A transforming kif5b and ret gene fusion software

The development of novel ret inhibitors with improved potency andor reduced toxicity is thus an unmet need. However, kif5bret fusion gene coincided with egfr or kras mutation in 6 patients. The kif5bret fusion gene contains the entire kinase domain of ret and resulted in increased ret kinase activity. This suggests that multiple kinase components of this kif5bret hub. This fusion gene overexpressed chimeric ret receptor tyrosine kinase, which spontaneously induced cellular transformation. Thus, a metaanalysis was conducted to evaluate the correlation of kif5b ret expression based on rtpcr detection with clinicopathological features and prognosis of lung cancer. This is a remarkable finding given that met is a known oncogenic driver of.

Identification of new alk and ret gene fusions from colorectal and. This study constructed and analyzed transgenic mice expressing kif5bret, the predominant form of ret fusion gene specific for. In this study, we investigated the molecular mechanisms underlying oncogenic ret fusion in ladcs. Eml4alkil3 8 d day0 day1 day2 day3 day4 day5 thi s fi n di ng f ur th er suppor t e d th e oncogen i c potential of kif5bret. Inflame fusion of the ret tyrosine kinase gene with kinesin family member 5b kif5b or coiledcoil domain containing 6 ccdc6 genes, resulting in constitutive activation. Identification of novel small molecule inhibitors of. Our results suggested that kif5bret fusion gene promoted cell invasion and migration, which were probably mediated through src signaling pathway. Immunohistochemical detection of eml4alk has proved difficult, however, likely as a result of low transcriptional activity conferred by the promoterenhancer region of eml4. Rxdx105 is a small molecule kinase inhibitor that potently inhibits ret.

The existence of kif5bret fusion gene was identified in 9 patients. Novel fusion transcripts in human gastric cancer revealed by transcriptome analysis. The sensitivity of eml4alk detection by immunohistochemistry should be increased adequately. After the alignment steps, the software can generate final gene fusion candidates and integrating our software into the pipeline will come very easily to you. Previously, we screened for alk, ros1, and ret fusion genes in 795 lung adenocarcinoma specimens and identified the novel kiaa1217 ret fusion gene containing kiaa1217 exon 11 and ret exon 11 7, 25 from a patient with a 4cm tumor mass figure figure1a, 1a, red arrow.

Apatinib exerted its anticancer effect not only via cytotoxicity, but also via inhibition of migration and invasion by suppressing ret src signaling pathway, supporting a potential role for apatinib. Driver kinase fusions in cancer tcga 4 th thannual scientific symposium may 12, 2015. Review article clinical and translational implications of ret. Jun 14, 2016 identification of the kiaa1217 ret fusion gene. Although many fusion detection tools encode their own filters in order to cut down on false positive calls, the criteria are most often based on read mapping quality and the. Our results suggested that kif5b ret fusion gene promoted cell invasion and migration, which were probably mediated through src signaling pathway. In this study, we verified the oncogenic activity of kif5bret fusion and investigated how kif5bret activates the specific signaling pathways for cellular transformation. Kif5b ret fusion is an oncogene identified in nonsmall cell lung cancers. Novel algorithm for rapid kinase gene fusion detection. Alectinib, an approved alk inhibitor, is reported to inhibit kif5bret and ccdc6ret.

Ret gene fusion variants are illustrated in figure 1. The transforming ability of the kif5bret fusion gene could be shown in preclinical models using baf3 cells, which were shown to grow interleukin3. About installation part, most of them including soapfuse, were mixed bag of different tools and hence installation was a pain. Ret expression and detection of kif5bret gene rearrangements. A graphical representation of wholegenome and transcriptome sequencing data from the liver metastatic lung cancer tissue. R12 was validated in 5 patients, and kif5b exon 22 fused to ret exon 12 k22. Coverage of cancer wholegenome sequencing is shown in the first middle layer. Oncogenic ptcret translocations detected in thyroid cancer and cell lines are sensitive in vitro and in vivo to ret inhibitors 16 19, suggested the possibility that sunitinib, sorafinib, vandetanib, or other ret inhibitors might. This suggests that multiple kinase components of this kif5b ret hub need to be simultaneously targeted therapeutically.

