Oncogenic Gene Fusions Found in Some Types of Lung Cancer

A certain subset of lung adenocarcinomas (a form of non-small-cell lung cancer) are triggered by a mutation that creates oncogenic "fusion genes.”

Investigators at the Dana-Farber Cancer Institute (Boston, MA, USA) and the University of Colorado Cancer Center (Denver, USA) performed next-generation DNA sequencing on tumor samples taken from 36 patients with lung adenocarcinomas whose tumors did not contain any previously known oncogenic mutations. They found that in samples taken from two female nonsmokers a region of the NTRK1 (neurotrophic tyrosine kinase receptor type 1) gene had become fused to normally distant genes (to the MPRIP gene in one patient and the CD74 gene in the other).

NTRK1 encodes the protein TrkA, which is the high affinity catalytic receptor for the neurotrophin NGF (nerve growth factor). As such, it mediates the multiple effects of NGF, which include neuronal differentiation and avoidance of programmed cell death. The fusion of NTRK1 to a second gene resulted in constant TRKA kinase activity, which was oncogenic. Treatment of cells expressing NTRK1 fusions with inhibitors of TRKA kinase activity inhibited autophosphorylation of TRKA and blocked cell growth.

Overall, tumor samples from 91 patients with lung cancers without known oncogenic alterations were assayed by next-generation sequencing or fluorescence in situ hybridization (FISH). Results published in the October 27, 2013, online edition of the journal Nature Medicine revealed that three of the samples (3.3%) demonstrated evidence of NTRK1 gene fusions.

"These findings suggest that in a few percent of lung adenocarcinoma patients—people in whose cancer cells we had previously been able to find no genetic abnormality—tumor growth is driven by a fusion involving NTRK1," said contributing author Dr. Pasi A. Jänne, associate professor of medicine at the Dana- Farber Cancer Institute. "Given that lung cancer is a common cancer, even a few percent is significant and translates into a large number of patients. Our findings suggest that targeted therapies may be effective for this subset of lung cancer patients."

"Treatment with targeted therapies is now superior to standard chemotherapy for many patients with lung cancers that harbor genetic changes including those with fusions involving the gene ALK,” said Dr. Jänne. “We know of several other genes that are fused in lung cancer and that offer attractive targets for new therapies. Our discovery places lung adenocarcinomas with NTRK1 fusions squarely within that group."

Related Links:
Dana-Farber Cancer Institute
University of Colorado Cancer Center