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1.
Genome Res ; 29(3): 356-366, 2019 03.
Artículo en Inglés | MEDLINE | ID: mdl-30692147

RESUMEN

Circular RNAs (circRNAs) are a class of RNAs that is under increasing scrutiny, although their functional roles are debated. We analyzed RNA-seq data of 348 primary breast cancers and developed a method to identify circRNAs that does not rely on unmapped reads or known splice junctions. We identified 95,843 circRNAs, of which 20,441 were found recurrently. Of the circRNAs that match exon boundaries of the same gene, 668 showed a poor or even negative (R < 0.2) correlation with the expression level of the linear gene. In silico analysis showed only a minority (8.5%) of circRNAs could be explained by known splicing events. Both these observations suggest that specific regulatory processes for circRNAs exist. We confirmed the presence of circRNAs of CNOT2, CREBBP, and RERE in an independent pool of primary breast cancers. We identified circRNA profiles associated with subgroups of breast cancers and with biological and clinical features, such as amount of tumor lymphocytic infiltrate and proliferation index. siRNA-mediated knockdown of circCNOT2 was shown to significantly reduce viability of the breast cancer cell lines MCF-7 and BT-474, further underlining the biological relevance of circRNAs. Furthermore, we found that circular, and not linear, CNOT2 levels are predictive for progression-free survival time to aromatase inhibitor (AI) therapy in advanced breast cancer patients, and found that circCNOT2 is detectable in cell-free RNA from plasma. We showed that circRNAs are abundantly present, show characteristics of being specifically regulated, are associated with clinical and biological properties, and thus are relevant in breast cancer.


Asunto(s)
Biomarcadores de Tumor/genética , Neoplasias de la Mama/genética , ARN/genética , Biomarcadores de Tumor/metabolismo , Neoplasias de la Mama/patología , Proteína de Unión a CREB/genética , Proteína de Unión a CREB/metabolismo , Proteínas Portadoras/genética , Proteínas Portadoras/metabolismo , Femenino , Humanos , Metástasis Linfática , Células MCF-7 , ARN/metabolismo , ARN Circular , Proteínas Represoras/genética , Proteínas Represoras/metabolismo , Transcriptoma
2.
EMBO Rep ; 21(5): e48780, 2020 05 06.
Artículo en Inglés | MEDLINE | ID: mdl-32173982

RESUMEN

Pancreatic ductal adenocarcinoma (PDAC) is characterized by an abundance of stroma. Multiple molecular classification efforts have identified a mesenchymal tumor subtype that is consistently characterized by high-grade growth and poor clinical outcome. The relation between PDAC stroma and tumor subtypes is still unclear. Here, we aimed to identify how PDAC cells instruct the main cellular component of stroma, the pancreatic stellate cells (PSCs). We found in primary tissue that high-grade PDAC had reduced collagen deposition compared to low-grade PDAC. Xenografts and organotypic co-cultures established from mesenchymal-like PDAC cells featured reduced collagen and activated PSC content. Medium transfer experiments using a large set of PDAC cell lines revealed that mesenchymal-like PDAC cells consistently downregulated ACTA2 and COL1A1 expression in PSCs and reduced proliferation. We identified colony-stimulating factor 1 as the mesenchymal PDAC-derived ligand that deactivates PSCs, and inhibition of its receptor CSF1R was able to counteract this effect. In conclusion, high-grade PDAC features stroma that is low in collagen and activated PSC content, and targeting CSF1R offers direct options to maintain a tumor-restricting microenvironment.


Asunto(s)
Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Carcinoma Ductal Pancreático/genética , Línea Celular Tumoral , Movimiento Celular , Humanos , Factor Estimulante de Colonias de Macrófagos/genética , Neoplasias Pancreáticas/genética , Células Estrelladas Pancreáticas , Células del Estroma , Microambiente Tumoral
3.
Gynecol Obstet Invest ; 87(6): 389-397, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-36450222

RESUMEN

OBJECTIVES: Ovarian cancer has the worst overall survival rate of all gynecologic malignancies. For the majority of patients, the 5-year overall survival rate of less than 50% has hardly improved over the last decades. To improve the outcome of patients with all subtypes of ovarian cancer, large-scale fundamental and translational research is needed. To accommodate these types of ovarian cancer research, we have established a Dutch nationwide, interdisciplinary infrastructure and biobank: the Archipelago of Ovarian Cancer Research (AOCR). The AOCR will facilitate fundamental and translational ovarian cancer research and enhance interdisciplinary, national, and international collaboration. DESIGN: The AOCR biobank is a prospective ovarian cancer biobank in which biomaterials are collected, processed, and stored in a uniform matter for future (genetic) scientific research. All 19 Dutch hospitals in which ovarian cancer surgery is performed participate and collaborate in the AOCR biobank. PARTICIPANTS/MATERIALS, SETTING, METHODS: Patients of 16 years and older with suspected or diagnosed ovarian, fallopian tube, or primary peritoneal cancer are recruited for participation. Patients who agree to participate give written informed consent for collection, storage, and issue of their biomaterials for future studies. After inclusion, different blood samples are taken at various predefined time points both before and during treatment. In case of a diagnostic paracentesis or biopsy, the residual biomaterials of these procedures are stored in the biobank. During surgery, primary tumor tissue and, if applicable, tissue from metastatic sites are collected and stored. From each patient, a representative histological hematoxylin and eosin stained slide is digitalized for research purposes, including reassessment by a panel of gynecologic pathologists. Clinical and pathological data are obtained on a per-study basis from Dutch registries. Research proposals for the issue of biomaterials and data are evaluated by both the Archipelago Scientific Committee and the Steering Committee. Researchers using the biomaterials from the AOCR biobank are encouraged to enrich the biobank with data and materials resulting from their analyses and experiments. LIMITATIONS: The implementation and first 4 years of collection are financed by an infrastructural grant from the Dutch Cancer Society. Therefore, the main limitation is that the costs for sustaining the biobank after the funding period will have to be covered. This coverage will come from incorporation of budget for biobanking in future grant applications and from fees from external researchers and commercial parties using the biomaterials stored in the AOCR biobank. Moreover, we will apply for grants aimed at sustaining and improving research infrastructures and biobanks. CONCLUSIONS: With the establishment of the Dutch nationwide, interdisciplinary Archipelago of Ovarian Cancer Research infrastructure and biobank, fundamental and translational research on ovarian cancer can be greatly improved. The ultimate aim of this infrastructure is that it will lead to improved diagnostics, treatment, and survival of patients with ovarian cancer.