Precision targeted therapy with blu667 for retdriven. Fusion of kif5b and ret transforming gene in lung adenocarcinoma revealed from wholegenome and. Expression of cterminal alk, ret, or ros1 in lung cancer. These have been proven to be driver genes in some subgroups of lung cancers. Molecular mechanisms underlying oncogenic ret fusion in lung.

Ret fusions in chinese patients with nonsmall cell lung cancer kif5b. Research a transforming kif5b and ret gene fusion in lung adenocarcinoma revealed from wholegenome and transcriptome sequencing young seok ju,1,2. The first ret rearrangement identified in nsclc patients was an inframe fusion transcript of the kinesin family 5b gene kif5b with ret gene kif5b ret. In this study, we verified the oncogenic activity of kif5b ret fusion and investigated how kif5b ret activates the specific signaling pathways for cellular transformation. Discovery of a transforming kif5bmet fusion variant in nonsmall cell lung cancer. R12 variant of kif5bret fusion genetransformed cells into nude mice resulted in the development of the tumor in vivo, indicating the fusion genes oncogenic potential 6,7. Ju ys, lee wc, shin jy, lee s, bleazard t, won jk, kim yt, kim ji, kang jh and seo js. A transforming kif5b and ret gene fusion in lung adenocarcinoma. R12s did not grow in the absence of il3 although the fusion induced in the 3t3 cells clearly showed oncogenic. Rnaseq has the potential to discover such rearrangements generating functional proteins chimerafusion. Ret fusions in chinese patients with nonsmall cell.

Promise of vandetanib, a fdaapproved ret kinase inhibitor. Novel fusion transcripts in human gastric cancer revealed by. Kif5bret fusion is an oncogene identified in nonsmall cell lung cancers. For ros1, ncounter showed similar agreement with ihc and fish. Of 108 ffpe samples, 98 were successfully analyzed by ncounter 91%, which identified 55 fusionpositive cases 32 alk, 21 ros1, and 2 ret. The kif5bret fusion gene mutation as a novel mechanism of. Of 9 patients, 3 patients harbored wild type of egfr and kras gene. Kif5balk, a novel fusion oncokinase identified by an. Ju ys, lee wc, shin jy, lee s, bleazard t, won jk, et al. Beyond alkret, ros1 and other oncogene fusions in lung cancer. Eml4alkil3 8 d day0 day1 day2 day3 day4 day5 thi s fi n di ng f ur th er suppor t e d th e oncogen i c potential of kif5b ret. Fusion of kif5b and ret transforming gene in lung adenocarcinoma.

A transforming kif5b and ret gene fusion in lung adenocarcinoma revealed from wholegenome and transcriptome sequencing young seok ju, won chul lee, jong yeon shin, seungbok lee, thomas bleazard, jae kyung won, young tae kim, jong il kim, jin hyoung kang, jeong sun seo. To investigate the role of kif5b ret in lung tumorigenesis, we generated transgenic mice that specifically expressed the fusion gene in the lung. It was first identified in nonsmoking korean man as adenocarcinoma by wholegenome and transcriptome sequencing 7. Integrated analysis of dna methylation and microrna. Kif5b ret fusion gene may coincide oncogenic mutations of egfr or kras gene in lung adenocarcinomas diagnostic pathology, aug 2015 jeongoh kim, jieun lee, jungyoung shin, jieun oh, chankwon jung, jae park, sookwhan sung, sangju bae, hyunjung min, dowon kim, et al. Oncogenic ptc ret translocations detected in thyroid cancer and cell lines are sensitive in vitro and in vivo to ret inhibitors 16 19, suggested the possibility that sunitinib, sorafinib, vandetanib, or other ret inhibitors might. Jul 21, 2014 our results have consolidated the role of kif5b ret fusion gene in the pathogenesis of nsclc and identified stat3 as a key mediator of the transforming activity of kif5b ret positive lung cancer cells. Molecular mechanisms underlying oncogenic ret fusion in. Ret gene rearrangement results in fusing the ret kinase domain with another protein that contains dimerisation domains, leading to ligandindependent ret activation. Kohno t, ichikawa h, totoki y, yasuda k, hiramoto m, nammo t, et al. However, by performing effective filtering, sensitive and accurate gene fusion detection is possible. Ret fusions have been found in lung adenocarcinoma, of which kif5bret is the most prevalent.

