Yu Hikosaka

Nagoya City University, Nagoya, Aichi, Japan

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Publications (48)52.29 Total impact

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    ABSTRACT: The number of cases of wedge resection of small-sized pulmonary nodules performed under video-assisted thoracoscopic surgery (VATS) is increasing. Computed tomography (CT)-guided marking with hook wires has been used to locate the nodules that are not identifiable under VATS. However, this method is invasive and is associated with a risk of complications.
    Surgery Today 10/2014; · 0.96 Impact Factor
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    ABSTRACT: Objectives Thymic carcinoma is a rare mediastinal neoplasm and little is known about its tumorigenesis. There is no effective treatment except for complete resection, and the prognosis of advanced cases is poor. To identify the mutations associated with tumorigenesis, we analyzed genetic profile of thymic carcinoma using targeted Next-Generation Sequencing. Materials and Methods We sequenced about 409 cancer related genes in 12 thymic squamous cell carcinoma tissues including 10 tumor/normal tissue pairs using Ion AmpliSeq Cancer Panel and Ion PGM Sequencer. We filtered the mutations with Ingenuity Variant Analysis, SIFT, PolyPhen-2, and PROVEAN. Results and Conclusion Twenty five candidate mutations in 24 genes were identified, including six tyrosine kinase genes (KIT, DDR2, PDGFRA, ROS1, IGF1R). There was no recurrent mutation among the samples studied. The KIT exon 11 deletion mutation in 1 patient was an activating mutation and may be an oncogenic driver mutation. Genetic profiling of thymic carcinoma using targeted next-generation sequencing was performed. The mutation status of thymic squamous cell carcinoma is highly heterogeneous.
    Lung Cancer 09/2014; · 3.39 Impact Factor
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    ABSTRACT: Advances in the molecular segmentation of lung cancer has raised the possibility that neurotrophic tyrosine kinase receptor (NTRK) 1 fusions and NTRK1-3 expression may be promising molecular targets for future therapeutic interventions. We investigated the antitumor effects of a selective pan-NTRK inhibitor, AZD7451, by evaluating its antiproliferative effects on the KM12 cell line (a colorectal cancer cell line harboring a tropomyosin-NTRK1 fusion) and the H460 and H810 cell lines [large-cell neuroendocrine carcinoma (LCNEC) cell lines expressing NTRK2]. Relative quantitative polymerase chain reaction (qPCR) was performed to measure the mRNA levels of the NTRK1-3 tyrosine kinase domain using cDNA extracted from KM12, H460 and H810 cells. The cultures were grown in 6-well plates at a density of 1.0×10(6) cell/well and treated with AZD7451 at different doses (1, 2.5, 4, 5, 7.5 and 10 nM) using dimethyl sulfoxide as a control. Following a 24-h incubation, the number of surviving cells was measured using a hemocytometer. Furthermore, we performed western blotting of the high-affinity nerve growth factor receptor (TRKA) and NTRK2 (TRKB) proteins and monitored the effects on the downstream signaling pathways Akt and ERK in these cell lines following treatment with AZD7451 (KM12 and H460: 0, 1 and 5 nM; H810: 0 and 5 nM). Immunohistochemical analyses of the surgically resected samples were also performed, using anti-NTRK1,2 antibodies. We performed reverse-transcription PCR and direct sequencing to investigate NTRK fusions in 268 patients; however, were unable to confirm the presence of NTRK fusions in this cohort. Further immunohistochemical analyses of the primary patient samples demonstrated that none of 61 tumors had NTRK1 overexpression and 7 of 39 samples exhibited NTRK2 expression, including 1 LCNEC sample. The qPCR results from the KM12 cell line revealed an apparent increase and overexpression of NTRK1 mRNA levels, while H460 cells exhibited a modest increase and the H810 cell line showed no apparent increase in the expression of any NTRK1-3 isoforms. There were no increases in the NTRK2 mRNA levels in any of the three cell lines, although KM12 and H460 cells exhibited low levels of NTRK2 expression. In vitro growth and proliferation of the KM12 cell line harboring the NTRK1-fusion was found to be potently inhibited by AZD7451 at a concentration of 2 nM. The proliferation of H460 cells was also found to be inhibited at a concentration of 5 nM, while there was no apparent inhibitory effect of AZD7451 on the growth or proliferation of H810 cells. Western blotting of KM12 cells treated with AZD7451 also revealed a potent inhibition of TRKA phosphorylation following AZD7451 treatment. Analysis of H460 cells confirmed the expression and inhibition of phosphorylation of NTRK2, whereas there was little to no expression of TRKA/B in H810 cells. Subsequent in vitro analysis of cell lines treated with the pan-TRK inhibitor AZD7451 suggested that the proliferation of KM12 and H460 cells was significantly inhibited by AZD7451, while H810 cells expressing low levels of wild-type NTRK1-3 were not inhibited. Based on these results, there is potential for a NTRK-dependent proliferation driver in a subpopulation of lung cancer patients with NTRK expression. In addition, pharmacological inhibition with a NTRK inhibitor, such as AZD7451, in cells harboring NTRK1 fusions, may be associated with beneficial antitumor effects.