Asunto(s)
Bancos de Muestras Biológicas , Neoplasias Ováricas , Humanos , Femenino , Investigación Biomédica Traslacional , Estudios Prospectivos , Neoplasias Ováricas/cirugía
4.
Int J Cancer ; 146(5): 1445-1456, 2020 03 01.
Artículo en Inglés | MEDLINE | ID: mdl-31340061

RESUMEN

Circulating tumor DNA (ctDNA) is assumed to reflect tumor burden and has been suggested as a tool for prognostication and follow-up in patients with metastatic pancreatic ductal adenocarcinoma (mPDAC). However, the prognostic value of ctDNA and its relation with tumor burden has yet to be substantiated, especially in mPDAC. In this retrospective analysis of prospectively collected samples, cell-free DNA from plasma samples of 58 treatment-naive mPDAC patients was isolated and sequenced using a custom-made pancreatobiliary NGS panel. Pathogenic mutations were detected in 26/58 (44.8%) samples. Cross-check with droplet digital PCR showed good agreement in Bland-Altman analysis (p = 0.217, nonsignificance indicating good agreement). In patients with liver metastases, ctDNA was more frequently detected (24/37, p < 0.001). Tumor volume (3D reconstructions from imaging) and ctDNA variant allele frequency (VAF) were correlated (Spearman's ρ = 0.544, p < 0.001). Median overall survival (OS) was 3.2 (95% confidence interval [CI] 1.6-4.9) versus 8.4 (95% CI 1.6-15.1) months in patients with detectable versus undetectable ctDNA (p = 0.005). Both ctDNA VAF and tumor volume independently predicted OS after adjustment for carbohydrate antigen 19.9 and treatment regimen (hazard ratio [HR] 1.05, 95% CI 1.01-1.09, p = 0.005; HR 1.00, 95% CI 1.01-1.05, p = 0.003). In conclusion, our study showed that ctDNA detection rates are higher in patients with larger tumor volume and liver metastases. Nevertheless, measurements may diverge and, thus, can provide complementary information. Both ctDNA VAF and tumor volume were strong predictors of OS.


Asunto(s)
Biomarcadores de Tumor/sangre , Carcinoma Ductal Pancreático/mortalidad , ADN Tumoral Circulante/sangre , Neoplasias Hepáticas/mortalidad , Neoplasias Pancreáticas/mortalidad , Carga Tumoral , Anciano , Biomarcadores de Tumor/aislamiento & purificación , Carcinoma Ductal Pancreático/sangre , Carcinoma Ductal Pancreático/secundario , ADN Tumoral Circulante/aislamiento & purificación , Femenino , Estudios de Seguimiento , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Neoplasias Hepáticas/sangre , Neoplasias Hepáticas/secundario , Masculino , Persona de Mediana Edad , Neoplasias Pancreáticas/sangre , Neoplasias Pancreáticas/patología , Pronóstico , Estudios Prospectivos , Estudios Retrospectivos
5.
Breast Cancer Res ; 21(1): 151, 2019 12 26.
Artículo en Inglés | MEDLINE | ID: mdl-31878981

RESUMEN

BACKGROUND: Breast cancer (BC) immune infiltrates play a critical role in tumor progression and response to treatment. Besides stromal tumor infiltrating lymphocytes (sTILs) which have recently reached level 1B evidence as a prognostic marker in triple negative BC, a plethora of methods to assess immune infiltration exists, and it is unclear how these compare to each other and if they can be used interchangeably. METHODS: Two experienced pathologists scored sTIL, intra-tumoral TIL (itTIL), and 6 immune cell types (CD3+, CD4+, CD8+, CD20+, CD68+, FOXP3+) in the International Cancer Genomics Consortium breast cancer cohort using hematoxylin and eosin-stained (n = 243) and immunohistochemistry-stained tissue microarrays (n = 254) and whole slides (n = 82). The same traits were evaluated using transcriptomic- and methylomic-based deconvolution methods or signatures. RESULTS: The concordance correlation coefficient (CCC) between pathologists for sTIL was very good (0.84) and for cell-specific immune infiltrates slightly lower (0.63-0.66). Comparison between tissue microarray and whole slide pathology scores revealed systematically higher values in whole slides (ratio 2.60-5.98). The Spearman correlations between microscopic sTIL and transcriptomic- or methylomic-based assessment of immune infiltrates were highly variable (r = 0.01-0.56). Similar observations were made for cell type-specific quantifications (r = 0.001-0.54). We observed a strong inter-method variability between the omics-derived estimations, which is further cell type dependent. Finally, we demonstrated that most methods more accurately identify highly infiltrated (sTIL ≥ 60%; area under the curve, AUC, 0.64-0.99) as compared to lowly infiltrated tumors (sTIL ≤ 10%; AUC 0.52-0.82). CONCLUSIONS: There is a lower inter-pathologist concordance for cell-specific quantification as compared to overall infiltration quantification. Microscopic assessments are underestimated when considering small cores (tissue microarray) instead of whole slides. Results further highlight considerable differences between the microscopic-, transcriptomic-, and methylomic-based methods in the assessment of overall and cell-specific immune infiltration in BC. We therefore call for extreme caution when assessing immune infiltrates using current methods and emphasize the need for standardized immune characterization beyond TIL.


