RESUMEN
BACKGROUND: Ten-eleven translocation methylcytosine dioxygenase 1 (TET1) is involved in DNA demethylation and transcriptional regulation, plays a key role in the maintenance of stem cell pluripotency, and is dysregulated in malignant cells. The identification of cancer stem cells (CSCs) driving tumor growth and metastasis is the primary objective of biomarker discovery in aggressive prostate cancer (PCa). In this context, we analyzed TET1 expression in PCa. METHODS: A large-scale immunohistochemical analysis of TET1 was performed in normal prostate (NOR) and PCa using conventional slides (50 PCa specimens) and tissue microarrays (669 NOR and 1371 PCa tissue cores from 371 PCa specimens). Western blotting, RT-qPCR, and 450 K methylation array analyses were performed on PCa cell lines. Genome-wide correlation, gene regulatory network, and functional genomics studies were performed using publicly available data sources and bioinformatics tools. RESULTS: In NOR, TET1 was exclusively expressed in normal cytokeratin 903 (CK903)-positive basal cells. In PCa, TET1 was frequently detected in alpha-methylacyl-CoA racemase (AMACR)-positive tumor cell clusters and was detectable at all tumor stages and Gleason scores. Pearson's correlation analyses of PCa revealed 626 TET1-coactivated genes (r > 0.5) primarily encoding chromatin remodeling and mitotic factors. Moreover, signaling pathways regulating antiviral processes (62 zinc finger, ZNF, antiviral proteins) and the pluripotency of stem cells were activated. A significant proportion of detected genes exhibited TET1-correlated promoter hypomethylation. There were 161 genes encoding transcription factors (TFs), of which 133 were ZNF-TFs with promoter binding sites in TET1 and in the vast majority of TET1-coactivated genes. CONCLUSIONS: TET1-expressing cells are an integral part of PCa and may represent CSCs with oncogenic potential.
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Oxigenasas de Función Mixta/análisis , Neoplasias de la Próstata/genética , Proteínas Proto-Oncogénicas/análisis , Anciano , Metilación de ADN/genética , Expresión Génica/genética , Expresión Génica/inmunología , Humanos , Masculino , Persona de Mediana Edad , Oxigenasas de Función Mixta/sangre , Oxigenasas de Función Mixta/genética , Proteínas Proto-Oncogénicas/sangre , Proteínas Proto-Oncogénicas/genéticaRESUMEN
Gastric cancer is still a relevant malignant disease with high morbidity and mortality. Current molecular genetic data show that gastric cancer, as other solid tumors as well, is not a single entity but consists of several molecular subtypes of gastric cancer with diverse biology. The increasing understanding of molecular pathways is the basis for innovative therapies. These either directly target altered signaling pathways or genes in tumor cells or as in immune checkpoint inhibitors, indirectly target tumor cells by blocking tumor-induced immune inhibition leading to improvement in the prognosis. The selection of eligible patients is a prerequisite for the successful clinical application of these targeted drugs. Pathologists play an important role in integrating tissue-based biomarkers and established pathological parameters (typing, grading and staging) into one comprehensive morphomolecular report.
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Biomarcadores de Tumor/genética , Neoplasias Gástricas/diagnóstico , Humanos , Pronóstico , Transducción de Señal/genética , Neoplasias Gástricas/clasificación , Neoplasias Gástricas/genéticaRESUMEN
Valid HER2 testing is essential for optimal therapy of patients with HER2 positive gastric cancer and the correct use of first-line treatment. While each breast cancer is routinely being tested for the HER2 status, HER2 testing in gastric cancer has still not become part of the routine and is often only done upon request by the therapist. An interdisciplinary German expert group took the challenges of HER2 testing in gastric cancer as an opportunity to address essential aspects and questions for the practical use of HER2 testing in this indication from the perspective of pathologists and therapists. The recommendations made in this manuscript reflect the consensus of all participants and correspond to their opinions and long-term experience.
