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2.
Front Oncol ; 11: 669270, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34055636

RESUMO

To investigate the relationship between non-coding RNAs [especially circular RNAs (circRNAs)] and docetaxel resistance in breast cancer, and to find potential predictive biomarkers for taxane-containing therapies, we have performed transcriptome and microRNA (miRNA) sequencing for two established docetaxel-resistant breast cancer (DRBC) cell lines and their docetaxel-sensitive parental cell lines. Our analyses revealed differences between circRNA signatures in the docetaxel-resistant and -sensitive breast cancer cells, and discovered circRNAs generated by multidrug-resistance genes in taxane-resistant cancer cells. In DRBC cells, circABCB1 was identified and validated as a circRNA that is strongly up-regulated, whereas circEPHA3.1 and circEPHA3.2 are strongly down-regulated. Furthermore, we investigated the potential functions of these circRNAs by bioinformatics analysis, and miRNA analysis was performed to uncover potential interactions between circRNAs and miRNAs. Our data showed that circABCB1, circEPHA3.1 and circEPHA3.2 may sponge up eight significantly differentially expressed miRNAs that are associated with chemotherapy and contribute to docetaxel resistance via the PI3K-Akt and AGE-RAGE signaling pathways. We also integrated differential expression data of mRNA, long non-coding RNA, circRNA, and miRNA to gain a global profile of multi-level RNA changes in DRBC cells, and compared them with changes in DNA copy numbers in the same cell lines. We found that Chromosome 7 q21.12-q21.2 was a common region dominated by multi-level RNA overexpression and DNA amplification, indicating that overexpression of the RNA molecules transcribed from this region may result from DNA amplification during stepwise exposure to docetaxel. These findings may help to further our understanding of the mechanisms underlying docetaxel resistance in breast cancer.

3.
Front Oncol ; 11: 637431, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33889545

RESUMO

Esophageal squamous cell cancer (ESCC) is the eighth most common cancer around the world. Several reports have focused on somatic mutations and common germline mutations in ESCC. However, the contributions of pathogenic germline alterations in cancer susceptibility genes (CSGs), highly frequently mutated CSGs, and pathogenically mutated CSG-related pathways in ESCC remain unclear. We obtained data on 571 ESCC cases from public databases and East Asian from the 1000 Genomes Project database and the China Metabolic Analytics Project database to characterize pathogenic mutations. We detected 157 mutations in 75 CSGs, accounting for 25.0% (143/571) of ESCC cases. Six genes had more than five mutations: TP53 (n = 15 mutations), GJB2 (n = 8), BRCA2 (n = 6), RECQL4 (n = 6), MUTYH (n = 6), and PMS2 (n = 5). Our results identified significant differences in pathogenic germline mutations of TP53, BRCA2, and RECQL4 between the ESCC and control cohorts. Moreover, we identified 84 double-hit events (16 germline/somatic double-hit events and 68 somatic/somatic double-hit events) occurring in 18 tumor suppressor genes from 83 patients. Patients who had ESCC with germline/somatic double-hit events were diagnosed at younger ages than patients with the somatic/somatic double-hit events, though the correlation was not significant. Fanconi anemia was the most enriched pathway of pathogenically mutated CSGs, and it appeared to be a primary pathway for ESCC predisposition. The results of this study identified the underlying roles that pathogenic germline mutations in CSGs play in ESCC pathogenesis, increased our awareness about the genetic basis of ESCC, and provided suggestions for using highly mutated CSGs and double-hit features in the early discovery, prevention, and genetic counseling of ESCC.

