New Mutation May Act as Driver in Subset of Lung Cancer Patients

A study has identified a gene fusion from a never-smoker lung cancer patient that may act as a driver in a subset of lung cancer cases. The study comes from a team of researchers from the Seoul National University College of Medicine in South Korea and Macrogen, a Korean genomics firm, and was published in Genome Research (doi:10.1101/gr.133645.111).

Representation of adenocarcinoma

The fusion was identified from sequencing the genome and transcriptome of cancerous tissue and normal tissue from a 33-year-old lung adenocarcinoma patient who has never smoked and does not have a familial cancer history. While the sequencing did not show an EGFR, KRAS, or EML4-ALK mutation that are known drivers of lung cancer, a novel fusion gene between the KIF5B and the RET genes, both on chromosome 10, was identified.

This fusion gene over-expresses the chimeric RET receptor tyrosine kinase that can spontaneously lead to cellular transformation. The RET gene is a proto-oncogene that may be a new molecular target for treatment of lung cancer, according to the authors. The oncogenic effect of the RET gene was identified in papillary thyroid carcinoma and documentation of a RET mutation in lung cancer. The study confirmed that the KIF5B-RET fusion was present not only in the liver metastasis and bone metastasis but also in the patient’s primary lung.

"Our data demonstrate that a subset of [non–small-cell lung cancers] could be caused by a fusion of KIF5B and RET, and suggest the chimeric oncogene as a promising molecular target for the personalized diagnosis and treatment of lung cancer," wrote the authors.

While there are known mutational drivers of lung cancer, including the newly identified EML4-ALK fusion for which there is now a targeted treatment, crizotonib, approved for metastatic lung cancer in 2011, drivers of approximately 40% of non–small-cell lung cancers (NSCLCs) are not known. Identifying the molecular events that result in cancer transformation is necessary for developing novel and promising targeted treatments.

Approximately 25% of lung cancers worldwide originate in people that have never smoked. Lung cancers of never-smokers tend to be driven by a single somatic mutation. In Asia, never-smokers comprise 30% to 40% of NSCLC. The aim of the authors was to identify the genetic features that may predispose nonsmokers to lung cancer.

The same KIF5B-RET fusion was also identified in two of the twenty primary lung adenocarcinomas that were negative for EGFR and EML4-ALK in a follow-up. The results suggest that the newly identified fusion is not that rare and that the mutation exists in primary lung adenocarcinomas. Furthermore, identification of the mutation in different cancer tissues provides evidence, albeit indirect, that this newly identifiable fusion may be a driver of lung cancer.