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Biomarcadores de Tumor/metabolismo , Técnicas de Diagnóstico del Sistema Digestivo/normas , Oncología Médica/normas , Guías de Práctica Clínica como Asunto , Receptor ErbB-2/metabolismo , Neoplasias Gástricas/diagnóstico , Neoplasias Gástricas/metabolismo , Medicina Basada en la Evidencia , Alemania , Reproducibilidad de los Resultados , Sensibilidad y EspecificidadRESUMEN
Disseminated tumor cells require a special microenvironment to form metastases. This metastatic niche is organ specific and forms prior to the establishment of visible metastases. The niche is characterized by vascular remodeling and bone marrow-derived cells which have migrated into it. Studies by other groups and our own results have already shown that intranodal lymphangiogenesis is an important prerequisite for regional lymph node metastases in rectal cancer patients, and can be used as a prognostic marker for progression-free survival. Niche cells such as endothelia secrete factors that attract tumor and bone marrow-derived cells. CXCL12 is one of these factors. CXCL12 activates the CXCR4 chemokine axis and induces migration along its gradient. Several factors, such as hypoxia, have been described to regulate CXCR4 function and surface expression on tumor cells. Low molecular weight agents have been used to block CXCR4 activation. This review focuses on the function and regulation of CXCR4 and its ligand CXCL12 in metastases formation. It also discusses potential options for therapeutic blockage.
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Metástasis de la Neoplasia/patología , Microambiente Tumoral/fisiología , Quimiocina CXCL12/fisiología , Progresión de la Enfermedad , Supervivencia sin Enfermedad , Humanos , Metástasis Linfática/patología , Metástasis de la Neoplasia/terapia , Especificidad de Órganos , Pronóstico , Receptores CXCR4/fisiologíaAsunto(s)
Pólipos del Colon/patología , Pólipos del Colon/cirugía , Eliminación de Residuos Sanitarios , Garantía de la Calidad de Atención de Salud , Investigación Biomédica Traslacional , Colon/patología , Colon/cirugía , Colonoscopía , Conducta Cooperativa , Alemania , Adhesión a Directriz , Humanos , Comunicación InterdisciplinariaRESUMEN
The standard treatment for invasive bladder cancer is radical cystectomy. In selected patients, bladder-sparing therapy can be performed by transurethral resection (TURBT) and radio-chemotherapy (RCT) or radiotherapy (RT). Our published in vitro data suggest that the Neuropilin-2 (NRP2)/VEGF-C axis plays a role in therapy resistance. Therefore, we studied the prognostic impact of NRP2 and VEGF-C in 247 bladder cancer patients (cN0M0) treated with TURBT and RCT (n = 198) or RT (n = 49) and a follow-up time up to 15 years. A tissue microarray was analyzed by immunohistochemistry. NRP2 expression emerged as a prognostic factor in overall survival (OS; HR: 3.42; 95% CI: 1.48 - 7.86; p = 0.004) and was associated with a 3.85-fold increased risk of an early cancer specific death (95% CI: 0.91 - 16.24; p = 0.066) in multivariate analyses. Cancer specific survival (CSS) dropped from 166 months to 85 months when NRP2 was highly expressed (p = 0.037). Patients with high VEGF-C expression have a 2.29-fold increased risk of shorter CSS (95% CI: 1.03-5.35; p = 0.043) in univariate analysis. CSS dropped from 170 months to 88 months in the case of high VEGF-C expression (p = 0.041). Additionally, NRP2 and VEGF-C coexpression is a prognostic marker for OS in multivariate models (HR: 7.54; 95% CI: 1.57-36.23; p = 0.012). Stratification for muscle invasiveness (T1 vs. T2-T4) confirmed the prognostic role of NRP2 and NRP2/VEGF-C co-expression in patients with T2-T4 but also with high risk T1 disease. In conclusion, immunohistochemistry for NRP2 and VEGF-C has been determined to predict therapy outcome in bladder cancer patients prior to TURBT and RCT.
