SUELI MIEKO OBA SHINJO
Projetos de Pesquisa
Unidades Organizacionais
Departamento de Neurologia, Faculdade de Medicina
LIM/15 - Laboratório de Investigação em Neurologia, Hospital das Clínicas, Faculdade de Medicina
LIM/15 - Laboratório de Investigação em Neurologia, Hospital das Clínicas, Faculdade de Medicina
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article 60 Citação(ões) na Scopus Exomic Sequencing of Four Rare Central Nervous System Tumor Types(2013) BETTEGOWDA, Chetan; AGRAWAL, Nishant; JIAO, Yuchen; WANG, Yuxuan; WOOD, Laura D.; RODRIGUEZ, Fausto J.; HRUBAN, Ralph H.; GALLIA, Gary L.; BINDER, Zev A.; RIGGINS, Callen J.; SALMASI, Vafi; RIGGINS, Gregory J.; REITMAN, Zachary J.; RASHEED, Ahmed; KEIR, Stephen; SHINJO, Sueli; MARIE, Suely; MCLENDON, Roger; JALLO, George; VOGELSTEIN, Bert; BIGNER, Darell; YAN, Hai; KINZLER, Kenneth W.; PAPADOPOULOS, NickolasA heterogeneous population of uncommon neoplasms of the central nervous system (CNS) cause significant morbidity and mortality. To explore their genetic origins, we sequenced the exomes of 12 pleomorphic xanthoastrocytomas (PXA), 17 non-brainstem pediatric glioblastomas (PGBM), 8 intracranial ependymomas (IEP) and 8 spinal cord ependymomas (SCEP). Analysis of the mutational spectra revealed that the predominant single base pair substitution was a C: G>T: A transition in each of the four tumor types. Our data confirm the critical roles of several known driver genes within CNS neoplasms, including TP53 and ATRX in PGBM, and NF2 in SCEPs. Additionally, we show that activating BRAF mutations play a central role in both low and high grade glial tumors. Furthermore, alterations in genes coding for members of the mammalian target of rapamycin (mTOR) pathway were observed in 33% of PXA. Our study supports the hypothesis that pathologically similar tumors arising in different age groups and from different compartments may represent distinct disease processes with varied genetic composition.bookPart Biologia molecular das neoplasias do sistema nervoso central(2013) MARIE, Suely Kazue Nagahashi; SHINJO, Sueli Mieko Oba- Stathmin is involved in the maternal embryonic leucine zipper kinase pathway in human astrocytomas.(2013) UNO, Miyuki; OBA-SHINJO, Sueli Mieko; SILVA, Roseli; GIMENEZ, Marcela; REIS, Gisele; ROSA, Jose C.; MARIE, Suely K. N.
conferenceObject THE ROLE OF PARCIAL AZFC MICRODELETIONS ON THE SEX-RATIO OF CHILDREN BORN TO FERTILE MEN OF JAPANESE ORIGIN IN BRASIL: REGULATION OF SECONDARY SEX-RATIO MAY ALSO BE INFLUENCED BY GENETIC FACTORS(2013) PIERI, Patricia; OBA-SHINJO, Sueli; MELO, Brian; MARIE, Suely; HALLAK, JorgeIntroduction: Deletions of the human azoospermic factors (AZFa, AZFb, AZFc) located on the Yq chromosome are one of the main causes of male infertility. Complete AZFc deletion is the most frequent worldwide but the effect of partial AZFc deletions are yet to be fully understood. Methods: We first performed a first round screening for classical AZFc microdeletion in 223 Japanese-of-origin men using STSs sY254, followed by PCR using specific STSs (G73166-MboI; G73168-AluI; G73167-FspI) and restriction analysis (2U overnight at 37o C) directed to the SNVs that characterize each specific DAZ copy (Fernandes et al. 2002). Results: No partial deletion (del-) was identified in 28 (12.6%) men; deletion of DAZ4 (del4) was found in 120 (53.8%) men and of DAZ1/DAZ2/DAZ3 (del123) in 75 (33.6%). The three groups showed similar mean number of children (del- 2,07; del4 2.13; del123 1.93) and sex-ra-tio (del- 1.23; del4 1.21; del123 0.93). The highest sex-ratio was found in the spring time (del- 1.88; del4 1.68; del123 1.44) and the lowest in the summer with a significant difference (p<0.05) for the del123 group (del- 0.91; del4 0.96; del123 0.56). Conclusion: Partial AZFc deletions are frequent in Japan and seasonal differences in sperm count was recently reported (Nakahori et al, 2012). To the best of our knowledge, this is the first report on the influence of Y chromosome microdeletion in the modeling of human populations. We propose a hypothesis according to which AZFc partial deletion, together with environmental factors, may be an important event in regulating the overall fertility of populations by means of lowering the secondary sex-ratio.conferenceObject Quantitative proteomic analysis reveals a molecular triad signature as biomarker candidates for astrocytomas and oligodendrogliomas(2013) ROSA, Jose Cesar; MARIE, Suely K. N.; OBA-SHINJO, Sueli; GIMENEZ, Marcela- CTNNB1, AXIN1 and APC expression analysis of different medulloblastoma variants(2013) SILVA, Roseli da; MARIE, Suely K. N.; UNO, Miyuki; MATUSHITA, Hamilton; WAKAMATSU, Alda; ROSEMBERG, Sergio; OBA-SHINJO, Sueli M.OBJECTIVES: We investigated four components of the Wnt signaling pathway in medulloblastomas. Medulloblastoma is the most common type of malignant pediatric brain tumor, and the Wnt signaling pathway has been shown to be activated in this type of tumor. METHODS: Sixty-one medulloblastoma cases were analyzed for beta-catenin gene (CTNNB1) mutations, beta-catenin protein expression via immunostaining and Wnt signaling pathway-related gene expression. All data were correlated with histological subtypes and patient clinical information. RESULTS: CTNNB1 sequencing analysis revealed that 11 out of 61 medulloblastomas harbored missense mutations in residues 32, 33, 34 and 37, which are located in exon 3. These mutations alter the glycogen synthase kinase-3 beta phosphorylation sites, which participate in beta-catenin degradation. No significant differences were observed between mutation status and histological medulloblastoma type, patient age and overall or progression-free survival times. Nuclear beta-catenin accumulation, which was observed in 27.9% of the cases, was not associated with the histological type, CTNNB1 mutation status or tumor cell dissemination. The relative expression levels of genes that code for proteins involved in the Wnt signaling pathway (CTNNB1, APC, AXIN1 and WNT1) were also analyzed, but no significant correlations were found. In addition, large-cell variant medulloblastomas presented lower relative CTNNB1 expression as compared to the other tumor variants. CONCLUSIONS: A small subset of medulloblastomas carry CTNNB1 mutations with consequent nuclear accumulation of beta-catenin. The Wnt signaling pathway plays a role in classic, desmoplastic and extensive nodularity medulloblastoma variants but not in large-cell medulloblastomas.
