Smoking is a well-known risk factor for lung cancer , but nearly 25% of all lung cancer patients have never smoked. Ina study published online in Genome Research ( ), researchers have identified a previously unknown gene fusionevent that could explain a significant proportion of lung cancercases in never-smokers, and might serve as a target for newtherapies. Recent strides have been made to identify gene mutation eventsdriving cases of lung adenocarcinoma in never-smokers, but theunderlying genetic events leading to these lung cancers stillremain unknown in a large number of cases. In this report, using acombination of genome sequencing and RNA sequencing, a team ofresearchers in South Korea has characterized a previously unknowngene fusion event in a case of lung adenocarcinoma striking a33-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 cancerand normal tissue (blood), but they found no mutations inknown-cancer related genes, such as EGFR, KRAS, and EML4-ALKmutations, that were likely to explain this case. Delving deeper,they also sequenced RNA isolated from the cancer cells, which whenanalyzed, can reveal gene rearrangement events that are difficultto detect by genome sequencing and may be driving the cancer. From the RNA sequencing analysis they built a list of candidategene fusions, narrowing it down to a single gene fusion that couldbe a cancer-causing event. A genomic inversion event occurred onchromosome 10 in the cancer, fusing the KIF5B and RET genes.
Thisfusion was particularly interesting because RET has been previouslyimplicated in other gene fusion events known to drive thyroidcancers, and although it is normally expressed at low levels in thelung, chimeric RET in this patient is highly expressed.Furthermore, KIF5B contains a protein domain that is necessary foractivation of the fusion gene. They then confirmed that the KIF5B-RET fusion occurs in other lungcancer cases, finding two instances in twenty additional cases oflung cancer, indicating that this fusion event is not rare. Theauthors suggest that the KIF5B-RET fusion occurs in about 6% of alllung adenocarcinoma cases. The authors note that although furtherepidemiological studies are needed to accurately define thefrequency of KIF5B-RET in lung cancers, they expect that the fusiongene may be a promising molecular target for treatment.
"We showed that genome sequencing technology could reveal apreviously hidden cause of human cancer, which can be used as atherapeutic target for personal cancer therapy", said Dr. Jeong-SunSeo, director of the Genomic Medicine Institute-Seoul NationalUniversity, chairman of Macrogen Inc., and senior author of thestudy. Scientists from the Genomic Medicine Institute-Seoul NationalUniversity (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 PsomaTherapeutics Inc.
(Seoul, South Korea) contributed to this study. This work was supported by Macrogen Inc. Additional References Citations.
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