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Biomarcadores de Tumor/metabolismo , Carcinoma in Situ/metabolismo , Neuropilina-2/metabolismo , Neoplasias de la Vejiga Urinaria/metabolismo , Factor C de Crecimiento Endotelial Vascular/metabolismo , Carcinoma in Situ/mortalidad , Carcinoma in Situ/patología , Carcinoma in Situ/terapia , Quimioradioterapia , Terapia Combinada , Femenino , Estudios de Seguimiento , Humanos , Técnicas para Inmunoenzimas , Masculino , Persona de Mediana Edad , Clasificación del Tumor , Estadificación de Neoplasias , Tratamientos Conservadores del Órgano , Complicaciones Posoperatorias , Pronóstico , Estudios Retrospectivos , Tasa de Supervivencia , Neoplasias de la Vejiga Urinaria/mortalidad , Neoplasias de la Vejiga Urinaria/patología , Neoplasias de la Vejiga Urinaria/terapiaRESUMEN
PURPOSE: Studies have shown that GIPC1/Synectin is an essential adaptor protein of receptors that play an important role in cancer progression and therapy resistance. This is the first study to explore the role of GIPC1/Synectin in radioresistance of prostate cancer and as a possible predictive marker for outcome of primary radiation therapy. MATERIALS AND METHODS: The effect of RNA interference-mediated GIPC1/Synectin depletion on clonogenic cell survival after irradiation with 0, 2, 4, or 6 Gy was assayed in two different GIPC1/Synectin-expressing human prostate cancer cell lines. The clinical outcome data of 358 men who underwent radiotherapy of prostate cancer with a curative intention were analyzed retrospectively. Uni- and multivariate analysis was performed of prostate-specific antigen recurrence-free survival and overall survival in correlation with protein expression in pretreatment biopsy specimens. Protein expression was evaluated by standard immunohistochemistry methods. RESULTS: In cell culture experiments, no change was detected in radiosensitivity after depletion of GIPC1/Synectin in GIPC1/Synectin-expressing prostate cancer cell lines. Furthermore, there was no correlation between GIPC1/Synectin expression in human pretreatment biopsy samples and overall or biochemical recurrence-free survival after radiotherapy in a retrospective analysis of the study cohort. CONCLUSION: Our results do not show a predictive or prognostic function of GIPC1/Synectin expression for the outcome of radiotherapy in prostate cancer. Furthermore, our in vitro results do not support a role of GIPC1 in the cellular radiation response. However, the role of GIPC1 in the progression of prostate cancer and its precursors should be subject to further research.
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Proteínas Adaptadoras Transductoras de Señales/genética , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/radioterapia , Tolerancia a Radiación/genética , Anciano , Anciano de 80 o más Años , Línea Celular Tumoral , Supervivencia Celular , Estudios de Cohortes , Supervivencia sin Enfermedad , Estudios de Seguimiento , Regulación Neoplásica de la Expresión Génica/genética , Humanos , Masculino , Persona de Mediana Edad , Clasificación del Tumor , Estadificación de Neoplasias , Pronóstico , Neoplasias de la Próstata/mortalidad , Neoplasias de la Próstata/patología , Interferencia de ARN , Tasa de Supervivencia , Células Tumorales Cultivadas/efectos de la radiación , Ensayo de Tumor de Célula MadreRESUMEN
In recent years, colorectal cancer (CRC), once a uniform disease with well-understood carcinogenesis, has been divided into at least five different subgroups with distinct precursor lesions, pathways of carcinogenesis, morphological, and molecular characteristics. Moreover, new therapeutic concepts with 'targeted' substances have added to the complexity of the management of CRC patients. The clinical value of biomarkers in advanced CRC is indisputable ever since activating mutations of the KRAS oncogene have been shown to predict resistance to anti-epidermal growth factor receptor antibodies. Prognostic biomarkers predicting patient outcomes and predictive biomarkers forecasting response to a certain therapy may help us to improve therapeutic agent selection and patient management with the ultimate goal of maximizing the benefit of treatment and minimizing toxicity. Biomarkers with known implications in advanced CRC will be discussed in this paper.
