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1.
Nature ; 629(8013): 910-918, 2024 May.
Artículo en Inglés | MEDLINE | ID: mdl-38693263

RESUMEN

International differences in the incidence of many cancer types indicate the existence of carcinogen exposures that have not yet been identified by conventional epidemiology make a substantial contribution to cancer burden1. In clear cell renal cell carcinoma, obesity, hypertension and tobacco smoking are risk factors, but they do not explain the geographical variation in its incidence2. Underlying causes can be inferred by sequencing the genomes of cancers from populations with different incidence rates and detecting differences in patterns of somatic mutations. Here we sequenced 962 clear cell renal cell carcinomas from 11 countries with varying incidence. The somatic mutation profiles differed between countries. In Romania, Serbia and Thailand, mutational signatures characteristic of aristolochic acid compounds were present in most cases, but these were rare elsewhere. In Japan, a mutational signature of unknown cause was found in more than 70% of cases but in less than 2% elsewhere. A further mutational signature of unknown cause was ubiquitous but exhibited higher mutation loads in countries with higher incidence rates of kidney cancer. Known signatures of tobacco smoking correlated with tobacco consumption, but no signature was associated with obesity or hypertension, suggesting that non-mutagenic mechanisms of action underlie these risk factors. The results of this study indicate the existence of multiple, geographically variable, mutagenic exposures that potentially affect tens of millions of people and illustrate the opportunities for new insights into cancer causation through large-scale global cancer genomics.


Asunto(s)
Carcinoma de Células Renales , Exposición a Riesgos Ambientales , Geografía , Neoplasias Renales , Mutágenos , Mutación , Femenino , Humanos , Masculino , Ácidos Aristolóquicos/efectos adversos , Carcinoma de Células Renales/genética , Carcinoma de Células Renales/epidemiología , Carcinoma de Células Renales/inducido químicamente , Exposición a Riesgos Ambientales/efectos adversos , Exposición a Riesgos Ambientales/análisis , Genoma Humano/genética , Genómica , Hipertensión/epidemiología , Incidencia , Japón/epidemiología , Neoplasias Renales/genética , Neoplasias Renales/epidemiología , Neoplasias Renales/inducido químicamente , Mutágenos/efectos adversos , Obesidad/epidemiología , Factores de Riesgo , Rumanía/epidemiología , Serbia/epidemiología , Tailandia/epidemiología , Fumar Tabaco/efectos adversos , Fumar Tabaco/genética
2.
Pathol Int ; 67(8): 425-430, 2017 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-28603942

RESUMEN

We present a case of primary hepatic choriocarcinoma in an 83-year-old Japanese woman with gastric wall and lymph node metastases and a splenic vein tumor thrombus. Multiple irregular hepatic tumors with massive necrosis and hemorrhage were observed during autopsy. Syncytiotrophoblast-like and mononucleated cytotrophoblast-like cell morphology with focal hepatocellular carcinoma (HCC)-like trabecular structures was observed. In immunohistochemical analyses, the tumor cells expressed human chorionic gonadotropin (hCG) and cytokeratins (AE1/AE3, CK7, CK19) but were negative for alpha-fetoprotein (AFP), glypican-3, and vimentin. Immunohistochemical findings did not reveal evidence of HCC or angiosarcoma. We concluded the liver tumor was primary hepatic choriocarcinoma.


Asunto(s)
Coriocarcinoma/patología , Neoplasias Hepáticas/patología , Anciano de 80 o más Años , Biomarcadores de Tumor/análisis , Femenino , Humanos
3.
Cancer Sci ; 104(9): 1189-97, 2013 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-23786209

RESUMEN

Epithelial-mesenchymal transition (EMT) is a crucial event in wound healing, tissue repair, and cancer progression in adult tissues. Transforming growth factor (TGF)-ß induces EMT in mouse epithelial cells. During prolonged treatment, TGF-ß successively induces myofibroblastic differentiation with increased expression of myofibroblast marker proteins, including smooth muscle α actin and calponin. We recently showed that fibroblast growth factor-2 prevented myofibroblastic differentiation induced by TGF-ß, and transdifferentiated the cells to those with much more aggressive characteristics (enhanced EMT). To identify the molecular markers specifically expressed in cells undergoing enhanced EMT induced by the combination of TGF-ß and fibroblast growth factor-2, we carried out a microarray-based analysis and found that integrin α3 (ITGA3) and Ret were upregulated. Intriguingly, ITGA3 was also overexpressed in breast cancer cells with aggressive phenotypes and its expression was correlated with that of δEF-1, a key regulator of EMT. Moreover, the expression of both genes was downregulated by U0126, a MEK 1/2 inhibitor. Therefore, ITGA3 is a potential marker protein for cells undergoing enhanced EMT and for cancer cells with aggressive phenotypes, which is positively regulated by δEF-1 and the MEK-ERK pathway.