Ret fusions have been found in lung adenocarcinoma, of which kif5b ret is the most prevalent. However, the activity of alectinib with respect to ret with other fusion partners is unknown. In addition, this drug interferes with other pathways that also cause cancer cells to grow, form new blood vessels, and spread to other parts of. We established inducible kif5bret transgenic mice and kif5bretdependent cell lines for preclinical. Gene fusion in lung cancer afflicting neversmokers may be. Kif5bret fusion protein regulates stat3 activation at multilevels which may target cyclind1 and play a key role in oncogenesis. We established inducible kif5bret transgenic mice and kif5bretdependent cell lines for preclinical modeling of kif5bret associated lung adenocarcinoma. The kif5bret rearrangement is detected with the frequency of 1 2 % in triple markernegative lung adenocarcinomas, i. Oncogenic ptcret translocations detected in thyroid cancer and cell lines are sensitive in vitro and in vivo to ret inhibitors 16 19, suggested the possibility that sunitinib, sorafinib, vandetanib, or other ret inhibitors. The first ret rearrangement identified in nsclc patients was an inframe fusion transcript of the kinesin family 5b gene kif5b with ret gene kif5bret. Kif5bret is a novel fusion gene of the kinesin family member 5b gene.

R12 cdna, the most frequently occurring ret fusion variant,19, the spc promoter, an rna splicing cassette, and a polyadenylation signal. Novel fusion transcripts in human gastric cancer revealed. This transforming gene arise from the fusion of kif5b and the ret protooncogene, and it is mutually exclusive with egfr, kras and eml4alk alterations. Oncogenic fusion of the ret rearranged during transfection gene was recently identified as a novel driver gene aberration not only for the development of thyroid carcinoma but also of lung adenocarcinoma, the most frequent histological type of lung cancer. We established inducible kif5b ret transgenic mice and kif5b ret dependent cell lines for preclinical. Kif5b ret fusion protein regulates stat3 activation at multilevels which may target cyclind1 and play a key role in oncogenesis. Mar 01, 2017 c, targetspecific oligonucleotide probes n 47 designed for simultaneous detection of aberrant transcripts and housekeeping genes.

Gene fusions arising from chromosomal translocations have been implicated in cancer. The recent association of four oncogenic driver genes, alk, ros1, ret, and ntrk1, as lung tumor predictive biomarkers has increased the need for development of uptodate technologies for detection of these biomarkers in limited amounts of material. A transforming kif5b and ret gene fusion in lung adenocarcinoma revealed from wholegenome and transcriptome sequencing. A transforming kif5b and ret genefusion in lung adenocarcinoma revealed from wholegenome and transcriptome sequencing. Mar 18, 2016 this fusion gene overexpressed chimeric ret receptor tyrosine kinase, which spontaneously induced cellular transformation.

Kif5b ret is a novel fusion gene of the kinesin family member 5b gene kif5b and the rearranged during transfection gene ret resulting from the chromosome inversion inv 10 p11. Eml4alk is a transforming fusion tyrosine kinase, several isoforms of which have been identified in lung cancer. Aug 14, 2015 moreover, the correlation of kif5bret fusion gene with smoking is still ambiguous. Moreover, the correlation of kif5bret fusion gene with smoking is still ambiguous. Research open access kif5bret fusion kinase promotes.