Asunto(s)
Neoplasias de la Mama/etiología , Susceptibilidad a Enfermedades , Linfocitos Infiltrantes de Tumor/inmunología , Biomarcadores de Tumor , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Epigenoma , Femenino , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Humanos , Linfocitos/inmunología , Linfocitos/metabolismo , Linfocitos/patología , Linfocitos Infiltrantes de Tumor/metabolismo , Linfocitos Infiltrantes de Tumor/patología , Análisis de Matrices Tisulares , Transcriptoma , Microambiente Tumoral/inmunología
6.
Eur Radiol ; 29(12): 6728-6740, 2019 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-31134367

RESUMEN

AIM: This study was conducted in order to investigate the role of gray-scale ultrasound (US) and optoacoustic imaging combined with gray-scale ultrasound (OA/US) to better differentiate between breast cancer molecular subtypes. MATERIALS AND METHODS: All 67 malignant masses included in the Maestro trial were retrospectively reviewed to compare US and OA/US feature scores and histopathological findings. Kruskal-Wallis tests were used to analyze the relationship between US and OA/US features and molecular subtypes of breast cancer. If a significant relationship was found, additional Wilcoxon-Mann-Whitney tests were used to identify the differences between molecular subtype groups. RESULTS: US sound transmission helped to differentiate between LUMA and LUMB, LUMB and TNBC, and LUMB and all other molecular subtypes combined (p values < 0.05). Regarding OA/US features, the sum of internal features helped to differentiate between TNBC and HER2-enriched subtypes (p = 0.049). Internal vessels (p = 0.025), sum of all internal features (p = 0.019), and sum of internal and external features (p = 0.028) helped to differentiate between LUMA and LUMB. All internal features, the sum of all internal features, the sum of all internal and external features, and the ratio of internal and external features helped to differentiate between LUMA and TNBC. The same features also helped to differentiate between LUMA and TNBC from other molecular subtypes (p values < 0.05). CONCLUSIONS: The use of OA/US might help radiologists to better differentiate between breast cancer molecular subtypes. Further studies need to be carried out in order to validate these results. KEY POINTS: • The combination of functional and morphologic information provided by optoacoustic imaging (OA) combined with gray-scale US helped to differentiate between breast cancer molecular subtypes.


Asunto(s)
Neoplasias de la Mama/diagnóstico por imagen , Neoplasias de la Mama/patología , Técnicas Fotoacústicas/métodos , Ultrasonografía Mamaria/métodos , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores de Tumor , Mama/diagnóstico por imagen , Mama/patología , Diagnóstico Diferencial , Femenino , Humanos , Persona de Mediana Edad , Estudios Retrospectivos
7.
Radiology ; 288(2): 355-365, 2018 08.
Artículo en Inglés | MEDLINE | ID: mdl-29664342

RESUMEN

Purpose To assess the ability of optoacoustic (OA) ultrasonography (US) to help correctly downgrade benign masses classified as Breast Imaging Reporting and Data System (BI-RADS) 4a and 4b to BI-RADS 3 or 2. Materials and Methods OA/US technology uses laser light to detect relative amounts of oxygenated and deoxygenated hemoglobin in and around suspicious breast masses. In this prospective, multicenter study, results of 209 patients with 215 breast masses classified as BI-RADS 4a or 4b at US are reported. Patients were enrolled between 2015 and 2016. Masses were first evaluated with US with knowledge of previous clinical information and imaging results, and from this information a US imaging-based probability of malignancy (POM) and BI-RADS category were assigned to each mass. The same masses were then re-evaluated at OA/US. During the OA/US evaluation, radiologists scored five OA/US features, and then reassigned an OA/US-based POM and BI-RADS category for each mass. BI-RADS downgrade and upgrade percentages at OA/US were assessed by using a weighted sum of the five OA feature scores. Results At OA/US, 47.9% (57 of 119; 95% CI: 0.39, 0.57) of benign masses classified as BI-RADS 4a and 11.1% (three of 27; 95% CI: 0.03, 0.28) of masses classified as BI-RADS 4b were correctly downgraded to BI-RADS 3 or 2. Two of seven malignant masses classified as BI-RADS 4a at US were incorrectly downgraded, and one of 60 malignant masses classified as BI-RADS 4b at US was incorrectly downgraded for a total of 4.5% (three of 67; 95% CI: 0.01, 0.13) false-negative findings. Conclusion At OA/US, benign masses classified as BI-RADS 4a could be downgraded in BI-RADS category, which would potentially decrease biopsies negative for cancer and short-interval follow-up examinations, with the limitation that a few masses may be inappropriately downgraded.