- Differential Expression of ID4 and Its Association with TP53 Mutation, SOX2, SOX4 and OCT-4 Expression Levels(2013) GALATRO, Thais Fernanda de Almeida; UNO, Miyuki; OBA-SHINJO, Sueli Mieko; ALMEIDA, Antonio Nogueira; TEIXEIRA, Manoel J.; ROSEMBERG, Sergio; MARIE, Suely Kazue N.Inhibitor of DNA Binding 4 (ID4) is a member of the helix-loop-helix ID family of transcription factors, mostly present in the central nervous system during embryonic development, that has been associated with TP53 mutation and activation of SOX2. Along with other transcription factors, ID4 has been implicated in the tumorigenic process of astrocytomas, contributing to cell dedifferentiation, proliferation and chemoresistance. In this study, we aimed to characterize the ID4 expression pattern in human diffusely infiltrative astrocytomas of World Health Organization (WHO) grades II to IV of malignancy (AGII-AGIV); to correlate its expression level to that of SOX2, SOX4, OCT-4 and NANOG, along with TP53 mutational status; and to correlate the results with the clinical end-point of overall survival among glioblastoma patients. Quantitative real time PCR (qRT-PCR) was performed in 130 samples of astrocytomas for relative expression, showing up-regulation of all transcription factors in tumor cases. Positive correlation was found when comparing ID4 relative expression of infiltrative astrocytomas with SOX2 (r = 0.50; p < 0.005), SOX4 (r = 0.43; p < 0.005) and OCT-4 (r = 0.39; p < 0.05). The results from TP53 coding exon analysis allowed comparisons between wild-type and mutated status only in AGII cases, demonstrating significantly higher levels of ID4, SOX2 and SOX4 in mutated cases (p < 0.05). This pattern was maintained in secondary GBM and further confirmed by immunohistochemistry, suggesting a role for ID4, SOX2 and SOX4 in early astrocytoma tumorigenesis. Combined hyperexpression of ID4, SOX4 and OCT-4 conferred a much lower (6 months) median survival than did hypoexpression (18 months). Because both ID4 alone and a complex of SOX4 and OCT-4 activate SOX2 transcription, it is possible that multiple activation of SOX2 impair the prognosis of GBM patients. These observational results of associated expression of ID4 with SOX4 and OCT-4 may be used as a predictive factor of prognosis upon further confirmation in a larger GBM series.
- Modulation of HJURP (Holliday Junction-Recognizing Protein) Levels Is Correlated with Glioblastoma Cells Survival(2013) VALENTE, Valeria; SERAFIM, Rodolfo Bortolozo; OLIVEIRA, Leonardo Cesar de; ADORNI, Fernando Soares; TORRIERI, Raul; TIRAPELLI, Daniela Pretti da Cunha; ESPREAFICO, Enilza Maria; OBA-SHINJO, Sueli Mieko; MARIE, Suely Kazue Nagahashi; PACO-LARSON, Maria Luisa; CARLOTTI JR., Carlos GilbertoBackground: Diffuse astrocytomas are the most common type of primary brain cancer in adults. They present a wide variation in differentiation and aggressiveness, being classified into three grades: low-grade diffuse astrocytoma (grade II), anaplastic astrocytoma (grade III) and glioblastoma multiforme (grade IV), the most frequent and the major lethal type. Recent studies have highlighted the molecular heterogeneity of astrocytomas and demonstrated that large-scale analysis of gene expression could help in their classification and treatment. In this context, we previously demonstrated that HJURP, a novel protein involved in the repair of DNA double-strand breaks, is highly overexpressed in glioblastoma. Methodology/Principal Findings: Here we show that HJURP is remarkably overexpressed in a cohort composed of 40 patients with different grade astrocytomas. We also observed that tumors presenting the higher expression levels of HJURP are associated with poor survival prognosis, indicating HJURP overexpression as an independent prognostic factor of death risk for astrocytoma patients. More importantly, we found that HJURP knockdown strongly affects the maintenance of glioblastoma cells in a selective manner. Glioblastoma cells showed remarkable cell cycle arrest and premature senescence that culminated in elevated levels of cell death, differently from non-tumoral cells that were minimally affected. Conclusions: These data suggest that HJURP has an important role in the maintenance of extremely proliferative cells of high-grade gliomas and point to HJURP as a potential therapeutic target for the development of novel treatments for glioma patients.