4.
Theranostics ; 10(23): 10606-10618, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32929369

RESUMO

Esophageal squamous cell carcinoma (ESCC) patients with a synchronous or metachronous lung tumor can be diagnosed with lung metastasis (LM) or a second primary tumor (SPT), but the accurate discrimination between LM and SPT remains a clinical dilemma. This study aimed to investigate the feasibility of using the whole-exome sequencing (WES) technique to distinguish SPT from LM. Methods: We performed WES on 40 tumors from 14 patients, including 12 patients with double squamous cell carcinomas (SCCs) of the esophagus and lung (lymph node metastases were sequenced as internal controls) diagnosed as LM according to pathological information and 2 patients with paired primary ESCC and non-lung metastases examined as external controls. Results: Shared genomic profiles between esophageal (T) and lung (D) tumors were observed in 7 patients, suggesting their clonal relatedness, thus indicating that the lung tumors of these patients should be LM. However, distinct genomic profiles between T and D tumors were observed in the other 5 patients, suggesting the possibility of SPTs that were likely formed through independent multifocal oncogenesis. Conclusions: Our data demonstrate the limitations and insufficiency of clinicopathological criteria and that WES could be useful in understanding the clonal relationships of multiple SCCs.


Assuntos
Biomarcadores Tumorais/genética , Neoplasias Esofágicas/patologia , Carcinoma de Células Escamosas do Esôfago/diagnóstico , Neoplasias Pulmonares/diagnóstico , Segunda Neoplasia Primária/diagnóstico , Adulto , Idoso , Idoso de 80 Anos ou mais , Diagnóstico Diferencial , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/cirurgia , Carcinoma de Células Escamosas do Esôfago/genética , Carcinoma de Células Escamosas do Esôfago/secundário , Carcinoma de Células Escamosas do Esôfago/cirurgia , Esofagectomia , Esôfago/patologia , Feminino , Humanos , Pulmão/patologia , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/secundário , Neoplasias Pulmonares/cirurgia , Masculino , Pessoa de Meia-Idade , Segunda Neoplasia Primária/genética , Segunda Neoplasia Primária/patologia , Segunda Neoplasia Primária/cirurgia , Pneumonectomia , Sequenciamento Completo do Exoma
5.
mSystems ; 5(2)2020 Apr 14.
Artigo em Inglês | MEDLINE | ID: mdl-32291348

RESUMO

As research focusing on the colorectal cancer fecal microbiome using shotgun sequencing continues, increasing evidence has supported correlations between colorectal carcinomas (CRCs) and fecal microbiome dysbiosis. However, large-scale on-site and off-site (surrounding adjacent) tissue microbiome characterization of CRC was underrepresented. Here, considering each taxon as a feature, we demonstrate a machine learning-based method to investigate tissue microbial differences among CRC, colorectal adenoma (CRA), and healthy control groups using 16S rRNA data sets retrieved from 15 studies. A total of 2,099 samples were included and analyzed in case-control comparisons. Multiple methods, including differential abundance analysis, random forest classification, cooccurrence network analysis, and Dirichlet multinomial mixture analysis, were conducted to investigate the microbial signatures. We showed that the dysbiosis of the off-site tissue of colonic cancer was distinctive and predictive. The AUCs (areas under the curve) were 80.7%, 96.0%, and 95.8% for CRC versus healthy control random forest models using stool, tissue, and adjacent tissue samples and 69.9%, 91.5%, and 89.5% for the corresponding CRA models, respectively. We also found that the microbiota ecologies of the surrounding adjacent tissues of CRC and CRA were similar to their on-site counterparts according to network analysis. Furthermore, based on the enterotyping of tissue samples, the cohort-specific microbial signature might be the crux in addressing classification generalization problems. Despite cohort heterogeneity, the dysbiosis of lesion-adjacent tissues might provide us with further perspectives in demonstrating the role of the microbiota in colorectal cancer tumorigenesis.IMPORTANCE Turbulent fecal and tissue microbiome dysbiosis of colorectal carcinoma and adenoma has been identified, and some taxa have been proven to be carcinogenic. However, the microbiomes of surrounding adjacent tissues of colonic cancerous tissues were seldom investigated uniformly on a large scale. Here, we characterize the microbiome signatures and dysbiosis of various colonic cancer sample groups. We found a high correlation between colorectal carcinoma adjacent tissue microbiomes and their on-site counterparts. We also discovered that the microbiome dysbiosis in adjacent tissues could discriminate colorectal carcinomas from healthy controls effectively. These results extend our knowledge on the microbial profile of colorectal cancer tissues and highlight microbiota dysbiosis in the surrounding tissues. They also suggest that microbial feature variations of cancerous lesion-adjacent tissues might help to reveal the microbial etiology of colonic cancer and could ultimately be applied for diagnostic and screening purposes.