    Molecular and clinical oncology. 09/2014; 2(5):725-730.
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    ABSTRACT: Recent study results have demonstrated that a subclass of apolipoprotein B mRNA-editing enzyme, catalytic polypeptide-like (APOBEC) cytidine deaminase may induce mutation clusters in various types of cancer. From the Cancer Genome Altas, an APOBEC mutation pattern was identified in bladder, cervical, breast, head and neck and lung cancers. In the present study, APOBEC3B mRNA expression was investigated using quantitative reverse transcription-polymerase chain reaction (RT-qPCR) assay using LightCycler in surgically treated non-small-cell lung cancer (NSCLC) cases. Additionally, 88 surgically removed Japanese NSCLC cases were analyzed for mRNA level. The results showed that APOBEC3B/β-actin mRNA levels were significantly higher in lung cancer (1,598.481±6,465.781) when compared to adjacent normal lung tissues (2,116.639±8,337.331, P=0.5453). The tumor/normal (T/N) ratio of APOBEC3B/β-actin mRNA levels was not different within the gender, age, smoking status and pathological stages. The T/N ratio of APOBEC3B/β-actin mRNA levels was not significantly different in epidermal growth factor receptor (EGFR) or Kras mutation-positive cases as compared to the wild-type cases.
    Biomedical reports. 05/2014; 2(3):392-395.
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    ABSTRACT: The use of staplers for thoracic surgery has been widely accepted and regarded as a safe procedure. However, complications of stapling are occasionally experienced. The aim of this retrospective study was to analyze complications of bronchial stapling. A retrospective multi-institutional review was conducted by the Central Japan Lung Cancer Surgery Study Group, comprising 29 institutions. All instances of bronchial stapling in thoracic surgery were reviewed during the research period. Bronchial stapling was performed 2,030 times, using 36 kinds of staplers. The total number of complications related to stapling was 36 (1.8 %); 31 events occurred intraoperatively and five events occurred postoperatively. The intraoperative complications were air leakage (N = 20) and stapling failure (N = 11), which were caused by stapler-tissue thickness mismatch (N = 17), stapler defect (N = 3), tissue fragility (N = 2), and unknown reasons (N = 9). In all 31 cases, intraoperative complications were recovered intraoperatively with additional suturing, and no further complications were observed postoperatively. The postoperative complications were bronchopleural fistula (BPF) (N = 4) and bleeding from the chest wall (intercostal artery) (N = 1). The rate of BPF was 0.2 % (4 of 2,030). Two of four BPFs induced critical conditions. Postoperative bleeding was caused by the use of Duet TRS(TM). Both total complications and BPF occurred more frequently in the main bronchus than in the lobar or segmental bronchus. No relationship was seen between the incidence of complications and cartridge colors in lobar bronchial stapling. The compression types of staplers were associated with the incidence of complication. Intraoperative and postoperative complications of bronchial stapling were studied. Generally, bronchial stapling in recent thoracic surgery was safe, but rare postoperative complications may induce critical conditions. Knowledge of potential complications and causes of bronchial stapling may decrease the incidence of stapling complications.