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Biomarcadores de Tumor , Neoplasias Colorrectales , Receptores ErbB , Proteínas Proto-Oncogénicas , Proteínas ras , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Transformación Celular Neoplásica , Fosfatidilinositol 3-Quinasa Clase I , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/metabolismo , Neoplasias Colorrectales/patología , Toma de Decisiones , Receptores ErbB/genética , Receptores ErbB/metabolismo , Regulación Neoplásica de la Expresión Génica , Humanos , Inestabilidad de Microsatélites , Patología Molecular , Fosfatidilinositol 3-Quinasas/genética , Fosfatidilinositol 3-Quinasas/metabolismo , Pronóstico , Proteínas Proto-Oncogénicas/genética , Proteínas Proto-Oncogénicas/metabolismo , Proteínas Proto-Oncogénicas B-raf/genética , Proteínas Proto-Oncogénicas B-raf/metabolismo , Proteínas Proto-Oncogénicas p21(ras) , Transducción de Señal , Proteínas ras/genética , Proteínas ras/metabolismoRESUMEN
Barrett's esophagus (BE), a well-known complication of gastroesophageal reflux disease (GERD), constitutes a precancerous condition for adenocarcinoma of the distal esophagus. The so-called Barrett's carcinoma shows increasing incidences in countries of the western hemisphere; new data, however, indicate that the rise in incidence is not quite as dramatic as previously assumed. The definition of BE is currently changing: despite good reasons for a purely endoscopic definition of BE, goblet cells are still mandatory for this diagnosis in Germany and the USA. Dysplastic changes in the epithelium are the most important risk factor for the development of Barrett's adenocarcinoma and recently dysplasia was subclassified into a more frequent adenomatous (intestinal) and a non-adenomatous (gastric-foveolar) types. The gold standard for diagnosing dysplasia is still H&E staining. The histological diagnosis of dysplasia is still encumbered by a significant interobserver variability, especially regarding the differentiation between low grade dysplasia and inflammatory/reactive changes and the discrimination between high grade dysplasia and adenocarcinoma. Current data, however, show much higher interobserver agreement in endoscopic resection specimens than in biopsies. Nevertheless, the histological diagnosis of dysplasia should be corroborated by an external second opinion because of its clinical consequences. In endoscopic resections of early Barrett's adenocarcinoma, the pathological report has to include a risk stratification for the likelihood of lymphogenic metastases.
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Adenocarcinoma/patología , Esófago de Barrett/patología , Lesiones Precancerosas/patología , Biomarcadores de Tumor/análisis , Transformación Celular Neoplásica/patología , Diagnóstico Diferencial , Diagnóstico Precoz , Esofagoscopía , Esófago/patología , Reflujo Gastroesofágico/complicaciones , Reflujo Gastroesofágico/patología , Células Caliciformes/patología , Humanos , Metástasis Linfática/patología , Metaplasia , Estadificación de Neoplasias , Variaciones Dependientes del Observador , PronósticoRESUMEN
The so-called serrated pathway has in recent years been well established as a second route of colorectal carcinogenesis. Sessile serrated polyps, especially sessile serrated adenomas (SSA) and traditional serrated adenomas (TSA) were identified as precursor lesions of this pathway. Activating mutations in either the BRAF (in SSAs) or the KRAS oncogene (in TSAs) have been determined as the initiating molecular alterations, followed by epigenetic methylation of CpG islands in promoter regions of genes which are implicated in cell cycle control or DNA repair. These findings have led to a paradigm shift in gastrointestinal pathology as lesions without cytological dysplasia, such as SSAs and certain forms of hyperplastic polyps, are now accepted to be precancerous lesions. In addition, carcinomas that have developed through the serrated pathway of colorectal carcinogenesis show varying biological behavior relevant for the clinical management of these tumors depending on the molecular aberrations.