Asunto(s)
Neoplasias de la Mama/diagnóstico por imagen , Técnicas Fotoacústicas/métodos , Ultrasonografía Mamaria/métodos , Mama/diagnóstico por imagen , Femenino , Humanos , Persona de Mediana Edad , Imagen Multimodal/métodos , Estudios Prospectivos , Reproducibilidad de los Resultados
9.
Breast Cancer Res Treat ; 156(2): 249-59, 2016 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-26965286

RESUMEN

Metastatic cancer remains the leading cause of death for patients with breast cancer. To understand the mechanisms underlying the development of distant metastases to specific sites is therefore important and of potential clinical value. From 157 primary breast tumours of the patients with known metastatic disease, gene expression profiling data were generated and correlated to metastatic behaviour including site-specific metastasis, metastasis pattern and survival outcomes. We analysed gene expression signatures specifically associated with the development of bone metastases. As a validation cohort, we used a published dataset of 376 breast carcinomas for which gene expression data and site-specific metastasis information were available. 80.5 % of luminal-type tumours developed bone metastasis as opposed to 41.7 % of basal and 55.6 % of HER2-like tumours. A novel 15-gene signature identified 82.4 % of the tumours with bone metastasis, 85.2 % of the tumours which had bone metastasis as first site of metastasis and 100 % of the ones with bone metastasis only (p 9.99e-09), in the training set. In the independent dataset, 81.2 % of the positive tested tumours had known metastatic disease to the bone (p 4.28e-10). This 15-gene signature showed much better correlation with the development of bone metastases than previously identified signatures and was predictive in both ER-positive as well as in ER-negative tumours. Multivariate analyses revealed that together with the molecular subtype, our 15-gene expression signature was significantly correlated to bone metastasis status (p <0.001, 95 % CI 3.86-48.02 in the training set; p 0.001, 95 % CI 1.54-5.00 in the independent set). The 15 genes, APOPEC3B, ATL2, BBS1, C6orf61, C6orf167, MMS22L, KCNS1, MFAP3L, NIP7, NUP155, PALM2, PH-4, PGD5, SFT2D2 and STEAP3, encoded mainly membrane-bound molecules with molecular function of protein binding. The expression levels of the up-regulated genes (NAT1, BBS1 and PH-4) were also found to be correlated to epithelial to mesenchymal transition status of the tumour. We have identified a novel 15-gene expression signature associated with the development of bone metastases in breast cancer patients. This bone metastasis signature is the first to be identified using a supervised classification approach in a large series of patients and will help forward research in this area towards clinical applications.


Asunto(s)
Neoplasias Óseas/genética , Neoplasias Óseas/secundario , Neoplasias de la Mama/patología , Perfilación de la Expresión Génica/métodos , Neoplasias Óseas/patología , Neoplasias de la Mama/genética , Bases de Datos Genéticas , Transición Epitelial-Mesenquimal , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Análisis de Supervivencia
10.
BMC Cancer ; 16: 587, 2016 08 02.
Artículo en Inglés | MEDLINE | ID: mdl-27484095

RESUMEN

BACKGROUND: The basal-like breast cancer (BLBC) subtype is characterized by positive staining for basal mammary epithelial cytokeratin markers, lack of hormone receptor and HER2 expression, and poor prognosis with currently no approved molecularly-targeted therapies. The oncogenic signaling pathways driving basal-like tumorigenesis are not fully elucidated. METHODS: One hundred sixteen unselected breast tumors were subjected to integrated analysis of phosphoinositide 3-kinase (PI3K) pathway related molecular aberrations by immunohistochemistry, mutation analysis, and gene expression profiling. Incidence and relationships between molecular biomarkers were characterized. Findings for select biomarkers were validated in an independent series. Synergistic cell killing in vitro and in vivo tumor therapy was investigated in breast cancer cell lines and mouse xenograft models, respectively. RESULTS: Sixty-four % of cases had an oncogenic alteration to PIK3CA, PTEN, or INPP4B; when including upstream kinases HER2 and EGFR, 75 % of cases had one or more aberration including 97 % of estrogen receptor (ER)-negative tumors. PTEN-loss was significantly associated to stathmin and EGFR overexpression, positivity for the BLBC markers cytokeratin 5/14, and the BLBC molecular subtype by gene expression profiling, informing a potential therapeutic combination targeting these pathways in BLBC. Combination treatment of BLBC cell lines with the EGFR-inhibitor gefitinib plus the PI3K pathway inhibitor LY294002 was synergistic, and correspondingly, in an in vivo BLBC xenograft mouse model, gefitinib plus PI3K-inhibitor PWT-458 was more effective than either monotherapy and caused tumor regression. CONCLUSIONS: Our study emphasizes the importance of PI3K/PTEN pathway activity in ER-negative and basal-like breast cancer and supports the future clinical evaluation of combining EGFR and PI3K pathway inhibitors for the treatment of BLBC.