    World Journal of Surgery 10/2013; · 2.23 Impact Factor
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    ABSTRACT: The purpose of this study was to determine the clinicopathological findings and prognosis of small-sized anterior mediastinal tumors (SSAMTs). A retrospective study was conducted on 43 patients who underwent surgery between January 1989 and December 2011 for SSAMTs. From the preoperative radiological findings, the tumors were classified into solid (n = 28) and cystic lesions (n = 15). The pathological diagnoses of the solid lesions included thymoma (n = 24), thymic carcinoma (n = 1), mucosa-associated lymphoid tissue lymphoma (n = 1), teratoma (n = 1) and neurofibroma (n = 1), and those of the cystic lesions included thymic cysts (n = 8), thymoma (n = 3), bronchogenic cysts (n = 2), teratoma, (n = 1) and a pericardial cyst (n = 1). The 27 thymomas were composed of stages I (n = 22), II (n = 3), III (n = 1) and IVb (n = 1). The overall survival in the 43 patients was 97.1 % at 5 years. In the 28 patients with solid lesions, the overall survival was 95.8 % at 5 years. All patients with cystic lesions were still alive at the last follow-up. Cystic lesions of SSAMTs were benign lesions or stage I thymoma, and most of the solid lesions of SSAMTs were stage I or II thymomas. SSAMTs are good candidates for video-assisted thoracic surgery procedures, as conversion to sternotomy can be selected based on the intraoperative findings of pericardial invasion and a rapid pathological diagnosis of thymic carcinoma.
    Surgery Today 09/2013; · 0.96 Impact Factor
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    ABSTRACT: Kelch-like ECH-associated protein 1 (Keap1) inhibits nuclear factor erythroid 2-related 2 (NEF2L2; also named NRF2)-induced cytoprotection and has been hypothesized to represent a candidate tumor suppressor. We have previously reported the somatic mutations of the NRF2 gene (NFE2L2), however, the correlation between the Keap1 mutation and the clinicopathological features of lung cancer has not been well investigated. Therefore, in the present study, the Keap1 mutational status in non-small cell lung cancer (NSCLC) patients was investigated by reverse transcription PCR and direct sequencing. The study included 76 surgically-removed lung cancer cases from patients of the Nagoya City University Hospital in which the EGFR and NFE2L2 mutation status was already established. Keap1 mutations were identified in 2 (2.6%) adenocarcinoma patients with a history of heavy smoking. These mutations were identified to exist exclusively. The Keap1 mutation was only detected in patients with advanced adenocarcinoma (4.3%) and the completely exclusive status of this mutation and others, including EGFR, Kas, erbB2 and NRF2L2, is likely to improve the selection of personalized therapy for lung cancer.
    Oncology letters 09/2013; 6(3):719-721. · 0.24 Impact Factor
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    ABSTRACT: Mutations in components of the mitogen-activated protein kinase (MAPK) cascade may be a new candidate for target for lung cancer. The usefulness of immunohistochemistry (IHC) as a new approach for the detection of BRAF V600E in cancer patients has been recently reported. To increase the sensitivity, we modified BRAF V600E expression detection assay by IHC using mutation specific antibody. From the screening step, we found a novel 599 insertion T BRAF mutation in lung adenocarcinoma. In this study included 26 surgically removed cases with EGFR, Kras, erbB2, EML4-ALK and KIF5B-RET wild-type (wt) lung adenocarcinomas, including 7 BRAF mutants (5 V600E, 1 N581I, and 1 novel 599 insertion T mutation) analyzed by DNA sequencing. Detection of the BRAF V600E mutation was carried out by the Dako EnVision™ FLEX detection system using the VE1 clone antibody and compared with the results of direct sequencing. The autostainer IHC VE1 assay was positive in 5 of 5 (100%) BRAF V600E-mutated tumors and negative in 20 of 21 (95.2%) BRAF non-V600E tumors, except for a novel 599 insertion T case. IHC using the VE1 clone and FLEX linker is a specific method for the detection BRAF V600E and may be an alternative to molecular biology for the detection of mutations in lung adenocarcinomas. This method might be useful for screening to use molecular target therapy for lung adenocarcinomas.