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Transformación Celular Neoplásica/genética , Pólipos del Colon/genética , Pólipos del Colon/patología , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/patología , Lesiones Precancerosas/genética , Lesiones Precancerosas/patología , Islas de CpG/genética , Metilación de ADN/genética , Análisis Mutacional de ADN , Epigénesis Genética/genética , Humanos , Mucosa Intestinal/patología , Pronóstico , Regiones Promotoras Genéticas , Proteínas Proto-Oncogénicas/genética , Proteínas Proto-Oncogénicas B-raf/genética , Proteínas Proto-Oncogénicas p21(ras) , Proteínas ras/genéticaRESUMEN
The question of whether there are inflammatory changes in colorectal biopsy specimens is frequently asked, especially when the patient reports diarrhea or when the mucosa is reddened on endoscopy. The pathologist first has to find out whether there is, in fact, an increase in the inflammatory infiltrate of the colorectal mucosa which warrants the diagnosis of inflammation. If so, the second challenge is to ascertain the etiology of these inflammatory changes, in particular to differentiate between infectious and non-infectious causes. In principle, we can distinguish forms of colitis with distinct morphological hallmarks confirming the diagnosis (e.g. microscopic detection of the causative organism, as well as lymphocytic or collagenous colitis) from other forms of colitis which have a characteristic pattern of findings not necessarily allowing to deduce the etiology (e.g. infectious colitis without microscopic evidence of the germ vs. inflammatory bowel disease). The present article discusses the pathomorphology and differential diagnosis of the most important forms of bacterial colitis.
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Infecciones Bacterianas/patología , Colitis/patología , Mucosa Intestinal/patología , Colitis Colagenosa/patología , Colonoscopía , Diagnóstico Diferencial , Humanos , Enfermedades Inflamatorias del Intestino/patologíaRESUMEN
Aside from bacterial infections, viral, fungal, and parasitic infections are important differential diagnoses in inflammatory disorders of the colorectum. In contrast to bacterial infections, in which the causative organism can hardly ever be detected histologically, in non bacterial infections the germs can often be verified by either histology, immunohistochemistry, or at least by molecular pathology. This manuscript will give an overview of the spectrum of pathogenic germs, the clinical symptoms, and pathological findings of the most important infections.
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Colitis/patología , Virosis/patología , Infecciones Oportunistas Relacionadas con el SIDA/patología , Infecciones Bacterianas/patología , Colitis/etiología , Colon/patología , Diagnóstico Diferencial , Infecciones por VIH/patología , Helmintiasis/patología , Humanos , Mucosa Intestinal/patología , Micosis/patología , Infecciones por Protozoos/patología , Recto/patología , Sobreinfección/patologíaRESUMEN
Gastroenterologists removing colorectal polyps expect standardized and well-structured pathological reports, providing them with all relevant data for the further clinical management of the patient. Over the last year, a task force of clinicians and pathologists has developed a checklist to improve and harmonize endoscopic and pathological reporting of colorectal polyps. This checklist concentrates more on concrete recommendations from evidence-based guidelines and established international classifications for daily practice rather than detailed molecular pathological pathways of carcinogenesis. These recommendations are based on the current S3 guidelines for colorectal cancer (the chapter entitled "Management of colorectal polyps"), the histomorphological consensus manuscript of the GI working group of the German Society for Pathology, as well as the current WHO classification for tumors of the digestive system.