Antitumor activity of rxdx105 in multiple cancer types. New targetable oncogenes in nonsmallcell lung cancer. Other upstream fusion partners for ret rearrangement have been identified in nsclc, such as the coiledcoil domaincontaining protein 6 ccdc6, the nuclear receptor coactivator 4 ncoa4. The transformed kif5bret a549 cells were treated either with. Apatinib inhibits cellular invasion and migration by. Lung cancer in nonsmokers tends to be driven by a single somatic mutation or a gene fusion. Full text 1p19q codeletion and ret rearrangements in. Identification of a novel partner gene, kiaa1217, fused to. Our results have consolidated the role of kif5b ret fusion gene in the pathogenesis of nsclc and identified stat3 as a key mediator of the transforming activity of kif5b ret positive lung cancer cells. Kif5bret oncoprotein signals through a multikinase.

The kif5b ret fusion gene is a novel oncogene that has been observed in a subset of lung cancers in recent years. To elucidate clinicopathological characteristics of nonsmallcell lung carcinoma nsclc cases carrying ret rearrangements causing oncogenic. Isolation of supporting reads optimized for sensitivity and speed large speed improvement over public algorithms. In vitro and in vivo antitumor activity of alectinib in. These mutational changes are known to be mutually exclusive, but the coexistence of alk rearrangement with activating mutations of egfr is rarely found. Introduction the rearranged during transfection ret gene was discovered in 1985 as an oncogene produced by recombination during the transfection of nih 3t3 cells with human lymphoma dna 1. Gene fusion events resulting from chromosomal rearrangements play an important role in initiation of lung adenocarcinoma. R12 variant of kif5bret fusion genetransformed cells into nude mice resulted in the development of the tumor in vivo, indicating the fusion genes oncogenic potential 6, 7. This catalog of aggregated evidence for the ret gene is pulled from civic, genetic home reference, clinical genomic database and ncbi figure 2. Driver mutations in other genes including egfr, kras, her2, braf. Our results have consolidated the role of kif5bret fusion gene in the pathogenesis of nsclc and identified stat3 as a key mediator of the transforming activity of kif5bret positive lung cancer cells. Nov 18, 20 novel fusion transcripts in human gastric cancer revealed by transcriptome analysis. Supplementary information ret, ros1, and alk fusions in lung. Apatinib inhibits cellular invasion and migration by fusion.

The ret gene was fused to the kif5b and ccdc6 genes in 12% of ladc cases 68. A new ret fusion gene has been recently described in a subset of nonsmall cell lung cancer nsclc identified by specific clinicopathologic characteristics. Doxycyclineinduced ccsprttatetokif5bret transgenic mice developed invasive lung adenocarcinoma with desmoplastic reaction. This transforming gene arise from the fusion of kif5b and the ret protooncogene, and it is mutually exclusive with. Kif5bret fusion molecules and uses thereof foundation. Kif5bret fusion gene analysis in a selected series of. Successful targeting of the nrg1 pathway indicates novel. Recently, many methods for chimeras detection have been published.