    Lung cancer (Amsterdam, Netherlands) 08/2013; · 3.14 Impact Factor
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    ABSTRACT: Whole pericardial irradiation may be performed for mediastinal malignancies with pericardial dissemination or malignant pericardial effusion. Case 1 is a 57-year-old woman with a B1 thymoma, Masaoka stage IVa. She underwent whole pericardial irradiation and suffered post-irradiation constrictive pericarditis 3 years later. Diuresis, catecholamine infusions, drainage, and pericardiectomy were performed. However, she died of heart failure after 4 years and 1 month due to constrictive pericarditis. Case 2 is a 56-year-old woman with myasthenia gravis and a B2 thymoma, Masaoka stage III. She underwent an extended thymectomy with partial resection of the lung and pericardium and received adjuvant radiation therapy of the whole pericardium. She was affected by post-irradiation constrictive pericarditis 7 months later, for which she underwent pericardiectomy. However, her constrictive pericarditis remained. In conclusion, we report two advanced thymoma cases with post-irradiation constrictive pericarditis. Indicators for whole pericardial irradiation should be determined strictly and carefully.
    General Thoracic and Cardiovascular Surgery 08/2013;
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    ABSTRACT: The metabolism of xenobiotics plays a fundamental role in smoking-related lung function loss and the development of pulmonary disease. An NRF2-dependent response is a key protective mechanism against oxidative stress. In the present study, we evaluated the effect of single nucleotide polymorphisms in NRF2 genes on the level of forced expiratory volume in one second (FEV1) in lung cancers of smokers. We genotyped the status of NRF2 gene polymorphisms in 209 surgically treated lung cancer cases of smokers using TaqMan polymerase chain reaction (PCR). The results demonstrated the mean FEV1 in patients with rs2364723 C/C, C/G and G/G to be 2143.9, 2294.2 and 2335.4 ml, respectively, and there was a tendency towards lower FEV1 in C/C phenotype (P=0.0944). The mean FEV1 was significantly lower in the C/C phenotype (2143.9±566.0 ml) compared to C/G or G/G (2308.9±642.9 ml, P=0.05). The mean FEV1 in patients with rs6726395 A/A, G/A and G/G was 66.7, 71.2 and 72.3%, respectively, and there was a significant difference between A/A and G/G phenotype (P=0.043). A tendency towards a lower mean FEV1 in A/A phenotype (66.7±11.7%) was observed when compared to A/G or G/G (71.9±10.7%, P=0.07). This study demonstrated that an NRF2-dependent response to cigarette smoking has the potential to affect FEV1 decrease in a lung cancer population. In conclusion, the results have shown that NRF2 genetic changes may play a role in FEV1 loss in smokers with lung cancer.
    Biomedical reports. 05/2013; 1(3):484-488.
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    ABSTRACT: Nuclear factor (erythroid derived 2)-like 2 (NRF2, gene name NFE2L2) gene mutations have been previously identified in lung cancers. The constitutive activation of NRF2 resulting from gene mutations has been correlated with the poor prognosis of patients with squamous cell lung cancer. However, DNA sequencing using PCR methods described to date is time-consuming and requires significant quantities of DNA. Thus, this existing approach is not suitable for a routine pre-therapeutic screening program. We genotyped the NRF2 gene mutation status in 262 surgically treated lung cancer cases using LightCycler analysis. The presence of the NRF2 gene mutation was confirmed by direct sequencing. We detected 6 cases (2.3%) with NRF2 gene mutations in our cohort, particularly smokers (P=0.04) with squamous histology (P=0.0001). NRF2 gene mutations were present in 10% (6/60) of the lung squamous cell carcinoma (SqCC) cases. The NRF2 gene mutation was exclusive of epidermal growth factor receptor mutations. The NRF2 gene mutation occurred with a tendency towards a higher frequency in male patients. Patients with the NRF2 gene mutation (n=22, 11 succumbed to disease) had a significantly worse prognosis when compared with the patients with the wild-type NRF2 gene (n=521, 98 succumbed to disease) from a larger cohort study (log-rank test, P<0.0001) even upon multivariate analysis. In our study, NRF2 gene mutations played a role in the prognosis of patients with SqCC of the lung.