Asunto(s)
Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Transición Epitelial-Mesenquimal/efectos de los fármacos , Integrina alfa3/genética , Integrina alfa3/metabolismo , Animales , Diferenciación Celular/genética , Línea Celular Tumoral , Células Cultivadas , Regulación hacia Abajo , Factor 2 de Crecimiento de Fibroblastos/genética , Factor 2 de Crecimiento de Fibroblastos/metabolismo , Factor 2 de Crecimiento de Fibroblastos/farmacología , Perfilación de la Expresión Génica/métodos , Humanos , Sistema de Señalización de MAP Quinasas , Ratones , Miofibroblastos/metabolismo , Fenotipo , Proteínas Proto-Oncogénicas c-ret/genética , Proteínas Proto-Oncogénicas c-ret/metabolismo , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Factor de Crecimiento Transformador beta1/genética , Factor de Crecimiento Transformador beta1/metabolismo , Factor de Crecimiento Transformador beta1/farmacología , Regulación hacia Arriba
4.
Nat Commun ; 14(1): 3688, 2023 06 22.
Artículo en Inglés | MEDLINE | ID: mdl-37349325

RESUMEN

Structural variants (SVs) are responsible for driver events in gastric cancer (GC); however, their patterns and processes remain poorly understood. Here, we examine 170 GC whole genomes to unravel the oncogenic structural aberration landscape in GC genomes and identify six rearrangement signatures (RSs). Non-random combinations of RSs elucidate distinctive GC subtypes comprising one or a few dominant RS that are associated with specific driver events (BRCA1/2 defects, mismatch repair deficiency, and TP53 mutation) and epidemiological backgrounds. Twenty-seven SV hotspots are identified as GC driver candidates. SV hotspots frequently constitute complexly clustered SVs involved in driver gene amplification, such as ERBB2, CCNE1, and FGFR2. Further deconstruction of the locally clustered SVs uncovers amplicon-generating profiles characterized by super-large SVs and intensive segmental amplifications, contributing to the extensive amplification of GC oncogenes. Comprehensive analyses using adjusted SV allele frequencies indicate the significant involvement of extra-chromosomal DNA in processes linked to specific RSs.


Asunto(s)
Neoplasias Gástricas , Humanos , Neoplasias Gástricas/genética , Proteína BRCA1 , Proteína BRCA2
5.
Nat Commun ; 14(1): 8383, 2023 Dec 16.
Artículo en Inglés | MEDLINE | ID: mdl-38104198

RESUMEN

Renal cell carcinoma (RCC) comprises several histological types characterised by different genomic and epigenomic aberrations; however, the molecular pathogenesis of each type still requires further exploration. We perform whole-genome sequencing of 128 Japanese RCC cases of different histology to elucidate the significant somatic alterations and mutagenesis processes. We also perform transcriptomic and epigenomic sequencing to identify distinguishing features, including assay for transposase-accessible chromatin sequencing (ATAC-seq) and methyl sequencing. Genomic analysis reveals that the mutational signature differs among the histological types, suggesting that different carcinogenic factors drive each histology. From the ATAC-seq results, master transcription factors are identified for each histology. Furthermore, clear cell RCC is classified into three epi-subtypes, one of which expresses highly immune checkpoint molecules with frequent loss of chromosome 14q. These genomic and epigenomic features may lead to the development of effective therapeutic strategies for RCC.


Asunto(s)
Carcinoma de Células Renales , Neoplasias Renales , Humanos , Carcinoma de Células Renales/patología , Epigenómica , Japón , Genómica/métodos , Cromatina , Neoplasias Renales/patología
6.
Nat Genet ; 55(4): 581-594, 2023 04.
Artículo en Inglés | MEDLINE | ID: mdl-36914835

RESUMEN

Gastric cancer is among the most common malignancies worldwide, characterized by geographical, epidemiological and histological heterogeneity. Here, we report an extensive, multiancestral landscape of driver events in gastric cancer, involving 1,335 cases. Seventy-seven significantly mutated genes (SMGs) were identified, including ARHGAP5 and TRIM49C. We also identified subtype-specific drivers, including PIGR and SOX9, which were enriched in the diffuse subtype of the disease. SMGs also varied according to Epstein-Barr virus infection status and ancestry. Non-protein-truncating CDH1 mutations, which are characterized by in-frame splicing alterations, targeted localized extracellular domains and uniquely occurred in sporadic diffuse-type cases. In patients with gastric cancer with East Asian ancestry, our data suggested a link between alcohol consumption or metabolism and the development of RHOA mutations. Moreover, mutations with potential roles in immune evasion were identified. Overall, these data provide comprehensive insights into the molecular landscape of gastric cancer across various subtypes and ancestries.