The patient initiated treatment with 200 mg once daily blu667, and ctdna analysis at baseline revealed a canonical kif5bret fusion and cooccurring tp53 mutation. Identification of new alk and ret gene fusions from colorectal and lung cancer biopsies. Jul 12, 2012 the kif5bret fusion gene contains the entire kinase domain of ret and resulted in increased ret kinase activity. The breakpoints in these regions were dispersed at intervals. A phase ii study of cabozantinib in patients with advanced. Kif5bret fusion kinase promotes cell growth by multilevel. In 2012, oncogenic fusion of the ret gene, a driver of thyroid carcinogenesis, was rediscovered in a small subset of lung cancer by several groups. Many studies have reported genomic driver mutations in nonsmall cell. Full title a phase ii study of cabozantinib in patients with ret fusionpositive advanced nonsmall cell lung cancers purpose kif5bret is an abnormal gene that leads to the growth of lung cancer cells. These results suggest that alectinib may be a promising ret inhibitor against tumors positive for not only kif5b ret and ccdc6 ret, but also ncoa4 ret. To elucidate clinicopathological characteristics of nonsmallcell lung carcinoma nsclc cases carrying ret rearrangements causing oncogenic fusions to identify responders to therapy with ret. A kinesin family member 5b kif5bmet protooncogene, receptor tyrosine. Given the unprecedented sensitivity of gene fusion detection, and the repeated identification of fusion transcripts in normal cells, it is increasingly important to separate driver fusions from passenger mutations. Although we found the fusion gene in a small number of samples, the evidence for its transforming role is convincing for the following reasons.

However, the results of related epidemiological studies remain unclear. Fusion gene of kif5b gene and ret gene, and method for. Gene fusions are increasingly recognized as important cancer drivers. Identification of alk, ros1, and ret fusions by a multiplexed. Full text targeting retrearranged nonsmallcell lung. Discovery of novel transforming kif5b ret fusion gene in lung adenocarcinoma. Doxycyclineinduced ccsprttatetokif5bret transgenic mice developed invasive lung adenocarcinoma with desmoplastic. Kif5bret fusion gene may coincide oncogenic mutations of. Representative driver oncogenes include egfr, kras, braf, and. The cancer showed no known driver mutation in egfr or kras and no eml4 alk fusion. Oncogenic function of a kif5bmet fusion variant in nonsmall. Supplementary information ret, ros1, and alk fusions in. Ju ys, lee w, shin j, lee s, bleazard t, won j, kim yt, kim j, kang j, seo j.

Research open access kif5bret fusion kinase promotes cell. We examined the kif5bret fusion gene in frozen tissues from 154 surgically. Previously, we screened for alk, ros1, and ret fusion genes in 795 lung adenocarcinoma specimens and identified the novel kiaa1217ret fusion gene containing kiaa1217 exon 11 and ret exon 11 7, 25 from a patient with a 4cm tumor mass figure figure1a, 1a, red arrow. Full title a phase ii study of cabozantinib in patients with ret fusion positive advanced nonsmall cell lung cancers purpose kif5b ret is an abnormal gene that leads to the growth of lung cancer cells. These six pts were also positive for both ret breakapart probes 23. In the present study, we investigated the effects of alectinib on ncoa4ret fusionpositive tumor cells in vitro and in vivo. Apatinib exerted its anticancer effect not only via cytotoxicity, but also via inhibition of migration and invasion by suppressing retsrc signaling pathway, supporting a potential role for apatinib. The frequency and clinical implication of ros1 and ret.

We examined the kif5bret fusion gene in frozen tissues from 154. The kif5b ret fusion gene contains the entire kinase domain of ret and resulted in increased ret kinase activity. Integrative genome analyses identify key somatic driver mutations of. While multikinase inhibitors with ret activity are active in ret rearranged thyroid and lung cancers, objective response rates are relatively low and toxicity can be substantial. Research a transforming kif5b and ret gene fusion in lung adenocarcinoma revealed from wholegenome and transcriptome sequencing young seok ju,1,2 wonchul lee,1,3 jongyeon shin,1,4 seungbok lee. Ret fusions in chinese patients with nonsmall cell lung cancer cai, weijing. Hematoxylin and eosin staining revealed an adenocarcinoma with a. Kif5bret fusion gene may coincide oncogenic mutations of egfr or kras gene in lung adenocarcinomas diagnostic pathology, aug 2015 jeongoh kim, jieun lee, jungyoung shin, jieun oh, chankwon jung, jae park, sookwhan sung, sangju bae, hyunjung min, dowon kim, et al. The kif5b ret gene has been identified as a primary driver in a subset of lung a.