Hallazgos incidentales en medicina genómica / Incidental Findings in Genomic Medicine

Las técnicas de Biología Molecular de última generación, como es la secuenciación masiva en paralelo o NGS (Next Generation Sequencing), permite obtener gran cantidad de información genómica, la cual muchas veces va más allá de la detección de una variante patogénica en un gen que explique la patología (hallazgo primario). Es así como surgió desde hace años la discusión internacional respecto a la decisión a tomar frente a los hallazgos secundarios accionables, es decir, aquellos hallazgos de variantes clasificadas como patogénicas o probablemente patogénicas que no están relacionadas con el fenotipo del paciente, pero que tiene alguna medida preventiva o tratamiento posible y, por lo tanto, podría ser de utilidad para la salud del paciente. Luego de revisar la bibliografía internacional y debatir entre los expertos del Hospital de Pediatría Garrahan, se logró establecer una política institucional y reforzar el hecho de que se trata de una disciplina multidisciplinaria. Así, fue posible definir que solo se atenderá las cuestiones relacionadas con la edad pediátrica, dejando para un tratamiento posterior aquellas variantes detectadas en genes que sean accionables en edad adulta. En el Hospital Garrahan, ha sido posible definir claramente cómo proceder frente a los hallazgos secundarios, al adaptar el consentimiento informado a esta necesidad, definiendo cuándo serán informados, y sabiendo que serán buscados intencionalmente en los genes clínicamente accionables enlistados en la última publicación del American College of Medical Genetics and Genomics, siempre y cuando el paciente/padre/tutor lo consienta (AU)

The latest generation of molecular biology techniques, including massive parallel sequencing or NGS (Next Generation Sequencing), allows us to obtain a whealth of genomic information, which often goes beyond the detection of a pathogenic variant in a gene that explains the pathology (primary finding). As a result, an international discussion has arisen over the years regarding the decision-making concerning actionable secondary findings, it means, those findings of variants classified as pathogenic or probably pathogenic that are not related to the patient's phenotype, but which have some possible preventive measure or treatment and, therefore, could be useful for the patient's health. After reviewing the international literature and discussing among the experts of the Hospital de Pediatría Garrahan, an institutional policy was established and the concept that this is a multidisciplinary discipline was reinforced. Consequently, it has been defined that only issues related to children will be addressed, reserving those variants detected in genes that are actionable in adulthood for later treatment. At Garrahan Hospital, we were able to clearly define how to proceed with secondary findings by adapting the informed consent to this need, defining when they will be reported, and knowing that they will be intentionally searched for in the clinically actionable genes listed in the latest publication of the American College of Medical Genetics and Genomics, as long as the patient/parent/guardian consents (AU)

DNA rare copy number alterations in Reinke's Edema

Abstract Introduction: Reinke's Edema (RE) is a laryngeal lesion related to excessive tobacco smoking, voice overuse, and laryngopharyngeal reflux. Although the risk of malignancy has been considered low in literature, RE is classified among precancerous lesions. Objectives: We investigated DNA Copy Number Alterations (CNAs) in specimens of RE and its potential association with malignant progression. Methods: We used array-based comparative genomic hybridization (aCGH, Agilent 4 × 180 K platform) to study eight RE cases. All patients were heavy tobacco users for at least 30 years, and none of them progressed to cancer in the follow-up (>8 years). Two RE presented mild dysplasia, one moderate dysplasia, and no histological alterations were found in the remaining five cases. CNAs were compared with the Database of Genomic Variants (DGV) and genes mapped on altered regions had their functions annotated. Results: Six of eight patients showed different rare copy number alterations on chromosomes 2q37.3, 4q13.1, 4q13.3, 7q11.22, 10p14, and 13q34. A gain of the whole chromosome 8 were detected in one case. Of interest, four of eight RE cases showed copy number imbalances involving genes previously described in several tumor types (RASA3, COL6A3, LINC00707, LINP1, SMR3A, and SMR3B). Conclusion: The genomic imbalances herein found in RE have the potential to contribute to the phenotype but with limited or no risk of cancer. A long-term follow-up in a large series of patients could clarify the mechanisms involved in the malignant progression of RE. Level of evidence: 4.