Asunto(s)
Neoplasias de la Mama/tratamiento farmacológico , Redes Reguladoras de Genes , Mutación , Inhibidores de Proteínas Quinasas/administración & dosificación , Adulto , Anciano , Anciano de 80 o más Años , Androstadienos/administración & dosificación , Androstadienos/farmacología , Animales , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Cromonas/administración & dosificación , Cromonas/farmacología , Fosfatidilinositol 3-Quinasa Clase I/genética , Sinergismo Farmacológico , Receptores ErbB/genética , Femenino , Gefitinib , Perfilación de la Expresión Génica/métodos , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Redes Reguladoras de Genes/efectos de los fármacos , Humanos , Ratones , Persona de Mediana Edad , Morfolinas/administración & dosificación , Morfolinas/farmacología , Fosfohidrolasa PTEN/genética , Monoéster Fosfórico Hidrolasas/genética , Polietilenglicoles/administración & dosificación , Polietilenglicoles/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Quinazolinas/administración & dosificación , Quinazolinas/farmacología , Transducción de Señal/efectos de los fármacos , Análisis de Matrices Tisulares/métodos , Ensayos Antitumor por Modelo de Xenoinjerto
11.
Eur Radiol ; 26(8): 2762-70, 2016 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-26560732

RESUMEN

PURPOSE: Surveillance CT colonography (CTC) is a viable option for 6-9 mm polyps at CTC screening for colorectal cancer. We established participation and diagnostic yield of surveillance and determined overall yield of CTC screening. MATERIAL AND METHODS: In an invitational CTC screening trial 82 of 982 participants harboured 6-9 mm polyps as the largest lesion(s) for which surveillance CTC was advised. Only participants with one or more lesion(s) ≥6 mm at surveillance CTC were offered colonoscopy (OC); 13 had undergone preliminary OC. The surveillance CTC yield was defined as the number of participants with advanced neoplasia in the 82 surveillance participants, and was added to the primary screening yield. RESULTS: Sixty-five of 82 participants were eligible for surveillance CTC of which 56 (86.2 %) participated. Advanced neoplasia was diagnosed in 15/56 participants (26.8 %) and 9/13 (69.2 %) with preliminary OC. Total surveillance yield was 24/82 (29.3 %). No carcinomas were detected. Adding surveillance results to initial screening CTC yield significantly increased the advanced neoplasia yield per 100 CTC participants (6.1 to 8.6; p < 0.001) and per 100 invitees (2.1 to 2.9; p < 0.001). CONCLUSION: Surveillance CTC for 6-9 mm polyps has a substantial yield of advanced adenomas and significantly increased the CTC yield in population screening. KEY POINTS: • The participation rate in surveillance CT colonography (CTC) is 86 %. • Advanced adenoma prevalence in a 6-9 mm CTC surveillance population is high. • Surveillance CTC significantly increases the yield of population screening by CTC. • Surveillance CTC for 6-9 mm polyps is a safe strategy. • Surveillance CTC is unlikely to yield new important extracolonic findings.


Asunto(s)
Pólipos del Colon/diagnóstico , Colonografía Tomográfica Computarizada/métodos , Tamizaje Masivo/métodos , Vigilancia de la Población , Anciano , Pólipos del Colon/epidemiología , Colonoscopía/métodos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Países Bajos/epidemiología , Prevalencia
12.
Nature ; 464(7291): 1071-6, 2010 Apr 15.
Artículo en Inglés | MEDLINE | ID: mdl-20393566

RESUMEN

Large intervening non-coding RNAs (lincRNAs) are pervasively transcribed in the genome yet their potential involvement in human disease is not well understood. Recent studies of dosage compensation, imprinting, and homeotic gene expression suggest that individual lincRNAs can function as the interface between DNA and specific chromatin remodelling activities. Here we show that lincRNAs in the HOX loci become systematically dysregulated during breast cancer progression. The lincRNA termed HOTAIR is increased in expression in primary breast tumours and metastases, and HOTAIR expression level in primary tumours is a powerful predictor of eventual metastasis and death. Enforced expression of HOTAIR in epithelial cancer cells induced genome-wide re-targeting of Polycomb repressive complex 2 (PRC2) to an occupancy pattern more resembling embryonic fibroblasts, leading to altered histone H3 lysine 27 methylation, gene expression, and increased cancer invasiveness and metastasis in a manner dependent on PRC2. Conversely, loss of HOTAIR can inhibit cancer invasiveness, particularly in cells that possess excessive PRC2 activity. These findings indicate that lincRNAs have active roles in modulating the cancer epigenome and may be important targets for cancer diagnosis and therapy.


Asunto(s)
Ensamble y Desensamble de Cromatina/genética , Cromatina/genética , Metástasis de la Neoplasia/genética , ARN no Traducido/genética , Animales , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Línea Celular Tumoral , Proliferación Celular , Progresión de la Enfermedad , Epigénesis Genética , Femenino , Regulación Neoplásica de la Expresión Génica , Genes Homeobox/genética , Genoma Humano/genética , Histonas/metabolismo , Humanos , Metilación , Ratones , Ratones Desnudos , Ratones SCID , Persona de Mediana Edad , Invasividad Neoplásica , Trasplante de Neoplasias , Proteínas del Grupo Polycomb , Pronóstico , Interferencia de ARN , ARN no Traducido/biosíntesis , Proteínas Represoras/análisis , Proteínas Represoras/metabolismo , Tasa de Supervivencia
13.
Am J Gastroenterol ; 110(12): 1682-90, 2015 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-26482858