7.
Int J Cancer ; 145(11): 2986-2995, 2019 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-30977120

RESUMO

Primary hepatic neuroendocrine tumors (PHNETs) are extremely rare NETs originating from the liver. These tumors are associated with heterogeneous prognosis, and few treatment targets for PHNETs have been identified. Because the major genetic alterations in PHNET are still largely unknown, we performed whole-exome sequencing of 22 paired tissues from PHNET patients and identified 22 recurring mutations of somatic genes involved in the following activities: epigenetic modification (BPTF, MECP2 and WDR5), cell cycle (TP53, ATM, MED12, DIDO1 and ATAD5) and neural development (UBR4, MEN1, GLUL and GIGYF2). Here, we show that TP53 and the SET domain containing the 1B gene (SETD1B) are the most frequently mutated genes in this set of samples (3/22 subjects, 13.6%). A biological analysis suggests that one of the three SETD1B mutants, A1054del, promotes cell proliferation, migration and invasion compared to wild-type SETD1B. Our work unveils that SETD1B A1054del mutant is functional in PHNET and implicates genes including TP53 in the disease. Our findings thus characterize the mutational landscapes of PHNET and implicate novel gene mutations linked to PHNET pathogenesis and potential therapeutic targets.


Assuntos
Histona-Lisina N-Metiltransferase/genética , Neoplasias Hepáticas/genética , Mutação , Tumores Neuroendócrinos/genética , Sequenciamento Completo do Exoma/métodos , Movimento Celular , Proliferação de Células , Feminino , Predisposição Genética para Doença , Células HEK293 , Histona-Lisina N-Metiltransferase/química , Humanos , Masculino , Modelos Moleculares , Conformação Proteica , Proteína Supressora de Tumor p53/genética
8.
Sci Rep ; 8(1): 17970, 2018 12 19.
Artigo em Inglês | MEDLINE | ID: mdl-30568280

RESUMO

Resistance to adjuvant systemic treatment, including taxanes (docetaxel and paclitaxel) is a major clinical problem for breast cancer patients. lncRNAs (long non-coding RNAs) are non-coding transcripts, which have recently emerged as important players in a variety of biological processes, including cancer development and chemotherapy resistance. However, the contribution of lncRNAs to docetaxel resistance in breast cancer and the relationship between lncRNAs and taxane-resistance genes are still unclear. Here, we performed comprehensive RNA sequencing and analyses on two docetaxel-resistant breast cancer cell lines (MCF7-RES and MDA-RES) and their docetaxel-sensitive parental cell lines. We identified protein coding genes and pathways that may contribute to docetaxel resistance. More importantly, we identified lncRNAs that were consistently up-regulated or down-regulated in both the MCF7-RES and MDA-RES cells. The co-expression network and location analyses pinpointed four overexpressed lncRNAs located within or near the ABCB1 (ATP-binding cassette subfamily B member 1) locus, which might up-regulate the expression of ABCB1. We also identified the lncRNA EPB41L4A-AS2 (EPB41L4A Antisense RNA 2) as a potential biomarker for docetaxel sensitivity. These findings have improved our understanding of the mechanisms underlying docetaxel resistance in breast cancer and have provided potential biomarkers to predict the response to docetaxel in breast cancer patients.