Progress in the diagnosis and treatment of rare diseases in the era of genomic medicine / 中华内分泌代谢杂志

There are many different kinds of rare diseases, of which most are with serious, complicated, and non-specific symptoms, and great difficulties exist in both diagnosis and treatment of rare diseases. In the era of genomic medicine, with the extensive application of next-generation sequencing technology and in-depth research of gene therapy, the diagnosis and treatment of rare diseases has ushered in a new turn. The next-generation sequencing technology enables high-throughput detection, assists in clinically efficient phenotypic assessment and disease diagnosis and promotes research on the pathogenesis and treatment of rare diseases;gene therapy technology continues to improve, and drugs are successively acquired, which brings the hope for cure to patients with rare diseases. This article will provide a brief overview of the advances and challenges of the diagnosis and treatment of rare diseases in the era of genomic medicine.

Progress in the diagnosis and treatment of rare diseases in the era of genomic medicine / 中华内分泌代谢杂志

There are many different kinds of rare diseases, of which most are with serious, complicated, and non-specific symptoms, and great difficulties exist in both diagnosis and treatment of rare diseases. In the era of genomic medicine, with the extensive application of next-generation sequencing technology and in-depth research of gene therapy, the diagnosis and treatment of rare diseases has ushered in a new turn. The next-generation sequencing technology enables high-throughput detection, assists in clinically efficient phenotypic assessment and disease diagnosis and promotes research on the pathogenesis and treatment of rare diseases; gene therapy technology continues to improve, and drugs are successively acquired, which brings the hope for cure to patients with rare diseases. This article will provide a brief overview of the advances and challenges of the diagnosis and treatment of rare diseases in the era of genomic medicine.

La medicina personalizada, la revolución genómica y el Sistema Nacional de Salud / Customized medicine, genomic revolution and the national health care system

La profundización del conocimiento de los mecanismos moleculares del proceso salud-enfermedad ha hecho que avances científicos hayan encontrado lugar en la práctica clínica, como ha ocurrido en Cuba con las células madre. Los resultados derivados de la secuenciación del genoma humano y de otras especies mejora diagnósticos y tratamientos, sin embargo, dentro del sistema sanitario cubano no abundan las aplicaciones de las tecnologías genómicas. Esta nueva medicina necesita acumular todavía evidencia acerca de su seguridad y eficacia, se requiere una estrategia propia del Ministerio de Salud Pública en relación con la evaluación de sus usos, presentes y potenciales, en beneficio de la salud de la población. Se propone, entre otras acciones, constituir un grupo de trabajo multiinstitucional e intersectorial para estudiar las dimensiones clínicas, tecnológicas, reguladoras y bioéticas de la medicina genómica. Resulta imprescindible la preparación inmediata del personal que estudia en el pregrado o ya ejerce en las ciencias médicas, pues corresponderá a ellos la introducción y la extensión de estas tecnologías en el ejercicio de su práctica profesional. De manera inmediata es posible conformar cohortes que sean representativas de la población cubana, estudiarlas y conservar sus muestras en biobancos establecidos para tales fines. La progresiva introducción de las aplicaciones en la práctica clínica de la genómica y las tecnologías relacionadas, reclama del Sistema Nacional de Salud una atención que conduzca al estudio, la evaluación y propuesta de las acciones que permitan su implementación, según las evidencias y las condiciones y necesidades del modelo cubano de atención sanitaria(AU)

Deepening into the knowledge of the molecular mechanisms of the health/disease process has made many scientific advances to find a place into the clinical practice, as is the case of stem cells therapy in Cuba. The results derived from the sequencing of the human genome, as well of other species, have had an impact in the improvement of diagnoses and therapies; however, within the Cuban national health system the applications of genomic technologies are not widespread. Despite the fact that this new medicine still needs to accumulate much more evidence supporting its safety and efficacy, it is urgent to design a customized strategy by the Cuban Ministry of Public Health towards the assessment of current and potential uses of genomic medicine for the benefit of the population's health. Among other actions, this paper submitted the proposal of the creation of a multi-institutional and intersectoral taskforce to study the clinical, technological, regulatory and bioethical dimensions of genomic medicine. It is mandatory to train both undergraduate students and staff since they will be responsible to introduce and extend such technologies in their professional practice. It is already possible to make up cohorts resembling as much as possible the Cuban population, to study them and to collect and preserve their samples in biobanks established for such purposes(AU)

El Genoma en los Cordados: Introducción a la Genómica Comparada / The Genome in the Chordates: Introduction to Comparative Genomics