RESUMEN

OBJECTIVES: Volumetric growth assessment has been proposed for predicting advanced histology at surveillance computed tomography (CT) colonography (CTC). We examined whether is it possible to predict which small (6-9 mm) polyps are likely to become advanced adenomas at surveillance by assessing volumetric growth. METHODS: In an invitational population-based CTC screening trial, 93 participants were diagnosed with one or two 6-9 mm polyps as the largest lesion(s). They were offered a 3-year surveillance CTC. Participants in whom surveillance CTC showed lesion(s) of ≥6 mm were offered colonoscopy. Volumetric measurements were performed on index and surveillance CTC, and polyps were classified into growth categories according to ±30% volumetric change (>30% growth as progression, 30% growth to 30% decrease as stable, and >30% decrease as regression). Polyp growth was related to histopathology. RESULTS: Between July 2012 and May 2014, 70 patients underwent surveillance CTC after a mean surveillance interval of 3.3 years (s.d. 0.3; range 3.0-4.6 years). In all, 33 (35%) of 95 polyps progressed, 36 (38%) remained stable, and 26 (27%) regressed, including an apparent resolution in 13 (14%) polyps. In 68 (83%) of the 82 polyps at surveillance, histopathology was obtained; 15 (47%) of 32 progressing polyps were advanced adenomas, 6 (21%) of 28 stable polyps, and none of the regressing polyps. CONCLUSIONS: The majority of 6-9 mm polyps will not progress to advanced neoplasia within 3 years. Those that do progress to advanced status can in particular be found among the lesions that increased in size on surveillance CTC.


Asunto(s)
Adenoma/patología , Neoplasias del Colon/patología , Pólipos del Colon/patología , Colonografía Tomográfica Computarizada , Vigilancia de la Población/métodos , Adenoma/diagnóstico por imagen , Adulto , Anciano , Transformación Celular Neoplásica , Neoplasias del Colon/diagnóstico por imagen , Pólipos del Colon/diagnóstico por imagen , Progresión de la Enfermedad , Femenino , Humanos , Masculino , Persona de Mediana Edad , Factores de Tiempo
14.
Breast Cancer Res Treat ; 150(3): 547-57, 2015 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-25820592

RESUMEN

Among breast cancer patients who develop distant metastases, there is marked variability in the clinical course, including metastasis pattern. Here, we present a retrospective study of breast cancer patients who all developed distant metastases focusing on the association between breast cancer subtype and clinical course, including organ-specific metastasis. Tissue microarrays (TMAs) were assembled and stained for ER, PR, HER2, EGFR, CK5/6, CK14, E-Cadherin, TP53 and Ki67 for 263 breast cancer patients with metastatic disease. Tumours were classified into ER+/HER2-/Ki67high, ER+/HER2-/Ki67low, ER+/HER2+, ER-/HER2+ and ER-/HER2- groups. Relevant data related to metastasis pattern, metastasis timeline, systemic treatment and survival were retrieved. Associations between site-specific relapse and patient/tumour characteristics were assessed with multivariate models using logistic regression. Median time for development of distant metastasis was 30 months (range 0-15.3 years); 75.8 % of the distance metastases developed in the first 5 years after treatment of the primary tumour. Patients with ER-/HER2- tumours had a median overall survival of 27 months; those with HER2+ tumours of 52 months; those with ER+/HER2-/Ki67high of 76 months and those with ER+/HER2-/Ki67low of 79 months. Bone was the most common site for distant metastasis (70.6 %) followed by liver (54.5 %) and lung (31.4 %), respectively. Visceral metastasis was found in 76.8 % of the patients. Patients with ER-/HER2- tumours developed visceral metastases in 81 % and bone metastases in 55.2 %; those with HER2+ tumours developed visceral metastases in 77.4 % and bone metastases in 69.8 %; those with ER+/HER2-/Ki67high developed visceral metastases in 75.7 % and bone metastases in 87.8 % and those with ER+/HER2-/Ki67low developed visceral metastases in 76.9 % and bone metastases in 73.1 %. In metastatic breast cancer patients, tumour subtypes are associated with survival and pattern of distant metastases. These associations are of help in choices for surveillance and therapy in individual patients.


Asunto(s)
Biomarcadores de Tumor/metabolismo , Neoplasias de la Mama/clasificación , Neoplasias de la Mama/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias de la Mama/mortalidad , Neoplasias de la Mama/patología , Femenino , Humanos , Persona de Mediana Edad , Metástasis de la Neoplasia , Estudios Retrospectivos , Análisis de Supervivencia , Análisis de Matrices Tisulares
15.
J Transl Med ; 13: 115, 2015 Apr 11.
Artículo en Inglés | MEDLINE | ID: mdl-25884700

RESUMEN

BACKGROUND: The upper gastrointestinal tract is home to some of most notorious cancers like esophagogastric and pancreatic cancer. Several factors contribute to the lethality of these tumors, but one that stands out for both tumor types is the strong inter- as well as intratumor heterogeneity. Unfortunately, genetic tumor models do not match this heterogeneity, and for esophageal cancer no adequate genetic models exist. To allow for an improved understanding of these diseases, tissue banks with sufficient amount of samples to cover the extent of diversity of human cancers are required. Additionally, xenograft models that faithfully mimic and span the breadth of human disease are essential to perform meaningful functional experiments. METHODS: We describe here the establishment of a tissue biobank, patient derived xenografts (PDXs) and cell line models of esophagogastric and pancreatic cancer patients. Biopsy material was grafted into immunocompromised mice and PDXs were used to establish primary cell cultures to perform functional studies. Expression of Hedgehog ligands in patient tumor and matching PDX was assessed by immunohistochemical staining, and quantitative real-time PCR as well as flow cytometry was used for cultured cells. Cocultures with Hedgehog reporter cells were performed to study paracrine signaling potency. Furthermore, SHH expression was modulated in primary cultures using lentiviral mediated knockdown. RESULTS: We have established a panel of 29 PDXs from esophagogastric and pancreatic cancers, and demonstrate that these PDXs mirror several of the (immuno)histological and biochemical characteristics of the original tumors. Derived cell lines can be genetically manipulated and used to further study tumor biology and signaling capacity. In addition, we demonstrate an active (paracrine) Hedgehog signaling mode by both tumor types, the magnitude of which has not been compared directly in previous studies. CONCLUSIONS: Our established PDXs and their matching primary cell lines retain important characteristics seen in the original tumors, and this should enable future studies to address the responses of these tumors to different treatment modalities, but also help in gaining mechanistic insight in how some tumors respond to certain regimens and others do not.