    International Journal of Molecular Medicine 03/2013; · 1.96 Impact Factor
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    ABSTRACT: An imbalance in immune regulation affects tumor-specific T-cell immunity in the cancer microenvironment and reshapes tumor progression and metastasis. Blockade of interactions of immune function mediates anti-tumor activity in preclinical models. In the present study, we investigated programmed cell death 1 ligand 1 (PD-L1) mRNA expression by real-time polymerase chain reaction (RT-PCR) using a LightCycler in surgically treated non-small cell lung cancer (NSCLC) cases. This study included 123 surgically removed NSCLC cases for mRNA level analyses. The PD-L1/β-actin mRNA levels showed no marked difference in lung cancer (131.398±421.596) and adjacent normal lung tissues (78.182±254092, P=0.1482). The tumor/normal (T/N) ratio of PD-L1/β-actin mRNA levels was more than 2 in 49 cases and more than 1 in 63 cases. No difference was found in the T/N ratio of PD-L1/β actin mRNA levels among factors inlcuding gender, age, smoking status and pathological subtypes. The T/N ratio of PD-L1/β actin mRNA levels was markedly higher in pathological T4 cases (15.811±36.883) compared to T1 cases (3.492±8.494, P=0.0235). However, the PD-L1 mRNA status did not correlate with lymph node metastasis status. Thus, PD-L1 may drive tumor invasion, while providing a candidate for blockade of its function as a strategy to antagonize the progression process in NSCLC.
    Biomedical reports. 01/2013; 1(1):93-96.
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    ABSTRACT: Thymoma is the most common tumor of the anterior mediastinum for which surgical resection is currently the primary form of treatment. An increase in the incidence of a small-sized (≤3 cm) thymoma (SST) has recently been noted. Clinicopathological factors and prognosis of SST have not been reported previously. In this study, the clinicopathological data of 21 SST patients were reviewed and podoplanin and Ki67 immunohistochemistry were assessed to determine the biological behavior of SSTs. Pathological diagnosis of SSTs revealed the following types: A (n=1), AB (n=8), B1 (n=5), B2 (n=6) and B3 (n=1). The Masaoka-Koga stages of 21 thymoma patients were I (n=16), II (n=3), III (n=1) and IVb (n=1). In the case of the stage IVb thymoma, phrenic nerve, mediastinal pleura invasion and anterior mediastinal lymph node metastasis were observed. The Ki67 labeling index of this stage IVb was found to be 3.2. This case was also positive for podoplanin and was one of the only 2 cases that were positive for podoplanin. This patient succumbed to thymoma. Advanced stage thymomas are possibly included in SSTs although the majority of SSTs are classified into early stages of disease. Findings of this study suggest that podoplanin analyzed by immunohistochemistry may be useful to determine the malignant behavior of SSTs.
    Molecular and Clinical Oncology 01/2013; 1(1):88-92.
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    ABSTRACT: Inflammation plays key roles at various stages of tumor development, including invasion and metastasis. In mice, the angiopoietin-like protein (ANGPTL2) gene has been implicated in inflammatory carcinogenesis. ANGPTL2 mRNA expression was investigated by real-time polymerase chain reaction (RT-PCR) assay using LightCycler in surgically treated non-small cell lung cancer (NSCLC) cases. In total, 110 surgically resected NSCLC cases were used for mRNA level analyses. The ANGPTL2/β-actin mRNA levels were not significantly different between lung cancer (1598.481±6465.781) and adjacent normal lung tissues (2116.639±8337.331, P=0.5453). The tumor/normal (T/N) ratio of ANGPTL2/β-actin mRNA levels was not different between gender, age, smoking status and pathological stages. The T/N ratio of ANGPTL2/β-actin mRNA levels was significantly higher in lymph node metastasis-positive cases (2.173±3.151) compared with lymph node metastasis-negative cases (1.212±1.778, P=0.0464). However, ANGPTL2 mRNA status was not correlated with tumor invasion status. Thus, ANGPTL2 may drive metastasis and provide a candidate for blockade of its function as a strategy to antagonize the metastatic process in NSCLC.
    Oncology letters 12/2012; 4(6):1325-1328. · 0.24 Impact Factor
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    ABSTRACT: RagD is a member of the small G protein family, which encodes a recently discovered activator of the mTOR pathway. In vitro, RagD plays an important role in the proliferation of NRF2 gene (NFE2L2) mutated cancer cells. We hypothesized that tumor RagD expression may be correlated with the mutation status of NRF2 in lung cancers. RagD mRNA levels were analyzed by quantitative real-time polymerase chain reaction (qPCR) in 90 surgically-treated lung squamous cell cancer cases, including 14 NRF2 mutation cases, and normalized by β-actin mRNA levels. Mean RagD/β-actin mRNA levels of lung squamous cell carcinoma patients did not differ with age (≤65 vs. >65), Brinkman index (<400 vs. ≥400) or gender. RagD/β-actin mRNA levels were significantly higher in stage III samples (3.204±3.623) compared to stage I samples (1.357±1.560) (P= 0.0039). In addition, higher RagD/β-actin mRNA levels were identified in NRF2 mutant samples (3.107±3.633) compared to wild-type samples (1.774±2.301) (P=0.074). These results suggest that RagD induction by NRF2 activation plays a role in the proliferation of lung squamous cell cancers.