Assuntos
Antineoplásicos/farmacologia , Neoplasias da Mama/genética , Docetaxel/farmacologia , Resistencia a Medicamentos Antineoplásicos/genética , Regulação Neoplásica da Expressão Gênica , RNA Longo não Codificante/genética , RNA Mensageiro/genética , Neoplasias da Mama/tratamento farmacológico , Linhagem Celular Tumoral , Biologia Computacional/métodos , Feminino , Perfilação da Expressão Gênica , Ontologia Genética , Redes Reguladoras de Genes , Sequenciamento de Nucleotídeos em Larga Escala , Humanos
9.
Carcinogenesis ; 39(5): 708-718, 2018 05 03.
Artigo em Inglês | MEDLINE | ID: mdl-29546405

RESUMO

Synchronous colorectal cancers (syCRCs), which present two or more lesions at diagnosis, are rare and pose a great challenge for clinical management. Although some predisposing factors associated with syCRCs have been studied with limited accession, the full repertoire of genomic events among the lesions within an individual and the causes of syCRCs remain unclear. We performed whole-exome sequencing of 40 surgical tumour samples of paired lesions from 20 patients to characterize the genetic alterations. Lesions from same patient showed distinct landscapes of somatic aberrations and shared few mutations, which suggests that they originate and develop independently, although they shared the similar genetic background. Canonical genes, such as APC, KRAS, TP53 and PIK3CA, were frequently mutated in the syCRCs, and most of them show different mutation profile compared with solitary colorectal cancer. We identified a recurrent somatic alteration (K15fs) in RPL22 in 25% of the syCRCs. Functional analysis indicated that mutated RPL22 may suppress cell apoptosis and promote the epithelial-mesenchymal transition (EMT). Potential drug targets were identified in several signalling pathways, and they present great discrepancy between lesions from the same patient. Our data show that the syCRCs within the same patient present great genetic heterogeneity, and they may be driven by distinct molecular events and develop independently. The discrepancy of potential drug targets and mutation burden in lesions from one patient provides valuable information in clinical management for patients with syCRCs.


Assuntos
Neoplasias Colorretais/genética , Apoptose/genética , Variações do Número de Cópias de DNA/genética , Transição Epitelial-Mesenquimal/genética , Exoma/genética , Heterogeneidade Genética , Predisposição Genética para Doença/genética , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos , Mutação/genética , Transdução de Sinais/genética
11.
Sci Rep ; 7(1): 15324, 2017 11 10.
Artigo em Inglês | MEDLINE | ID: mdl-29127303

RESUMO

Oesophageal carcinoma is the fourth leading cause of cancer-related death in China, and more than 90% of these tumours are oesophageal squamous cell carcinoma (ESCC). Although several ESCC genomic sequencing studies have identified mutated somatic genes, the number of samples in each study was relatively small, and the molecular basis of ESCC has not been fully elucidated. Here, we performed an integrated analysis of 490 tumours by combining the genomic data from 7 previous ESCC projects. We identified 18 significantly mutated genes (SMGs). PTEN, DCDC1 and CUL3 were first reported as SMGs in ESCC. Notably, the AJUBA mutations and mutational signature4 were significantly correlated with a poorer survival in patients with ESCC. Hierarchical clustering analysis of the copy number alteration (CNA) of cancer gene census (CGC) genes in ESCC patients revealed three subtypes, and subtype3 exhibited more CNAs and marked for worse prognosis compared with subtype2. Moreover, database annotation suggested that two significantly differential CNA genes (PIK3CA and FBXW7) between subtype3 and subtype2 may serve as therapeutic drug targets. This study has extended our knowledge of the genetic basis of ESCC and shed some light into the clinical relevance, which would help improve the therapy and prognosis of ESCC patients.


