in a small subset of lung adenocarcinoma. The findings of the study not only help increase the understanding of how RET fusions are generated but are also an important step toward designing better methods to detect RET fusions in lung cancer.
Oncogenic RET (rearranged during transfection) fusion is a novel druggable driver mutation in approximately 1-2% of patients with lung adenocarcinoma. An inversion in chromosome 10 has been identified as the cause of RET fusion, and typical fusion partners have been either KIF5B (kinesin family member 5B) or CCDC6 (coiled-coil domain containing 6). However, the mechanism(s) responsible for the rearrangement of the RET locus have not been identified to date.
To explore these mechanisms, Takashi Kohno, PhD, of the National Cancer Center Research Institute, Tokyo, and colleagues cloned genomic segments containing breakpoint junctions for RET fusions and analyzed the segments with genomic polymerase chain reaction and genome capture sequencing using a next-generation sequencer. They compared the structures of the RET fusions in adenocarcinoma with those that have been identified in papillary thyroid carcinoma, another tumor in which RET fusion has been shown to be a driver mutation.
"The data strongly suggest that most DNA breaks triggering RET fusions occur at nonspecific sites in defined regions of a few kb in size," says Dr. Kohno. "Furthermore, this seems to hold true irrespective of etiology and tumor type: the distribution of breakpoints was not significantly different between ever-smokers and never-smokers."
The investigators found that, in 17 (94%) of 18 lung adenocarcinoma specimens, the breakpoints in RET were located within a 2.0-kb region between exon 11 and intron 11, with no breakpoint occurring within 4 bp of another. The findings of the study are published in the May issue of the Journal of Thoracic Oncology (JTO), the official journal of the International Association for the Study of Lung Cancer.
"The information provided by this study should aid in the design of more sensitive methods to detect these rearrangements in lung adenocarcinoma samples," says Matthew L. Meyerson, MD, PhD, of Harvard Medical School and Brigham and Women’s Hospital, Boston, who coauthored an editorial to accompany the report. "The diagnosis of RET fusions is of increasing potential clinical importance because response to RET inhibitors has already been reported in some patients," adds Dr. Meyerson, who is a member of IASLC.
Takashi Nakano, MD, PhD, a coauthor of the study, is also an IASLC member.
About the IASLC:
The International Association for the Study of Lung Cancer (IASLC) is the only global organization dedicated to the study of lung cancer. Founded in 1974, the association’s membership includes more than 3,800 lung cancer specialists in 80 countries. To learn more about IASLC please visit www.iaslc.org.