Asunto(s)
Infecciones por Virus de Epstein-Barr , Neoplasias Gástricas , Humanos , Neoplasias Gástricas/patología , Infecciones por Virus de Epstein-Barr/complicaciones , Infecciones por Virus de Epstein-Barr/genética , Transcriptoma , Herpesvirus Humano 4/genética , Genómica
7.
FEBS Lett ; 590(2): 270-8, 2016 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-26823172

RESUMEN

The epithelial-mesenchymal transition (EMT) is associated with tumor progression. We reported previously that expression of the δEF1 family proteins (δEF1/ZEB1 and SIP1/ZEB2), key regulators of the EMT, is positively correlated with EMT phenotypes and aggressiveness of breast cancer. Here, we show that the expression levels of regulator of G-protein signaling 16 (RGS16) are negatively correlated with those of the δEF1 family proteins. On the basis of the results of gain- and loss-of-function analyses, we suggest that δEF1 family proteins promote cell motility of breast cancer cells directly or indirectly through repressing expression of RGS16.


Asunto(s)
Movimiento Celular/fisiología , Proteínas de Homeodominio/fisiología , Proteínas RGS/fisiología , Proteínas Represoras/fisiología , Factores de Transcripción/fisiología , Neoplasias de la Mama/patología , Línea Celular Tumoral , Transición Epitelial-Mesenquimal/fisiología , Humanos , Caja Homeótica 2 de Unión a E-Box con Dedos de Zinc , Homeobox 1 de Unión a la E-Box con Dedos de Zinc
8.
Cancer Med ; 4(1): 125-35, 2015 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-25315069

RESUMEN

Abnormal DNA methylation at the C-5 position of cytosine (5mC) of CpG dinucleotides is a well-known epigenetic feature of cancer. Levels of E-cadherin, which is regularly expressed in epithelial tissues, are frequently reduced in epithelial tumors due to transcriptional repression, sometimes accompanied by hypermethylation of the promoter region. δEF1 family proteins (δEF1/ZEB1 and SIP1/ZEB2), key regulators of the epithelial-mesenchymal transition (EMT), suppress E-cadherin expression at the transcriptional level. We recently showed that levels of mRNAs encoding δEF1 proteins are regulated reciprocally with E-cadherin level in breast cancer cells. Here, we examined the mechanism underlying downregulation of E-cadherin expression in three basal-type breast cancer cells in which the E-cadherin promoter region is hypermethylated (Hs578T) or moderately methylated (BT549 and MDA-MB-231). Regardless of methylation status, treatment with 5-aza-2'-deoxycytidine (5-aza), which inhibits DNA methyltransferases, had no effect on E-cadherin expression. Knockdown of δEF1 and SIP1 resulted in recovery of E-cadherin expression in cells lacking hypermethylation, whereas combined treatment with 5-aza synergistically restored E-cadherin expression, especially when the E-cadherin promoter was hypermethylated. Moreover, δEF1 interacted with DNA methyltransferase 1 (DNMT1) through the Smad-binding domain. Sustained knockdown of δEF1 family proteins reduced the number of 5mC sites in the E-cadherin promoter region, suggesting that these proteins maintain 5mC through interaction with DNMT1 in breast cancer cells. Thus, δEF1 family proteins appear to repress expression of E-cadherin during cancer progression, both directly at the transcriptional level and indirectly at the epigenetic level.


Asunto(s)
Neoplasias de la Mama/genética , Neoplasias de la Mama/metabolismo , Cadherinas/genética , ADN (Citosina-5-)-Metiltransferasas/metabolismo , Metilación de ADN , Proteínas de Homeodominio/metabolismo , Regiones Promotoras Genéticas , Factores de Transcripción/metabolismo , Cadherinas/metabolismo , Línea Celular Tumoral , Islas de CpG , ADN (Citosina-5-)-Metiltransferasa 1 , Femenino , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Proteínas de Homeodominio/genética , Humanos , Proteínas del Tejido Nervioso/genética , Proteínas del Tejido Nervioso/metabolismo , Unión Proteica , Interferencia de ARN , ARN Interferente Pequeño/genética , Proteínas de Unión al ARN/genética , Proteínas de Unión al ARN/metabolismo , Factores de Transcripción/genética , Homeobox 1 de Unión a la E-Box con Dedos de Zinc
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