Assuntos
Carcinoma de Células Escamosas/genética , Bases de Dados de Ácidos Nucleicos , Neoplasias Esofágicas/genética , Mutação , Proteínas de Neoplasias/genética , Carcinoma de Células Escamosas/diagnóstico , Neoplasias Esofágicas/diagnóstico , Feminino , Humanos , Masculino , Prognóstico
12.
Cell Death Discov ; 3: 17039, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28725489

RESUMO

Bone morphogenetic protein 2 (BMP-2) has been reported to facilitate epithelial-to-mesenchymal transition (EMT) and bone metastasis in breast cancer xenograft models. To investigate the role of BMP-2 in the development of breast cancer stem cells (BCSCs), and to further elucidate the mechanisms underlying its influence on breast cancer metastasis, we conducted a comprehensive molecular study using breast cancer cell lines and clinical samples. Our results showed that downregulation of Rb by BMP-2 was associated with ubiquitin-mediated degradation activated by phosphorylation of Rb via the PI3K/AKT signal pathway. In addition, the Smad signaling pathways are implicated in upregulation of CD44 protein expression by BMP-2. It was suggested that cross-talk exists between Rb and CD44 signaling pathways, as recombinant human BMP-2 (rhBMP-2) was found to regulate CD44 expression partly through Rb signals. In clinical tissues, BMP-2 was positively and negatively correlated with CD44 and Rb expression, respectively. Based on the in vitro and in vivo results, we have established an integrated mechanism by which rhBMP-2 induces EMT and stemness of breast cancer cells via the Rb and CD44 signaling pathways, which then contribute to breast cancer metastasis. These findings may be helpful for developing new strategies for the treatment and prognosis of advanced breast cancer.

13.
Oncotarget ; 7(3): 2629-45, 2016 Jan 19.
Artigo em Inglês | MEDLINE | ID: mdl-26625313

RESUMO

Bladder cancer (BC) is distinguished by high rate of recurrence after surgery, but the underlying mechanisms remain poorly understood. Here we performed the whole-exome sequencing of 37 BC individuals including 20 primary and 17 recurrent samples in which the primary and recurrent samples were not from the same patient. We uncovered that MLL, EP400, PRDM2, ANK3 and CHD5 exclusively altered in recurrent BCs. Specifically, the recurrent BCs and bladder cancer cells with MLL mutation displayed increased histone H3 tri-methyl K4 (H3K4me3) modification in tissue and cell levels and showed enhanced expression of GATA4 and ETS1 downstream. What's more, MLL mutated bladder cancer cells obtained with CRISPR/Cas9 showed increased ability of drug-resistance to epirubicin (a chemotherapy drug for bladder cancer) than wild type cells. Additionally, the BC patients with high expression of GATA4 and ETS1 significantly displayed shorter lifespan than patients with low expression. Our study provided an overview of the genetic basis of recrudescent bladder cancer and discovered that genetic alterations of MLL were involved in BC relapse. The increased modification of H3K4me3 and expression of GATA4 and ETS1 would be the promising targets for the diagnosis and therapy of relapsed bladder cancer.


Assuntos
Biomarcadores Tumorais/genética , Exoma/genética , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Histona-Lisina N-Metiltransferase/genética , Mutação/genética , Proteína de Leucina Linfoide-Mieloide/genética , Recidiva Local de Neoplasia/genética , Neoplasias da Bexiga Urinária/genética , Animais , Apoptose , Western Blotting , Estudos de Casos e Controles , Proliferação de Células , Imunoprecipitação da Cromatina , Feminino , Fator de Transcrição GATA4/genética , Humanos , Técnicas Imunoenzimáticas , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Recidiva Local de Neoplasia/patologia , Prognóstico , Proteína Proto-Oncogênica c-ets-1/genética , RNA Mensageiro/genética , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Taxa de Sobrevida , Células Tumorais Cultivadas , Neoplasias da Bexiga Urinária/patologia , Ensaios Antitumorais Modelo de Xenoenxerto
14.
Eur Urol ; 65(2): 274-7, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24215939