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Pólipos Adenomatosos/patología , Lista de Verificación , Neoplasias del Colon/patología , Pólipos del Colon/patología , Pólipos Intestinales/patología , Neoplasias del Recto/patología , Proteínas Adaptadoras Transductoras de Señales/genética , Adenocarcinoma/clasificación , Adenocarcinoma/genética , Adenocarcinoma/patología , Pólipos Adenomatosos/clasificación , Pólipos Adenomatosos/genética , Transformación Celular Neoplásica/genética , Transformación Celular Neoplásica/patología , Inestabilidad Cromosómica/genética , Colon/patología , Neoplasias del Colon/clasificación , Neoplasias del Colon/genética , Pólipos del Colon/clasificación , Pólipos del Colon/genética , Colonoscopía , Neoplasias Colorrectales Hereditarias sin Poliposis/clasificación , Neoplasias Colorrectales Hereditarias sin Poliposis/genética , Neoplasias Colorrectales Hereditarias sin Poliposis/patología , Metilación de ADN , Análisis Mutacional de ADN , Diagnóstico Diferencial , Medicina Basada en la Evidencia , Adhesión a Directriz , Humanos , Pólipos Intestinales/clasificación , Pólipos Intestinales/genética , Inestabilidad de Microsatélites , Homólogo 1 de la Proteína MutL , Proteínas Nucleares/genética , Proteínas Proto-Oncogénicas B-raf/genética , Neoplasias del Recto/clasificación , Neoplasias del Recto/genética , Recto/patología , Organización Mundial de la SaludRESUMEN
Until recently, two major types of colorectal epithelial polyps were distinguished: the adenoma and the hyperplastic polyp. While adenomas - because of their cytological atypia - were recognized as precursor lesions for colorectal carcinoma, hyperplastic polyps were perceived as harmless lesions without any potential for malignant progression, mainly because hyperplastic polyps lack cytological atypia. Meanwhile, it is evident that the lesions formerly classified as hyperplastic represent a heterogeneous group of polyps, some of which exhibit a significant risk of neoplastic progression. These lesions show characteristic epigenetic alterations not commonly seen in colorectal adenomas and progress to colorectal carcinoma via the so-called serrated pathway (CIMP pathway). This group of polyps is comprised not only of hyperplastic polyps, but also of sessile serrated adenomas (SSA), traditional serrated adenomas (TSA) and mixed polyps, showing serrated and "classical" adenomatous features. In a consensus conference of the working group of gastroenterological pathology of the German Society of Pathology, standardization of nomenclature and diagnostic criteria as well as recommendations for clinical management of these serrated polyps were formulated and are presented herein.
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Adenoma/patología , Pólipos del Colon/patología , Neoplasias Colorrectales/patología , Lesiones Precancerosas/patología , Adenoma/diagnóstico , Adenoma/genética , Adenoma/terapia , Apoptosis/genética , Biopsia , División Celular/genética , Transformación Celular Neoplásica/genética , Transformación Celular Neoplásica/patología , Pólipos del Colon/diagnóstico , Pólipos del Colon/genética , Pólipos del Colon/terapia , Neoplasias Colorrectales/diagnóstico , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/terapia , Islas de CpG/genética , Metilación de ADN/genética , Diagnóstico Diferencial , Epigénesis Genética/genética , Marcadores Genéticos/genética , Humanos , Hiperplasia , Mucosa Intestinal/patología , Lesiones Precancerosas/diagnóstico , Lesiones Precancerosas/genética , Lesiones Precancerosas/terapia , Pronóstico , Terminología como AsuntoRESUMEN
The serrated pathway of colorectal carcinogenesis is heterogeneous with respect to its precursor lesions, molecular alterations and its prognosis. The low-risk-subtype of serrated adenocarcinomas is less frequent (<20% of all serrated adenocarcinomas) and characterized by proximal location, BRAF-mutation, high CpG-island methylation with loss of MLH1-expression and MSI-H phenotype. The assumed precursor lesion of this subtype is the sessile serrated adenoma and the 5-year overall survival is >70%. The high-risk-subtype is more frequent (>80% of all serrated adenocarcinomas) and characterized by distal location, KRAS mutation, MSI-L/MSS phenotype, lower CpG-island methylation, and possible p53 accumulation. The assumed precursor lesion is the traditional serrated adenoma and the prognosis is unfavorable (<30% 5-year overall survival). The analysis of MSI status, KRAS and BRAF mutational status and immunohistochemical analyses of hMLH1 and p53 expression enables the distinction between these two subtypes and is therefore clinically relevant, especially since treatment options for the two subtypes may differ in the future.