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Motohiro Kato,
Masashi Sanada,
Itaru Kato,
Yasuharu Sato,
Junko Takita,
Kengo Takeuchi,
Akira Niwa, Yuyan Chen,
Kumi Nakazaki,
Junko Nomoto, [......],
Shigeru Chiba,
Shigeo Mori,
Yuichi Ishikawa,
Koji Okamoto,
Kensei Tobinai,
Hitoshi Nakagama,
Tatsutoshi Nakahata,
Tadashi Yoshino,
Yukio Kobayashi,
Seishi Ogawa
[Rinshō ketsueki] The Japanese journal of clinical hematology 06/2011; 52(6):313-9.
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Junko Takita, Yuyan Chen,
Jun Okubo,
Masashi Sanada,
Masatoki Adachi,
Kentaro Ohki,
Riki Nishimura,
Ryoji Hanada,
Takashi Igarashi,
Yasuhide Hayashi,
Seishi Ogawa
[show abstract]
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ABSTRACT: MYEOV and NEGR1 are novel candidate gene targets in neuroblastoma that were identified by chromosomal gain in 11q13 and loss in 1p31, respectively, through single nucleotide polymorphism array analysis. In the present study, to assess the involvement of MYEOV and NEGR1 in the pathogenesis of neuroblastoma, we analyzed their mutation status and/or expression profiles in a panel of 55 neuroblastoma samples, including 25 cell lines, followed by additional functional studies. No tumor-specific mutations of MYEOV or NEGR1 were identified in our case series. Expression of MYEOV was upregulated in 11 of 25 cell lines (44%) and in seven of 20 fresh tumors (35%). The siRNA-mediated knockdown of MYEOV in NB-19 cells, which exhibit high expression of MYEOV, resulted in a significant decrease in cell proliferation (P = 0.0027). Conversely, expression studies of NEGR1 revealed significantly lower expression of this gene in neuroblastomas at an advanced stage of the disease. Exogenous NEGR1 expression in neuroblastoma cells induced significant inhibition of cell growth (P = 0.019). The results of these studies provide supporting evidence for MYEOV and NEGR1 as gene targets of 11q13 gains and 1p31 deletions in a neuroblastoma subset. In addition, the findings suggest a possible prognostic value for NEGR1 in neuroblastoma.
Cancer Science 05/2011; 102(9):1645-50. · 3.33 Impact Factor
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Motohiro Kato,
Junko Takita,
Kan Takahashi,
Masakazu Mimaki, Yuyan Chen,
Katsuyoshi Koh,
Kohmei Ida,
Akira Oka,
Masashi Mizuguchi,
Seishi Ogawa,
Takashi Igarashi
[show abstract]
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ABSTRACT: We report a case of hepatoblastoma that developed in a child with Sotos syndrome, an overgrowth syndrome with an increased risk of neoplasms. Genome-wide analysis of copy number alterations showed a gain of chromosome 2, uniparental disomy of 18q, and microdeletion of 5q35.
The Journal of pediatrics 12/2009; 155(6):937-9. · 4.02 Impact Factor
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Motohiro Kato,
Masashi Sanada,
Itaru Kato,
Yasuharu Sato,
Junko Takita,
Kengo Takeuchi,
Akira Niwa, Yuyan Chen,
Kumi Nakazaki,
Junko Nomoto, [......],
Shigeru Chiba,
Shigeo Mori,
Yuichi Ishikawa,
Koji Okamoto,
Kensei Tobinai,
Hitoshi Nakagama,
Tatsutoshi Nakahata,
Tadashi Yoshino,
Yukio Kobayashi,
Seishi Ogawa
[show abstract]
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ABSTRACT: A20 is a negative regulator of the NF-kappaB pathway and was initially identified as being rapidly induced after tumour-necrosis factor-alpha stimulation. It has a pivotal role in regulation of the immune response and prevents excessive activation of NF-kappaB in response to a variety of external stimuli; recent genetic studies have disclosed putative associations of polymorphic A20 (also called TNFAIP3) alleles with autoimmune disease risk. However, the involvement of A20 in the development of human cancers is unknown. Here we show, using a genome-wide analysis of genetic lesions in 238 B-cell lymphomas, that A20 is a common genetic target in B-lineage lymphomas. A20 is frequently inactivated by somatic mutations and/or deletions in mucosa-associated tissue lymphoma (18 out of 87; 21.8%) and Hodgkin's lymphoma of nodular sclerosis histology (5 out of 15; 33.3%), and, to a lesser extent, in other B-lineage lymphomas. When re-expressed in a lymphoma-derived cell line with no functional A20 alleles, wild-type A20, but not mutant A20, resulted in suppression of cell growth and induction of apoptosis, accompanied by downregulation of NF-kappaB activation. The A20-deficient cells stably generated tumours in immunodeficient mice, whereas the tumorigenicity was effectively suppressed by re-expression of A20. In A20-deficient cells, suppression of both cell growth and NF-kappaB activity due to re-expression of A20 depended, at least partly, on cell-surface-receptor signalling, including the tumour-necrosis factor receptor. Considering the physiological function of A20 in the negative modulation of NF-kappaB activation induced by multiple upstream stimuli, our findings indicate that uncontrolled signalling of NF-kappaB caused by loss of A20 function is involved in the pathogenesis of subsets of B-lineage lymphomas.