RESUMO

Activation of telomerase can be observed in almost all human tumor histotypes and detection of the urinary telomerase activities is useful for the diagnosis and surveillance of bladder cancer. In this study, we screened, by Sanger sequencing, 302 patients with various urogenital cancers for somatic mutations in the promoter of the telomerase reverse transcriptase (TERT) gene and determined the clinical relevance of TERT promoter mutations in urogenital cancer. In vitro assays were also performed to evaluate the functional influence of the discovered mutations. We found that the frequencies of somatic mutations in the TERT promoter varied substantially between different types of urogenital tumors (range: 0-63.7%), with urothelial carcinomas showing the highest mutation frequency and prostate cancer showing no mutation. The mutations upregulated the expression of TERT and enhanced the invasiveness of the tumor cells. The mutations were more prevalent in older patients with invasive diseases and advanced tumor stages, and were associated with significantly shorter survival time. Moreover, we also observed a significant co-occurrence of mutations between the TERT promoter and the tumor protein 51/retinoblastoma1 (TP53/RB1) signaling pathway. Hence, TERT promoter mutations may serve as important markers for the differential diagnosis and surveillance of urogenital tumors.


Assuntos
Linhagem da Célula/genética , Análise Mutacional de DNA , Testes Genéticos/métodos , Mutação , Regiões Promotoras Genéticas , Telomerase/genética , Neoplasias Urogenitais/enzimologia , Neoplasias Urogenitais/genética , Frequência do Gene , Predisposição Genética para Doença , Humanos , Invasividade Neoplásica , Estadiamento de Neoplasias , Valor Preditivo dos Testes , Proteína do Retinoblastoma/genética , Fatores de Risco , Proteína Supressora de Tumor p53/genética , Neoplasias Urogenitais/patologia
15.
Nat Genet ; 45(12): 1459-63, 2013 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-24121792

RESUMO

Bladder cancer is one of the most common cancers worldwide, with transitional cell carcinoma (TCC) being the predominant form. Here we report a genomic analysis of TCC by both whole-genome and whole-exome sequencing of 99 individuals with TCC. Beyond confirming recurrent mutations in genes previously identified as being mutated in TCC, we identified additional altered genes and pathways that were implicated in TCC. Notably, we discovered frequent alterations in STAG2 and ESPL1, two genes involved in the sister chromatid cohesion and segregation (SCCS) process. Furthermore, we also detected a recurrent fusion involving FGFR3 and TACC3, another component of SCCS, by transcriptome sequencing of 42 DNA-sequenced tumors. Overall, 32 of the 99 tumors (32%) harbored genetic alterations in the SCCS process. Our analysis provides evidence that genetic alterations affecting the SCCS process may be involved in bladder tumorigenesis and identifies a new therapeutic possibility for bladder cancer.


Assuntos
Carcinoma de Células de Transição/genética , Segregação de Cromossomos/genética , Exoma/genética , Troca de Cromátide Irmã/genética , Neoplasias da Bexiga Urinária/genética , Sequência de Bases , Estudos de Casos e Controles , Transformação Celular Neoplásica/genética , Frequência do Gene , Estudo de Associação Genômica Ampla , Humanos , Polimorfismo de Nucleotídeo Único , Análise de Sequência de DNA
16.
Mol Med Rep ; 6(3): 591-6, 2012 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-22711074

