Retos e implicaciones clínicas de la heterogeneidad intratumoral / Clinical challenges and implications of intratumor heterogeneity

Las neoplasias muestran un elevado, aunque variable, grado de heterogeneidad intratumoral (HIT) desde el punto de vista clínico y morfológico. Además, las técnicas de análisis molecular masivo están mostrando en los últimos tiempos hasta qué punto los tumores pueden ser heterogéneos también desde el punto de vista molecular. Este hecho tiene una importancia capital para los pacientes, ya que incide de forma decisiva en el éxito de las llamadas terapias de precisión y justifica una parte muy importante de los fracasos terapéuticos de la oncología moderna. Esta revisión pretende ser una puesta al día de los últimos hallazgos en este campo en un grupo de neoplasias con alto impacto social con las que los patólogos nos enfrentamos muy frecuentemente

Tumors display a high, albeit variable, grade of intratumor heterogeneity, both from a clinical and a morphological viewpoint. Furthermore, recent methods of large-scale molecular analysis demonstrate to what extent tumors can also be heterogeneous from a molecular perspective. This is of paramount importance for patients as it has a great impact on the success of so-called precision therapies and explains the reason for a significant number of therapeutic failures in modern oncology. We present an up-to-date review of the latest findings in a group of tumors with a high social impact, commonly seen in the daily routine of the pathology laboratory

Correlation of mRNA-PCA3 urine levels with the new grading system in prostate cancer / Correlación de mRNA-PCA3 en orina con el nuevo sistema de gradación de cáncer de próstata

Purpose: To evaluate the PCA3 (Prostate Cancer 3 gene) as a tool to improve prostate cancer (PCa) screening and its capability to predict PCa aggressiveness. Patients and methods: A retrospective study with data from consecutive patients with suspected PCa seen in the urology department between November 2009 and April 2016 and who were candidates for prostate biopsy. A total of 1038 urine samples were tested in our laboratory with a kit that generated a PCA3 score (s-PCA3). A prostate biopsy was recommended only in those patients with s-PCA3≥35. Associations between variables were analyzed using the R software. Results: In patients with a positive s-PCA3 (44.5%), a subsequent biopsy was recommended. Of a total of 151 biopsies studied, 56.3% yielded a diagnosis of PCa. The probability of a positive biopsy increased as the s-PCA3 increased (p=0.041). The percentage of affected cylinders increased as the s-PCA3 increased (p=0.015). A statistically significant relationship was observed between s-PCA3 and both the Gleason score and the Grade Group (p=0.001 and 0.008, respectively). The best log-linear models and a logistic model confirmed the relationships shown previously with Fisher's exact tests. Conclusions: S-PCA3 may serve as an additional marker to reduce the indication for biopsies and avoid overdiagnosis and overtreatment of patients with suspected PCa. The prognostic significance of s-PCA3 was confirmed, as it was associated with tumor volume and Gleason score. Importantly, to our knowledge this is the first time that an association has been demonstrated between s-PCA3 and the new Grade Group

Objetivo: Evaluar el estudio de PCA3 (gen Prostate Cancer 3) en orina como test complementario para mejorar el cribado de cáncer de próstata (CaP), así como su capacidad de predecir la agresividad tumoral antes de la biopsia. Pacientes y métodos: En este estudio retrospectivo se incluyeron pacientes consecutivos con sospecha de CaP y candidatos a biopsia, que se presentaron en la consulta del urólogo entre noviembre de 2009 y abril de 2016. Se testaron en nuestro laboratorio un total de 1.038 muestras de orina con un kit que generó un PCA3 score (s-PCA3). Se recomendó la biopsia en aquellos pacientes con s-PCA3≥35. Las asociaciones entre variables se analizaron con el software R. Resultados: En los pacientes con s-PCA3 positivo (44,5%) se recomendó la realización de una biopsia. Se estudiaron un total de 151 biopsias de las que un 56,3% fueron diagnosticadas de CaP. La probabilidad de obtener una biopsia positiva aumentó a medida que lo hacia el s-PCA3 (p=0,041). El porcentaje de cilindros afectados aumentó a medida que lo hacía el s-PCA3 (p=0,015). El s-PCA3 presentó una relación estadísticamente significativa con el grado de Gleason (p=0,001) y el grado grupo (p=0,008). El mejor modelo Log-lineal, así como el modelo logístico confirmaron las relaciones observadas previamente con las pruebas exactas de Fisher. Conclusiones: El s-PCA3 es una herramienta complementaria que permite reducir la indicación de biopsias y evitar el sobrediagnóstico y sobretratamiento de pacientes con sospecha de CaP. La significación pronóstica del s-PCA3 fue confirmada al demostrarse su asociación con el volumen tumoral y el grado de Gleason. Según la información de la que disponemos, este es el primer estudio en el que se demuestra la asociación entre el s-PCA3 y el nuevo sistema de gradación del CaP