El objetivo del presente trabajo es describir brevemente conceptos de la genómica de los cordados así como de la genómica comparada y sus aspectos éticos. El genoma de los cordados cambió ligeramente dando lugar al genoma de los vertebrados, entre ellos el de los mamíferos, entre los que se incluye el ser humano. La genómica comparada estudia las semejanzas y diferencias entre genomas de diferentes organismos; trata de explicar la información proporcionada por la selección natural para entender la función y los procesos evolutivos que actúan sobre los genomas. La complejidad de los procesos evolutivos constituye todo un desafío a la hora de analizar e interpretar la información biológica generada; en este sentido, la Bioinformática y la Biología Computacional proporcionan un amplio abanico de técnicas estadísticas, matemáticas y algorítmicas para el análisis de datos biológicos. Un reto clave es analizar el caudal de datos de secuencias de ADN con el fin de comprender la información almacenada en términos de estructura, función y evolución proteicas. En Biología computacional BLAST y ClustalW2 son las herramientas más empleadas para el análisis de alineamientos múltiples de secuencias. La Genómica está resultando clave también en el campo de la medicina; conocer la cartografía del genoma humano proporciona una valiosa información a tener en cuenta a la hora de detectar genes implicados en ciertas enfermedades. Esto conlleva que en la actualidad nos centremos más en la predicción de patologías que en la prevención, por lo que la tendencia es que en el futuro la Medicina Genómica acabe desbancando a la Medicina Preventiva. El Proyecto Genoma Humano presenta diversas aplicaciones que, al no tener una clara cobertura legal, traen consigo un nuevo paradigma con problemas éticos, sociales y legales que la comunidad científica trata de resolver para compaginar los aspectos morales con el progreso en la investigación.

The aim of this paper is to briefly describe concepts of genomics of chordates and comparative genomics and its ethical aspects. The genome of chordates changed slightly resulting in the genome of vertebrates, including mammals. The human being belongs to the phylum chordates. Comparative genomics studies the similarities and differences between genomes of different organisms, trying to explain the information provided by natural selection to understand the function and evolutionary processes that act on genomes. Evolutive processes' complexity is considered a major challenge in terms of analyzing and interpreting all the biological information generated; in this sense, Bioinformatics and Computational Biology provide an enormous range of statistical, mathematical and algorythmical techniques for biological data analyses. A key challenge for bioinformatics is to analyze the flow of DNA sequence data to understand the information stored in terms of structure, function and protein evolution. BLAST and ClustalW2 tools are used for the analysis of multiple sequence alignments in Computational Biology. Genomics is also playing a key role in Medicine; human genome's cartography provides valuable information to detect genes involved in certain diseases. It entails that nowadays it is better to focus on prediction much more than on prevention. The current tendency is that in the future Genomic Medicine will displace Preventive Medicine. The Human Genome Project implies diverse applications that do not have clear legal coverage. This brings a new paradigm with ethical, social and legal problems that the scientific community is trying to resolve in order to combine morality and research progress.

Personalized medicine: caught between hope, hype and the real world

Genomic and personalized medicine have become buzz phrases that pervade all fields of medicine. Rapid advances in "-omics" fields of research (chief of which are genomics, proteinomics, and epigenomics) over the last few years have allowed us to dissect the molecular signatures and functional pathways that underlie disease initiation and progression and to identify molecular profiles that help the classification of tumor subtypes and determine their natural course, prognosis, and responsiveness to therapies. Genomic medicine implements the use of traditional genetic information, as well as modern pangenomic information, with the aim of individualizing risk assessment, prevention, diagnosis, and treatment of cancers and other diseases. It is of note that personalizing medical treatment based on genetic information is not the revolution of the 21st century. Indeed, the use of genetic information, such as human leukocyte antigen-matching for solid organ transplantation or blood transfusion based on ABO blood group antigens, has been standard of care for several decades. However, in recent years rapid technical advances have allowed us to perform high-throughput, high-density molecular analyses to depict the genomic, proteinomic, and epigenomic make-up of an individual at a reasonable cost. Hence, the so-called genomic revolution is more or less the logical evolution from years of bench-based research and bench-to-bedside translational medicine.