    Oncology letters 12/2012; 4(6):1167-1170. · 0.24 Impact Factor
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    ABSTRACT: The epidermal growth factor receptor (EGFR) gene is highly polymorphic and its expression and activity may be affected by various polymorphisms. There have been several studies examining associations between EGFR polymorphisms and clinical outcome of lung cancer therapy; however, the underlying mechanism is largely unknown. The present study investigated EGFR polymorphism status and its correlation with clinicopathological features in Japanese non-small cell lung cancer (NSCLC) patients. We investigated 5 polymorphisms in the EGFR gene (-216G/T, -191C/A, 8227G/A, D994D and R497K) in 274 surgically-treated NSCLC patients. TaqMan single nucleotide polymorphism (SNP) genotyping assays and a PCR-based assay were used to analyze these polymorphisms. In our cohort of patients we did not find any evidence of the -191C/A polymorphism. Our results showed that the patients with the 8227GA or AA type in intron 1 had a significantly better prognosis with the anti-EGFR therapy than the patients with the GG type (p=0.0448) in terms of recurrence of lung cancer. No significant association was observed between 3 other SNPs (-216G/T, D994D and R497K) and clinicopathological features. The EGFR 8227G/A polymorphism in intron 1 may be associated with clinical outcome in NSCLC patients treated with EGFR tyrosine kinase inhibitors.
    Experimental and therapeutic medicine 11/2012; 4(5):785-789. · 0.34 Impact Factor
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    ABSTRACT: Thymic carcinoma is a rare thymic epithelial tumor in which chemotherapy for advanced disease has not yet been established. Thymidylate synthase (TS) and orotate phosphoribosyltransferase (OPRT) protein expression levels in thymic carcinoma were evaluated as possible indicators of the anticancer activity of 5-fluorouracil (5-FU) drugs using immunohistochemistry (IHC). A total of 24 samples of thymic carcinoma were used in the present study. The tumor sections were immunohistochemically stained for TS and OPRT. As a comparison with thymic carcinoma, we also assessed the TS and OPRT protein expression levels in 55 lung cancer samples. The TS expression was positive in 12 of 24 thymic carcinoma samples (50%) and OPRT expression was positive in 10 (42%). The association between TS and OPRT expression and Masaoka stages of thymic carcinoma was analyzed. The TS and OPRT expressions in stage IV were significantly higher compared to that in stages I, II or III. We also compared the TS and OPRT expression levels between thymic carcinoma and lung cancer (33 adenocarcinomas and 22 squamous cell carcinomas). TS expression in thymic carcinoma was significantly lower compared with lung squamous cell carcinoma. OPRT expression in thymic carcinoma was significantly higher compared to lung adenocarcinoma. The combination of a relatively low expression of TS and high expression of OPRT suggests an improved antitumor effect of 5-FU drugs in thymic carcinoma compared to in lung carcinoma.
    Experimental and therapeutic medicine 10/2012; 4(4):589-593. · 0.34 Impact Factor
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    ABSTRACT: RET encodes the tyrosine kinase receptor of growth factors belonging to the glial-derived neurotrophic factor family. Recently, RET gene rearrangements with N-terminal of KIF5B gene were identified in lung adenocarcinomas from large-scale sequencing. We investigated RET mRNA expression by real-time reverse-transcriptase polymerase chain reaction (RT-PCR) assay using LightCycler, and KIF5B/RET gene rearrangements using newly established fluorescence in situ hybridization (FISH) analysis in surgically treated nonsmall cell lung cancer (NSCLC) cases. RET protein expression was also investigated by immunohistochemistry (IHC). This study included 157 surgically removed NSCLC cases for mRNA level analyses. The RET/β actin mRNA levels were not significantly different between lung cancer (6.359 ± 15.268) and adjacent normal lung tissues (8.205 ± 28.931, P = 0.6332). Tumor/normal (T/N) ratio of RET/β actin mRNA levels was not different within gender, stage, smoking status, and pathological subtypes. T/N ratio of RET/β actin mRNA levels was significantly higher in KIF5B/RET rearrangement samples (161.763 ± 123.488) than in wild-type samples (5.9013 ± 17.148, P = 0.044). Although RET IHC positivity was not perfectly correlated with KIF5B/RET arrangement, we have detected the KIF5B/RET rearrangements using FISH analysis. Thus, we have successfully introduced FISH for diagnosing KIF5B/RET positive lung adenocarcinoma. This method facilitates the molecular evaluation for RET fusions and could be applicable in clinical practice to detect lung cancer that may be responsive to RET inhibitors.