Consenso 2018 de la Sociedad Española de Anatomía Patológica y la Sociedad Española de Oncología Médica sobre el diagnóstico y tratamiento del cáncer de origen desconocido / 2018 Consensus statement by the Spanish Society of Pathology and the Spanish Society of Medical Oncology on the diagnosis and treatment of cancer of unknown primary

El cáncer de origen desconocido se define como un grupo heterogéneo de tumores que se manifiestan con metástasis y para los que no se ha conseguido identificar su localización original. Sus características biológicas y forma de diseminación difieren del resto de tumores primarios, lo que hace que puedan considerarse como una entidad independiente. Aunque se han planteado varias hipótesis sobre su origen, la explicación más plausible sobre su agresividad y quimiorresistencia parece estar relacionada con la inestabilidad cromosómica. Dependiendo del tipo de estudio llevado a cabo, el cáncer de origen desconocido puede llegar a suponer entre el 2-9% de todos los pacientes con cáncer, principalmente entre los 60-75 años. En este artículo se revisan los principales estudios clínicos, patológicos y moleculares llevados a cabo para el análisis y determinación del origen del cáncer de origen desconocido, así como las principales estrategias terapéuticas y de manejo del paciente, tanto a nivel clínico como de anatomía patológica

Cancer of unknown primary is defined as a heterogeneous group of tumours that present with metastasis, and in which attempts to identify the original site have failed. They differ from other primary tumours in their biological features and how they spread, which means they can be considered a separate entity. There are several hypotheses regarding their origin, but the most plausible explanation for their aggressiveness and chemoresistance seems to involve chromosomal instability. Depending on the type of study done, cancer of unknown primary can account for 2-9% of all cancer patients, mostly 60-75 years old. This article reviews the main clinical, pathological and molecular studies conducted to analyse and determine the origin of cancer of unknown primary. The main strategies for patient management and treatment, by both clinicians and pathologists, are also addressed

Adaptación española de la Escala de Control Personal Percibido ("Perceived Personal Control") en Consejo Genético / Spanish adaptation of the Perceived Personal Control (PPC) in genetic counseling

Objetivo: Analizar la validez y la fiabilidad de la adaptación de la escala Perceived Personal Control (PPC) en el contexto español para pacientes portadoras de mutación en los genes BRCA1/2 responsables del cáncer de mama y ovario hereditario (CMOH). Método: Adaptación transcultural y validación de la escala Perceived Personal Control (PPC) desarrollada por Shiloh y colaboraradores mediante traducción, retrotraducción y validación a través de un análisis factorial exploratorio con rotación Oblimin en una muestra de 176 mujeres portadoras de genes BRCA 1/2 para CMOH. Resultados: La versión española de la PPC reduce a seis los nueve ítems de la escala original, dado que esta estructura es la que ofrece una solución factorial más satisfactoria. El análisis factorial mostró un solo factor que explica el 51,07% de la varianza, en el que todos los ítems tenían cargas factoriales por encima de 0,4. El coeficiente α de Cronbach fue de 0,84 para el conjunto de la escala, la cual permite obtener valores que oscilan entre 0 (bajo grado de percepción de control) y 2 (alto grado de percepción de control). Conclusiones: La adaptación española de la Escala de Percepción de Control (PPC6) posee propiedades psicométricas satisfactorias en la versión de 6 ítems con un solo factor, por lo que su utilización en contexto español Consejo Genético para cáncer hereditario parece adecuada (AU)