La medicina genómica: un cambio de paradigma de la medicina moderna retos para la bioética y el derecho / Genomic medicine; a paradigm shift in modern medicine challenges for bioethics an the law / A medicina genômica: uma mudança de paradigma da medicina moderna desafios para a bioética e para o direito

La medicina genómica y sus diferentes formas de aplicación medicinas personalizada o individualizada, de la que hacen parte la farmacogenómica, toxicogenómica y nutrigenómica; y la medicina predictiva, regenerativa o de reemplazo, molecular y reproductiva), sin lugar a dudas han transformado a la medicina moderna y se constituyen en un nuevo paradigma. Este artículo pretende hacer una revisión de las distintas formas de la medicina genómica, desde sus beneficios para la salud humana y cambios sustanciales en el abordaje del proceso salud-enfermedad, así como de las problemáticas y paradojas asociadas que deben ser abordadas desde la Bioética y el Derecho...

Genomic medicine and its different application forms, such as personalized (to which pharmacogenomics, toxicogenomics, nutrigenomics and predictive medicine belong), regenerative, molecular and reproductive medicines, have undoubtedly transformed modern medicine, becoming a new paradigm. The present study aims at reviewing the different forms of genomic medicine, from its benefits to human health, up to the problems and paradoxes that must be approached from bioethics and law...

A medicina genômica e suas diferentes formas de aplicação (medicinas personalizada ou individualizada, da qual fazem parte a farmacogenômica, a toxicogenômica e a nutrigenômica; e a medicina preditiva, regenerativa ou de substituição, molecular e reprodutiva) sem dúvidas têm transformado a medicina moderna e constituem um novo paradigma. Este artigo pretende fazer uma revisão das distintas formas da medicina genômica, desde seus benefícios para a saúde humana e mudanças substanciais na abordagem do processo saúde-doença, bem como das problemáticas e paradoxos associados que devem ser abordados a partir da Bioética e do Direito...

Parto pre-término: impacto perinatal y la medicina genómica / Pre-term birth: perinatal impact and the genomic medicine

El parto pre-término es el mayor reto de la medicina perinatal. Nos propusimos analizarlo para conocer su repercusión en la morbimortalidad perinatal y la morbilidad materna, y finalmente conocer los alcances de la medicina genómica sobre esta entidad perinatal. Se realiza una revisión sistemática y análisis de las publicaciones que sobre esta patología se han originado en este hospital desde 1970 a abril 2010 siguiendo una linea de investigación propia de 32 años. Ademas se revisó la literatura mundial en las bases de datos médicos en internet desde 1982 a la actualidad para obtener la relación científica de la medicina genómica y el parto pre-término. La incidencia del parto pre-término estudiada en dos series con 636 casos en el lapso 2003-2007 revelo promedio porcentual de 4.19. La incidencia de morbi-mortalidad perinatal analizada en cuatro series de parto pre-terminó que totalizan 1.441 casos 1991-2007, la morbilidad promedio fue 27,79%, la mortalidad perinatal 38,18%, lamortalidad fetal 21,66% y la mortalidad neonatal 15,62%, la patología primaria fue el síndrome de insuficiencia respiratoria. La participación del parto pre-término en la mortalidad perinatal (muerte fetal y neonatal) encontrada en cuatro publicaciones con total de 1430 muertes 1993-2002 fue de 68,65%. El aporte del parto pre-término en la morbilidad materna evaluada por hospitalización antenatal, en muestra de 256 gestantes años 1991-1993, se asoció al 23,4 como amenaza de parto pre-termino % y en una población de 1326 gestantes hospitalizadas aportó 25,72%. La medicina genómica se muestra como una alternativa novedosa ante el parto pre-término, con tecnólogía de avanzada, en los conocimientos etiogénicos, recursos diagnósticos y terapéuticos precoces y posibles acciones preventivas futurísticas. Se concluye que el parto pre-término implica elevadas cifras de morbimortalidad perinatal, aportada principalmente por deficiencias respiratorias, además incide en la morbilidad materna...