Nature 06/2009; 459(7247):712-6. · 36.28 Impact Factor
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Yuyan Chen,
Junko Takita,
Young Lim Choi,
Motohiro Kato,
Miki Ohira,
Masashi Sanada,
Lili Wang,
Manabu Soda,
Akira Kikuchi,
Takashi Igarashi,
Akira Nakagawara,
Yasuhide Hayashi,
Hiroyuki Mano,
Seishi Ogawa
[show abstract]
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ABSTRACT: Neuroblastoma in advanced stages is one of the most intractable paediatric cancers, even with recent therapeutic advances. Neuroblastoma harbours a variety of genetic changes, including a high frequency of MYCN amplification, loss of heterozygosity at 1p36 and 11q, and gain of genetic material from 17q, all of which have been implicated in the pathogenesis of neuroblastoma. However, the scarcity of reliable molecular targets has hampered the development of effective therapeutic agents targeting neuroblastoma. Here we show that the anaplastic lymphoma kinase (ALK), originally identified as a fusion kinase in a subtype of non-Hodgkin's lymphoma (NPM-ALK) and more recently in adenocarcinoma of lung (EML4-ALK), is also a frequent target of genetic alteration in advanced neuroblastoma. According to our genome-wide scans of genetic lesions in 215 primary neuroblastoma samples using high-density single-nucleotide polymorphism genotyping microarrays, the ALK locus, centromeric to the MYCN locus, was identified as a recurrent target of copy number gain and gene amplification. Furthermore, DNA sequencing of ALK revealed eight novel missense mutations in 13 out of 215 (6.1%) fresh tumours and 8 out of 24 (33%) neuroblastoma-derived cell lines. All but one mutation in the primary samples (12 out of 13) were found in stages 3-4 of the disease and were harboured in the kinase domain. The mutated kinases were autophosphorylated and displayed increased kinase activity compared with the wild-type kinase. They were able to transform NIH3T3 fibroblasts as shown by their colony formation ability in soft agar and their capacity to form tumours in nude mice. Furthermore, we demonstrate that downregulation of ALK through RNA interference suppresses proliferation of neuroblastoma cells harbouring mutated ALK. We anticipate that our findings will provide new insights into the pathogenesis of advanced neuroblastoma and that ALK-specific kinase inhibitors might improve its clinical outcome.