Purpose: The aim of this study was to analyze the reliability and validity of the spanish adaptation of the Perceived Personal Control (PPC) scale in women who were positive for BRCA1/2 genes, which are related with hereditary ovarian and breast cancer (HOBC). Method: PPC original items developed by Shiloh and co-workers were translated and back-translated in order to develop an spanish version which was analyzed by an exploratory factor analysis with Oblimin rotation. Answers to the spanish version were provided by a sample of 176 women who were positive for BRCA1/2 for HOBC. Results: Spanish version contains only six items of the nine original items, since this structure provided the optimal solution to the exploratory factor analysis. This version is a one-factor scale (51.07% of variance explained) and all items had factor loading values >0.4. The scale has good reliability (Cronbach's Alpha =0.84) and gives a range of values between 0 (low perceived control) and 2 (high perceived control). Conclusions: Spanish adaptation (PPC6) of the original 9-items version has enough reliability and psychometric properties, and it seems to be useful to be applied in Genetic Counseling at spanish cultural settings (AU)

Preventive treatments for breast cancer: recent developments

Breast cancer is a burden for western societies, and an increasing one in emerging economies, because of its high incidence and enormous psychological, social, sanitary and economic costs. However, breast cancer is a preventable disease in a significant proportion. Recent developments in the armamentarium of effective drugs for breast cancer prevention (namely exemestane and anastrozole), the new recommendation from the National Institute for Health and Care Excellence to use preventative drugs in women at high risk as well as updated Guidelines from the US Preventive Services Task Force and the American Society of Clinical Oncology should give renewed momentum to the pharmacological prevention of breast cancer. In this article we review recent major developments in the field and examine their ongoing repercussion for breast cancer prevention. As a practical example, the potential impact of preventive measures in Spain is evaluated and a course of practical actions is delineated (AU)

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Regulación del splicing alternativo: Implicaciones en el diagnóstico y tratamiento del cáncer / Alternative splicing regulation: Implications in cancer diagnosis and treatment

La expresión de la información genética es regulada por procesos como el splicing del ARN mensajero, mecanismo propuesto por Phil Sharp y Richard Roberts, quienes demostraron la existencia de secuencias intrónicas, las cuales interrumpen a la mayoría de los genes estructurales en eucariotes y deben ser removidas con gran precisión. Dicha remoción de intrones se denomina splicing, y permite generar variantes proteicas a partir de un solo gen, cada una con funciones diversas y, a menudo, antagónicas. Actualmente se sabe que el splicing es la principal fuente de diversidad proteica, ya que el 70% de los genes humanos lo sufren, y defectos en este proceso originan hasta el 50% de las enfermedades genéticas, incluido el cáncer. Cuando estos defectos se presentan en genes involucrados en adhesión, proliferación y ciclo celular, repercuten en la progresión de procesos cancerosos cuyo diagnóstico, tratamiento y prognosis puede determinarse en base a su perfil de splicing (AU)

The accurate expression of the genetic information is regulated by processes like mRNA splicing, proposed after the discoveries of Phil Sharp and Richard Roberts, who demonstrated the existence of intronic sequences, present in almost every structural eukaryotic gene, which should be precisely removed. This intron removal is called “splicing”, which generates different proteins from a single mRNA, with different or even antagonistic functions. We currently know that alternative splicing is the most important source of protein diversity, given that 70% of the human genes undergo splicing and that mutations causing defects in this process could originate up to 50% of genetic diseases, including cancer. When these defects occur in genes involved in cell adhesion, proliferation and cell cycle regulation, there is an impact on cancer progression, rising the opportunity to diagnose and treat some types of cancer according to a particular splicing profile (AU)

Genetic modification of hypoxia signaling in animal models and its effect on cancer