The pre-term birth is the greatest challenge in perinatal medicine. We set analyzes their repercussion to perinatal morbidity and maternal morbidity, and finally to know the scope of genomic medicine perinatal about this entity. We performed a systematic review and analysis of published literature on this entity that have sprung up in this hospital from 1970 to April 2010 following a line of own research of 32 years. Also reviewed the world literature in medical databases on the Internet from 1982 to present for the scientific relationship of genomic medicine and pre-term birth. The incidence of pre-term birth studied in two series with 636 cases in the period 2003-2007 showed an average percentage rate of 4.19. The incidence of perinatal morbidity and mortality analyzed in four series totaling 1441 cases of pre-term birth, period 1991-2007, the average morbidity was 27.79%, perinatal mortality 38.18%, fetal mortality 21.66% and neonatal mortality 15,62%, the primary pathology was respiratory distress syndrome. The morbidity and perinatal mortality (fetal and neonatal death) was studied in four publications with total of 1439 dealths, 1993-2002, 68,65% were the pre-term births. The impact of pre-term birth in morbidity assessed by antenatal hopitazation in a sample of 256 pregnant years 1991-1993, was associated with 23.4% and a population of 1326 pregnant women hospitalized contributed 25.72% with pre-term labor. Genomic medicine is shown as a novel alternative to pre-term birth with advanced technology, in knowledge etiology, early diagnostic and therapeutic resources and possible preventive actions futuristic. We conclude that pre-term birth involves high perinatal morbidity and mortality figures, contributed mainly by respiratory distress also affects maternal morbidity. Genomic medicine is looming, with promising hopes etiopathogenic and behavior. Meanwhile, we must emphasize prevention programs and improved neonatal care

Medicina genômica personalizada aqui e agora / Personal genomic medicine here and now

A Medicina Genômica é uma revolução em curso, baseada em testes genéticos que permitem o conhecimento do mapa de predisposições genéticas de cada indivíduo. O uso de técnicas de altíssima eficiência permite estudar simultaneamente variações individuais em centenas de milhares de genes, a custo cada dia mais baixo. O resultado dos testes possibilita praticar o que antes era impossível: uma medicina verdadeiramente personalizada, preditiva, pró-ativa, preventiva e participativa. Conhecendo a intimidade das variações genômicas que determinam predisposições e resistências de cada pessoa, é possível manipular o ambiente (estilo de vida, dieta, adição ou remoção de fármacos, cirurgias preventivas) de forma a manter o equilíbrio harmônico genoma/ ambiente que caracteriza a saúde. A partir do teste monitor genômico, e acesso à Medicina Genômica personalizada já é possível aqui e agora.

Genomic Medicine is a revolution in progress, based on genetic tests that allow the knowledge of each individual's map of genetic predispositions. Using high efficiency techniques allows the study of individual variations simultaneouslv in hundreds of thousands of genes, each day at a lower cost. The tests results make possible what was once impossible: to practice the actually personalized medicine, predictive, pro-active, preventive and participative. Knowing the privacy of genomic variations that determine biases and strengths of each person, you can manipulate the environment (lifestyle, diet, addition or removal of drugs, preventive surgeries) in order to maintain the harmonious balance genome / environment that characterizes the health. From the genomic test monitor, the access to personalized genomic medicine is already possible here and now.

Bases genómicas del cáncer de mama: avances hacia la medicina personalizada / Genomic basis for breast cancer: advances in personalized medicine

El análisis genómico del cáncer de mama ha permitido el desarrollo de nuevas herramientas de predicción de riesgo y respuesta al tratamiento en esta enfermedad. Los perfiles de expresión génica han generado una mejor clasificación de los tumores e identificado subgrupos tumorales con características clínicas particulares. También se han reconocido patrones de pérdida y ganancia de DNA y expresión de micro-RNA relacionados con la carcinogénesis mamaria, tras identificar nuevos blancos potenciales. Los estudios de asociación del genoma completo han identificado variantes genéticas vinculadas con un mayor riesgo a presentar esta enfermedad, lo que hará posible tomar decisiones de salud pública mejor fundamentadas. Asimismo, los avances en la tecnología de secuenciación de DNA permitirán obtener información acerca de todas las alteraciones genéticas en los tumores. En esta revisión se describe el estado que guarda la investigación genómica en el cáncer de mama, así como la transición de estos hallazgos a la práctica clínica y la creación de las bases para el desarrollo de la medicina personalizada.

Genomic analysis of breast cancer has allowed the development of new tools for the prediction of recurrence and the response to treatment of this disease. Gene expression profiles allow better tumor classification, identifying tumor subgroups with particular clinical outcomes. New potential molecular targets involved in breast carcinogenesis have also been identified through the analysis of DNA copy number aberrations and microRNA expression patterns. Whole genome association studies have identified genetic variants associated with a higher risk to develop this tumor, providing more information for public health decisions. Progress in DNA sequencing methods will also allow for the analysis of all the genetic alterations present in a tumor. In this review, we describe the current state of genomic research in breast cancer as well as how these findings are being translated into clinical practice, contributing to development of personalized medicine.