Nature 11/2008; 455(7215):971-4. · 36.28 Impact Factor
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Journal of Pediatric Hematology/Oncology 10/2007; 29(9):666-7. · 1.16 Impact Factor
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Yuyan Chen,
Junko Takita,
Masashi Mizuguchi,
Kiyoshi Tanaka,
Kohmei Ida,
Katsuyoshi Koh,
Takashi Igarashi,
Ryoji Hanada,
Yukichi Tanaka,
Myoung-Ja Park,
Yasuhide Hayashi
[show abstract]
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ABSTRACT: Rhabdomyosarcoma (RMS) is the most common soft-tissue sarcoma of childhood. The simultaneous loss of Ink4a/Arf function and disruption of Met signaling in Ink4a/Arf-/- mice transgenic for hepatocyte growth factor/scatter factor (HGF/SF) induces RMS with extremely high penetrance and short latency. To address the roles of MET and CDKN2A (p16INK4A/p14ARF) in human RMS, we performed mutational analyses in 39 samples of RMS by PCR-SSCP. No mutations were detected in exons 14-21 of MET whereas a nonsense mutation at codon 80 of p16(INK4A) was identified in an alveolar RMS cell line. We also quantified the relative expression levels and DNA copy numbers of these genes in seven cell lines and 17 fresh tumors by real-time quantitative PCR. Expression of MET was detected in all samples; however, more than 10-fold difference was found in the samples with higher or lower expression level, despite a normal DNA copy number. The protein expression level was consistent with that of mRNA, and in cell lines with a higher expression level, MET was constitutively activated. Notably, the expression level of MET was significantly higher in patients who died (P = 0.02), in patients with stage IV (P = 0.04), as well as in patients with PAX3-FKHR chimeric transcript (P = 0.04). On the other hand, reduced or absent expression of p16INK4A and/or p14(ARF) showed no significant correlation with the clinicopathological parameters, except for the age at diagnosis. Our data suggest that MET plays a role in the progression of RMS.
Genes Chromosomes and Cancer 05/2007; 46(4):348-58. · 3.31 Impact Factor
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Yuyan Chen,
Junko Takita,
Mitsuteru Hiwatari,
Takashi Igarashi,
Ryoji Hanada,
Akira Kikuchi,
Teruaki Hongo,
Tomohiko Taki,
Mizuho Ogasawara,
Akira Shimada,
Yasuhide Hayashi
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[hide abstract]
ABSTRACT: PTPN11 has been identified as a causative gene in Noonan syndrome (NS), responsible for about 50% of cases of NS. Given the association between NS and an increased risk of some malignancies, notably leukemia and probably some solid tumors including neuroblastoma (NB) and rhabdomyosarcoma (RMS), recent studies have reported that gain-of-function somatic mutations in PTPN11 occur in some hematological malignancies, especially de novo juvenile myelomonocytic leukemia (JMML) and in some solid tumors such as NB, although at a low frequency. In a screen for mutations of PTPN11 in 7 cell lines and 30 fresh tumors of RMS and in 25 cell lines and 40 fresh tumors of NB, we identified a missense mutation (A72T) in an embryonal RMS patient. In the RMS samples, we also detected mutations of NRAS in 1 cell line and 1 patient; both mutations were in embryonal RMSs and had no PTPN11 mutations. No mutations of PTPN11 were detected in NB. In 95 leukemia cell lines and 261 fresh leukemia samples including 22 JMMLs, 9 kinds of missense mutations were detected in 17 leukemia samples, which included 11 (50.0%) mutations in JMML samples and lower frequencies in other hematological malignancies. Furthermore, we identified 4 (18.2%) NRAS mutations and 1 (4.5%) KRAS mutation in 5 JMML samples, 1 of which had a concomitant PTPN11 mutation. Our data suggest that mutations of PTPN11 as well as RAS play a role in the pathogenesis of not only myeloid hematological malignancies but also a subset of RMS malignancies.
Genes Chromosomes and Cancer 07/2006; 45(6):583-91. · 3.31 Impact Factor
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[show abstract]
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ABSTRACT: Spinal muscular atrophy (SMA) is a common autosomal recessive disorder, caused by homozygous deletion of the survival motor neuron gene 1 (SMN1). SMN2, a gene highly homologous to SMN1, is considered to influence the severity of SMA. Patients with SMA have been classified into three types on the basis of age at onset and clinical severity. In the present study, we performed a quantitative analysis of SMN2 in 22 patients of SMA to further clarify the correlation between clinical severity and SMN2 gene dosage. We determined the SMN2 gene copy number based on real-time PCR. In 3 Type I patients with only one SMN2 copy, the clinical phenotype was the severest. The remaining 14 Type I patients had two or three copies of the SMN2 gene, and showed a variable clinical severity. A patient with 3 copies required artificial ventilation at 2 months old. Five Type II and Type III patients had at least 4 copies of the SMN2 gene. Although the SMN2 gene dosage correlates the clinical severity, the mechanism by which SMN2 shows compensation in some Type I patients remains to be determined.
No to hattatsu. Brain and development 10/2005; 37(5):407-12.
