Gene fusion in lung cancer afflicting never-smokers may be target for therapy

December 22, 2011

December 22, 2011 - Smoking is a well-known risk factor for lung cancer, but nearly 25% of all lung cancer patients have never smoked. In a study published online today in Genome Research (www.genome.org), researchers have identified a previously unknown gene fusion event that could explain a significant proportion of lung cancer cases in never-smokers, and might serve as a target for new therapies.

Recent strides have been made to identify gene mutation events driving cases of lung adenocarcinoma in never-smokers, but the underlying genetic events leading to these lung cancers still remain unknown in a large number of cases. In this report, using a combination of genome sequencing and RNA sequencing, a team of researchers in South Korea has characterized a previously unknown gene fusion event in a case of lung adenocarcinoma striking a 33-year-old Korean male with no history of smoking or cancer within his family.

The group sequenced and compared the genome of the patient's cancer and normal tissue (blood), but they found no mutations in known-cancer related genes, such as EGFR, KRAS, and EML4-ALK mutations, that were likely to explain this case. Delving deeper, they also sequenced RNA isolated from the cancer cells, which when analyzed, can reveal gene rearrangement events that are difficult to detect by genome sequencing and may be driving the cancer.

From the RNA sequencing analysis they built a list of candidate gene fusions, narrowing it down to a single gene fusion that could be a cancer-causing event. A genomic inversion event occurred on chromosome 10 in the cancer, fusing the KIF5B and RET genes. This fusion was particularly interesting because RET has been previously implicated in other gene fusion events known to drive thyroid cancers, and although it is normally expressed at low levels in the lung, chimeric RET in this patient is highly expressed. Furthermore, KIF5B contains a protein domain that is necessary for activation of the fusion gene.

They then confirmed that the KIF5B-RET fusion occurs in other lung cancer cases, finding two instances in twenty additional cases of lung cancer, indicating that this fusion event is not rare. The authors suggest that the KIF5B-RET fusion occurs in about 6% of all lung adenocarcinoma cases. The authors note that although further epidemiological studies are needed to accurately define the frequency of KIF5B-RET in lung cancers, they expect that the fusion gene may be a promising molecular target for treatment.

"We showed that genome sequencing technology could reveal a previously hidden cause of human cancer, which can be used as a therapeutic target for personal cancer therapy", said Dr. Jeong-Sun Seo, director of the Genomic Medicine Institute-Seoul National University, chairman of Macrogen Inc., and senior author of the study.
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Scientists from the Genomic Medicine Institute-Seoul National University (GMI-SNU; Seoul, South Korea), Seoul St. Mary's Hospital (Seoul, South Korea), Seoul National University Hospital (SNUH; Seoul South Korea), Macrogen Inc. (Seoul, South Korea) and Psoma Therapeutics Inc. (Seoul, South Korea) contributed to this study.

This work was supported by Macrogen Inc.

Media contacts:

The authors are available for more information by contacting Julie Yi, Press Officer at GMI-SNU (e-mail: nullepart@gmail.com; mobile: 82-10-8963-3652).

Interested reporters may obtain copies of the manuscript via email from Peggy Calicchia, Administrative Assistant, Genome Research (calicchi@cshl.edu).

About the article:

The manuscript will be published online ahead of print on December 22, 2011. Its full citation is as follows: Ju YS, Lee W, Shin J, Lee S, Bleazard T, Won J, Kim YT, Kim J, Kang J, Seo J. Fusion of KIF5B and RET transforming gene in lung adenocarcinoma revealed from whole-genome and transcriptome sequencing. Genome Res doi: 10.1101/gr.133645.111.

About Genome Research:

Launched in 1995, Genome Research (www.genome.org) is an international, continuously published, peer-reviewed journal that focuses on research that provides novel insights into the genome biology of all organisms, including advances in genomic medicine. Among the topics considered by the journal are genome structure and function, comparative genomics, molecular evolution, genome-scale quantitative and population genetics, proteomics, epigenomics, and systems biology. The journal also features exciting gene discoveries and reports of cutting-edge computational biology and high-throughput methodologies.

About Cold Spring Harbor Laboratory Press:

Cold Spring Harbor Laboratory is a private, nonprofit institution in New York that conducts research in cancer and other life sciences and has a variety of educational programs. Its Press, originating in 1933, is the largest of the Laboratory's five education divisions and is a publisher of books, journals, and electronic media for scientists, students, and the general public.

Genome Research issues press releases to highlight significant research studies that are published in the journal.

Cold Spring Harbor Laboratory

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