Asunto(s)
Neoplasias del Sistema Digestivo/patología , Tracto Gastrointestinal Superior/patología , Ensayos Antitumor por Modelo de Xenoinjerto , Anciano , Animales , Línea Celular Tumoral , Neoplasias del Sistema Digestivo/metabolismo , Femenino , Genes Reporteros , Proteínas Hedgehog/metabolismo , Humanos , Ligandos , Masculino , Ratones , Persona de Mediana Edad , Comunicación Paracrina , Transducción de Señal , Células del Estroma/patología , Bancos de Tejidos , Tracto Gastrointestinal Superior/metabolismo
16.
Histopathology ; 66(6): 761-70, 2015 May.
Artículo en Inglés | MEDLINE | ID: mdl-24845113

RESUMEN

In this review, we highlight adaptations in the WHO 2012 classification of papillary and neuroendocrine breast lesions as compared with the previous 2003 version. Consensus criteria for distinguishing atypical ductal hyperplasia from ductal carcinoma in situ within an intraductal papilloma are proposed. The absence of myoepithelial cells around the wall of an encapsulated papillary carcinoma, although raising consideration of an indolent tumour with minimal invasion, is currently regarded as in-situ disease for staging purposes. The majority of solid papillary carcinomas are classified as in-situ tumours, but lesions with irregular tumour islands within desmoplastic stroma may be considered to be invasive. The diagnosis of solid papillary carcinoma without further qualification as either in-situ or invasive disease is discouraged. When invasive papillary carcinoma is seen in the breast, metastatic papillary carcinoma from other organ sites needs to be excluded. WHO 2012 classifies neuroendocrine breast tumours as well-differentiated neuroendocrine tumour, small-cell carcinoma, and invasive breast carcinoma with neuroendocrine differentiation. There is currently no clinical impact of identifying neuroendocrine differentiation in conventional invasive breast carcinomas, apart from acknowledging its frequent occurrence in subtypes such as the hypercellular variant of mucinous carcinoma and solid papillary carcinoma.


Asunto(s)
Neoplasias de la Mama/clasificación , Carcinoma Neuroendocrino/clasificación , Carcinoma Papilar/clasificación , Neoplasias de la Mama/patología , Carcinoma Neuroendocrino/patología , Carcinoma Papilar/patología , Femenino , Humanos , Papiloma Intraductal/clasificación , Papiloma Intraductal/patología , Organización Mundial de la Salud
17.
Cancer Cell ; 12(4): 395-402, 2007 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-17936563

RESUMEN

A large-scale RNA interference screen to discover genes involved in trastuzumab resistance in breast cancer identified only PTEN as a modulator of drug sensitivity. Oncogenic mutants of PIK3CA (activator of the same pathway and frequently mutated in breast cancer) also conferred resistance to trastuzumab in cell culture. In a cohort of 55 breast cancer patients, activation of the PI3K pathway, as judged by the presence of oncogenic PIK3CA mutations or low PTEN expression, was associated with poor prognosis after trastuzumab therapy, and the combined analysis of PTEN and PIK3CA identified twice as many patients at increased risk for progression compared to PTEN alone. Thus, assessment of PI3K pathway activation may provide a biomarker to identify patients unlikely to respond to trastuzumab-based therapy.


Asunto(s)
Anticuerpos Monoclonales/farmacología , Antineoplásicos/farmacología , Biomarcadores de Tumor/metabolismo , Neoplasias de la Mama/tratamiento farmacológico , Resistencia a Antineoplásicos , Fosfatidilinositol 3-Quinasas/metabolismo , Receptor ErbB-2/antagonistas & inhibidores , Transducción de Señal/efectos de los fármacos , Adulto , Anciano , Anticuerpos Monoclonales/uso terapéutico , Anticuerpos Monoclonales Humanizados , Antineoplásicos/uso terapéutico , Biomarcadores de Tumor/genética , Neoplasias de la Mama/enzimología , Neoplasias de la Mama/genética , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/mortalidad , Línea Celular Tumoral , Fosfatidilinositol 3-Quinasa Clase I , Estudios de Cohortes , Progresión de la Enfermedad , Resistencia a Antineoplásicos/genética , Femenino , Perfilación de la Expresión Génica/métodos , Regulación Neoplásica de la Expresión Génica , Humanos , Estimación de Kaplan-Meier , Persona de Mediana Edad , Mutación , Análisis de Secuencia por Matrices de Oligonucleótidos , Fosfohidrolasa PTEN/genética , Fosfohidrolasa PTEN/metabolismo , Selección de Paciente , Fosfatidilinositol 3-Quinasas/genética , Interferencia de ARN , ARN Interferente Pequeño/metabolismo , Receptor ErbB-2/metabolismo , Transducción de Señal/genética , Transducción Genética , Trastuzumab , Resultado del Tratamiento
18.
Nature ; 459(7249): 1005-9, 2009 Jun 18.
Artículo en Inglés | MEDLINE | ID: mdl-19421193