    Cancer Medicine 08/2012; 1(1):68-75.
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    ABSTRACT: Recently, a novel fusion gene resulting from a linkage between the kinesin family member 5B gene (KIF5B; 10p11.22) and the rearranged during transfection gene (RET; 10q11.21) was identified in non-small cell lung cancer (NSCLC). However, the correlation between the KIF5B/RET fusion gene status and the clinicopathological features of surgically-treated lung cancer has not been well characterized. In this study, we have independently investigated the KIF5B/RET fusion gene status in 371 surgically-treated NSCLCs (270 were adenocarcinomas and 101 were squamous cell carcinomas), 60 breast cancers, 11 metastatic lung cancers from colon cancers and thyroid papillary adenocarcinoma cases at the Nagoya City University Hospital. The fusion gene status was analyzed by an RT-PCR-based assay and by using direct sequencing. We detected 3 of 270 cases of KIF5B/RET fusion genes in adenocarcinomas (1.1%) consisting of female and never smokers with mixed subtype adenocarcinomas. The fusion genes were detected exclusively with other mutations, such as EGFR, Kras, Braf, erbB2 mutations, and EML4/ALK fusion. KIF5B/RET fusion was not detected in the cases with squamous cell carcinoma or other types of cancers. From the 3 cases, 2 were KIF5B (exon 15); RET (exon 12) fusions with papillary dominant and 1 case was KIF5B (exon 22); RET (exon 12) fusion with solid dominant adenocarcinoma. The matched normal lung tissues did not display translocation. We reported KIF5B/RET fusion genes as a driver somatic mutation of lung adenocarcinomas. The cinicopathological backgrounds of the KIF5B/RET fusion-positive patients were similar with those of the EML4/ALK fusion-positive patients. The chimeric oncogene may be a promising molecular target for the personalized diagnosis and treatment of NSCLC.
    Oncology Reports 07/2012; 28(4):1187-92. · 2.30 Impact Factor
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    ABSTRACT: The expression of multidrug-resistant protein-3 (MRP3), a membrane-bound transporter, has been linked to drug resistance in non-small cell lung cancers (NSCLCs). Recently, we reported that NRF2 gene (NFE2L2) mutations are correlated with poor prognosis for lung squamous cell carcinomas. We hypothesized that tumor MRP3 expression may be correlated with the mutation status of upstream regulators, including NRF2, in NSCLC patients. MRP3 mRNA levels were analyzed by quantitative real-time polymerase chain reaction (qPCR) in 67 surgically-treated lung squamous cell cancer cases from the Nagoya City University Hospital and normalized by β-actin mRNA levels. Fourteen NRF2 mutation cases were included. The mean MRP3/β-actin mRNA levels did not differ according to age (≤65 vs. >65 years), Brinkman index (≤400 vs. >400) or the pathological stage of the lung squamous cell carcinoma. MRP3/β-actin mRNA levels were significantly higher in men (1.200±1.524) than in women (0.179±0.083; p=0.0036). In addition, the MRP3/β-actin mRNA levels were significantly higher in NRF2 mutants (2.598±2.373) than in wild-type NRF2 mutants (0.734±0.820; p=0.0002). These data support the hypothesis that the expression of MRP3 is induced by NRF2 activation in lung squamous cell cancers.
    Molecular Medicine Reports 07/2012; 6(4):705-8. · 1.17 Impact Factor

Publication Stats

125 Citations
52.29 Total Impact Points

Institutions

  • 2009–2013
    • Nagoya City University
      • • Department of Surgery
      • • Department of Oncology, Immunology and Surgery
      Nagoya, Aichi, Japan