Conditions that cause hypoxemia or generalized tissue hypoxia, which can last for days, months, or even years, are very common in the human population and are among the leading causes of morbidity, disability, and mortality. Therefore, the molecular pathophysiology of hypoxia and its potential deleterious effects on human health are important issues at the forefront of biomedical research. Generalized hypoxia is a consequence of highly prevalent medical disorders that can severely reduce the capacity for O 2 exchange between the air and pulmonary capillaries. In recent years, some of the key O 2 -dependent signaling pathways have been characterized at the molecular level. In particular, the prolyl hydroxylase (PHD)- hypoxia-inducible factor (HIF) cascade has emerged as the master regulator of a general gene expression program involved in cell/tissue/organ adaptation to hypoxia. Hypoxia has emerged as a critical factor in cancer because it can promote tumor initiation, progression, and resistance to therapy. Beyond its role in neovascularization as a mechanism of tumor adaptation to nutrient and O 2 deprivation, hypoxia has been linked to prolonged cellular lifespan and immortalization, the generation of ‘‘oncometabolites’’, deregulation of stem cell proliferation, and inflammation, among other tumor hallmarks. Hypoxia may contribute to cancer through several independent pathways, the inter-connections of which have yet to be elucidated. Furthermore, the relevance of chronic hypoxemia in the initiation and progression of cancer has not been studied in depth in the whole organism. Therefore, we explore here the contributions of hypoxia to the whole organism by reviewing studies on genetically modified mice with alterations in the key molecular factors regulating hypoxia (AU)

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Ethical and legal issues concerning the use of whole genome sequencing in basic research and clinical studies

El presente trabajo identifica los problemas y analiza los conflictos que plantea el proceso de secuencia completa del genoma (Whole Genome Sequencing - WGS), proceso que determina la secuencia completa del ADN del genoma de un organismo en una sola vez. En este sentido, las mejoras en las tecnologías de secuenciación han reducido sustancialmente tanto el costo como el tiempo requerido para secuenciar un genoma humano entero. Mientras que la secuenciación del primer genoma humano tardó siete años, hoy se puede hacer en tan solo unos días y se espera que dicha secuanciación pronto desempeñe un papel importante en la práctica clínica diaria. Este artículo ofrece una visión general sobre las cuestiones objeto de debate y también las respuestass y las soluciones desarrolladas y formuladas por el grupo EURAT de Heildelberg que estudia los aspectos ético-jurídicos del proceso de secuencia completa de genoma (WGS) (AU)

This paper identifies problems and analyzes those conflicts posed by the Whole Genome Sequencing (WGS) process which determines the complete DNA sequence of an organism´s genoma at single time. In this sense, improvements in sequencing technologies have substantially reduced both the cost and the time rquired to sequence an entire human genome. Whereas the sequencing of the first human genome took seven years, today it can be done in just a few days and it is expected that such sequencing will soon play a role in everyday clinical practice. This paper provides an overview about the questions at stake and also potential answers and solutions developed and formulated by EURAT - Ethical and Leggal Aspects of Whole Genome Sequencing - group in Heildelberg (AU)

Candidate genes and potential targets for therapeutics in Wilms' tumour

Wilms' tumour (WT) is the most common malignant renal tumour of childhood. During the past two decades or so, molecular studies carried out on biopsy specimens and tumour-derived cell lines have identified a multitude of chromosomal and epigenetic alterations in WT. In addition, a significant amount of evidence has been gathered to identify the genes and signalling pathways that play a defining role in its genesis, growth, survival and treatment responsiveness. As such, these molecules and mechanisms constitute potential targets for novel therapeutic strategies for refractory WT. In this report we aim to review some of the many candidate genes and intersecting pathways that underlie the complexities of WT biology (AU)

Bypassing cellular senescence by genetic screening tools

Bypassing cellular senescence is a prerequisite step in the tumorigenic transformation. It has long been known that loss of a key tumour suppressor gene, such as p53 or pRB, is necessary but not sufficient for spontaneous cellular immortalisation. Therefore, there must be additional mutations and/or epigenetic alterations required for immortalisation to occur. Early work on these processes included somatic-cell genetic studies to estimate the number of senescence genes and nowadays are completed by in vivo models and with the requirements to bypass senescence induced by oncogenic transformation in stem cells. These principal studies laid the foundation for the field of senescence/immortalisation but were labour intensive and the results were somewhat limited. Using retroviral-based functional genetic screening, we and others identified universal genes regulating senescence/immortalisation (either by gain or loss of function) and found that some of these genes are widely altered in human tumours. We also explored the molecular mechanisms throughout these genes that regulate senescence and established the causality of the genetic alteration in tumorigenesis. The identification of genes and pathways regulating senescence/immortalisation could provide novel molecular targets for the treatment and/or prevention of cancer (AU)