RESUMEN

The molecular basis for breast cancer metastasis to the brain is largely unknown. Brain relapse typically occurs years after the removal of a breast tumour, suggesting that disseminated cancer cells must acquire specialized functions to take over this organ. Here we show that breast cancer metastasis to the brain involves mediators of extravasation through non-fenestrated capillaries, complemented by specific enhancers of blood-brain barrier crossing and brain colonization. We isolated cells that preferentially infiltrate the brain from patients with advanced disease. Gene expression analysis of these cells and of clinical samples, coupled with functional analysis, identified the cyclooxygenase COX2 (also known as PTGS2), the epidermal growth factor receptor (EGFR) ligand HBEGF, and the alpha2,6-sialyltransferase ST6GALNAC5 as mediators of cancer cell passage through the blood-brain barrier. EGFR ligands and COX2 were previously linked to breast cancer infiltration of the lungs, but not the bones or liver, suggesting a sharing of these mediators in cerebral and pulmonary metastases. In contrast, ST6GALNAC5 specifically mediates brain metastasis. Normally restricted to the brain, the expression of ST6GALNAC5 in breast cancer cells enhances their adhesion to brain endothelial cells and their passage through the blood-brain barrier. This co-option of a brain sialyltransferase highlights the role of cell-surface glycosylation in organ-specific metastatic interactions.


Asunto(s)
Neoplasias Encefálicas/patología , Neoplasias Encefálicas/secundario , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Animales , Barrera Hematoencefálica/metabolismo , Encéfalo/enzimología , Neoplasias Encefálicas/enzimología , Neoplasias Encefálicas/genética , Neoplasias de la Mama/enzimología , Línea Celular Tumoral , Ciclooxigenasa 2/metabolismo , Receptores ErbB , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Factor de Crecimiento Similar a EGF de Unión a Heparina , Humanos , Péptidos y Proteínas de Señalización Intercelular/metabolismo , Ratones , Metástasis de la Neoplasia/genética , Metástasis de la Neoplasia/patología , Especificidad de Órganos , Sialiltransferasas/metabolismo
19.
Nat Genet ; 38(4): 421-30, 2006 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-16518402

RESUMEN

Gene expression signatures encompassing dozens to hundreds of genes have been associated with many important parameters of cancer, but mechanisms of their control are largely unknown. Here we present a method based on genetic linkage that can prospectively identify functional regulators driving large-scale transcriptional signatures in cancer. Using this method we show that the wound response signature, a poor-prognosis expression pattern of 512 genes in breast cancer, is induced by coordinate amplifications of MYC and CSN5 (also known as JAB1 or COPS5). This information enabled experimental recapitulation, functional assessment and mechanistic elucidation of the wound signature in breast epithelial cells.


Asunto(s)
Neoplasias de la Mama/genética , Transcripción Genética/genética , Neoplasias de la Mama/patología , Línea Celular Tumoral , Mapeo Cromosómico , Técnica del Anticuerpo Fluorescente , Genes myc , Ligamiento Genético , Humanos , Repeticiones de Microsatélite
20.
Endoscopy ; 46(3): 219-24, 2014 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-24254386

RESUMEN

BACKGROUND AND STUDY AIMS: Serrated polyps of the large intestine comprise a heterogeneous group of lesions with distinct histological and malignant features. The aim of the study was to estimate the prevalence of serrated polyp subtypes in a cohort of individuals undergoing screening colonoscopy, and to identify associations between the detection of serrated polyp subtypes and advanced neoplasia. PATIENTS AND METHODS: Data on serrated polyps, adenomas, and cancers were collected from participants of a randomized screening trial that compared colonoscopy with computed tomography colonography. Only data from participants in the colonoscopy arm were used. Logistic regression analyses were performed to identify associations between patients' age, sex, and prevalence of the different types of serrated polyps and to identify associations between the detection of these polyps and advanced neoplasia (defined as an adenoma ≥ 10 mm, villous component, high grade dysplasia or colorectal cancer). RESULTS: A total of 1426 screen-naïve individuals (51 % male) with a median age of 60 years (IQR 55 - 65) were included. The prevalence of hyperplastic polyps, sessile serrated adenomas/polyps (SSA/Ps), and traditional serrated adenomas (TSAs) was 23.8 %, 4.8 %, and 0.1 %, respectively. SSA/Ps comprised 7.3 % of all polyps. No differences based on age or sex were observed in the prevalence of SSA/Ps. Proximal and large (≥ 10 mm) hyperplastic polyps, as well as proximal and large (≥ 10 mm) SSA/Ps, were associated with synchronous advanced neoplasia. CONCLUSIONS: Serrated polyps, including SSA/Ps, were frequently encountered in routine screening colonoscopies. Large and proximal hyperplastic polyps, as well large and proximal SSA/Ps, were associated with advanced neoplasia.


Asunto(s)
Adenoma/epidemiología , Carcinoma/epidemiología , Pólipos del Colon/epidemiología , Pólipos del Colon/patología , Neoplasias Colorrectales/epidemiología , Neoplasias Primarias Múltiples/epidemiología , Adenoma/diagnóstico , Anciano , Carcinoma/diagnóstico , Colonoscopía , Neoplasias Colorrectales/diagnóstico , Detección Precoz del Cáncer , Femenino , Humanos , Hiperplasia/patología , Masculino , Persona de Mediana Edad , Neoplasias Primarias Múltiples/diagnóstico , Prevalencia
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