RESUMO

The expression of estrogen receptor-α (ERα) is one of the most important diagnostic and prognostic factors of breast cancer. Recently, ERα-36 has been identified as a novel variant of ER-α. ERα-36 lacks intrinsic transcription activity and mainly mediates non-genomic estrogen signaling. Bone morphogenetic proteins (BMPs) are recognized as key factors during the control of cell fate and cancer development. However, the correlation between BMP and the ER signaling pathway remains unclear. In this study, we show that BMP2, a member of the BMP family, is a novel inducer of ERα-36 expression in breast cancer cells. As shown by western blot assays, the upregulation of ERα-36 by BMP2 was significant. In MDA-MB-231 cells which are ERα-66-negative, BMP2 was able to induce the expression of ERα-36 in a dose-dependent manner, and the RNA interference assay indicated a correlation between BMP2 and ERα-36 expression. BMP2 inhibited the growth of MCF-7 and MDA-MB-231 cells; however, the inhibitory effect was antagonized by tamoxifen, suggesting that the ER signal was involved. The growth of MDA-MB­231 cells was stimulated by 17-ß-estradiol (E2) after BMP2 induction, even though the cells were previously insensitive to E2. These results suggest that BMP2 induces ERα-36 expression and alters tumor resistance to endocrine therapy by changing the expression profile of ERs.


Assuntos
Proteína Morfogenética Óssea 2/metabolismo , Receptor alfa de Estrogênio/metabolismo , Antineoplásicos Hormonais/farmacologia , Proteína Morfogenética Óssea 2/genética , Receptores de Proteínas Morfogenéticas Ósseas Tipo I/antagonistas & inibidores , Receptores de Proteínas Morfogenéticas Ósseas Tipo I/genética , Receptores de Proteínas Morfogenéticas Ósseas Tipo I/metabolismo , Neoplasias da Mama , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Estradiol/farmacologia , Receptor alfa de Estrogênio/genética , Estrogênios/farmacologia , Feminino , Humanos , Interferência de RNA , RNA Interferente Pequeno/metabolismo , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Proteínas Recombinantes/farmacologia , Transdução de Sinais/efeitos dos fármacos , Tamoxifeno/farmacologia , Regulação para Cima/efeitos dos fármacos
17.
Nat Genet ; 44(1): 17-9, 2011 Dec 04.
Artigo em Inglês | MEDLINE | ID: mdl-22138691

RESUMO

We sequenced whole exomes of ten clear cell renal cell carcinomas (ccRCCs) and performed a screen of ∼1,100 genes in 88 additional ccRCCs, from which we discovered 12 previously unidentified genes mutated at elevated frequencies in ccRCC. Notably, we detected frequent mutations in the ubiquitin-mediated proteolysis pathway (UMPP), and alterations in the UMPP were significantly associated with overexpression of HIF1α and HIF2α in the tumors (P = 0.01 and 0.04, respectively). Our findings highlight the potential contribution of UMPP to ccRCC tumorigenesis through the activation of the hypoxia regulatory network.


Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Carcinoma de Células Renais/genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Neoplasias Renais/genética , Mutação , Humanos , Taxa de Mutação , Proteólise , Transdução de Sinais , Ubiquitinação
18.
Nat Genet ; 43(9): 875-8, 2011 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-21822268

RESUMO

Transitional cell carcinoma (TCC) is the most common type of bladder cancer. Here we sequenced the exomes of nine individuals with TCC and screened all the somatically mutated genes in a prevalence set of 88 additional individuals with TCC with different tumor stages and grades. In our study, we discovered a variety of genes previously unknown to be mutated in TCC. Notably, we identified genetic aberrations of the chromatin remodeling genes (UTX, MLL-MLL3, CREBBP-EP300, NCOR1, ARID1A and CHD6) in 59% of our 97 subjects with TCC. Of these genes, we showed UTX to be altered substantially more frequently in tumors of low stages and grades, highlighting its potential role in the classification and diagnosis of bladder cancer. Our results provide an overview of the genetic basis of TCC and suggest that aberration of chromatin regulation might be a hallmark of bladder cancer.


Assuntos
Carcinoma de Células de Transição/genética , Montagem e Desmontagem da Cromatina/genética , Regulação Neoplásica da Expressão Gênica , Mutação , Neoplasias da Bexiga Urinária/genética , Aberrações Cromossômicas , Humanos
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