Telomeres and telomerase: three decades of progress.

Many recent advances have emerged in the telomere and telomerase fields. This Timeline article highlights the key advances that have expanded our views on the mechanistic underpinnings of telomeres and telomerase and their roles in ageing and disease. Three decades ago, the classic view was that telomeres protected the natural ends of linear chromosomes and that telomerase was a specific telomere-terminal transferase necessary for the replication of chromosome ends in single-celled organisms. While this concept is still correct, many diverse fields associated with telomeres and telomerase have substantially matured. These areas include the discovery of most of the key molecular components of telomerase, implications for limits to cellular replication, identification and characterization of human genetic disorders that result in premature telomere shortening, the concept that inhibiting telomerase might be a successful therapeutic strategy and roles for telomeres in regulating gene expression. We discuss progress in these areas and conclude with challenges and unanswered questions in the field.

International Divergence in Gene Patenting.

This review explores the recent divergence in international patent law relating to genes and associated subject matter. This divergence stems primarily from decisions of the highest courts in the United States and Australia on the eligibility of patent claims relating to the BRCA gene sequences. Patent offices, courts, and policy makers have struggled for many years to clearly articulate the bounds of patent claims on isolated and synthetic DNA and related products and processes, including methods for their use in genetic diagnostics. This review provides context to the current divergence by mapping key events in the gene patent journey from the early 1980s onward in five key jurisdictions: the United States, the member states of the European Patent Convention, Australia, Canada, and China. Early approaches to gene patenting had some commonalities across jurisdictions, which makes exploration of the recent divergence all the more interesting.There is insufficient empirical evidence to date to confidently predict the consequences of this recent divergence. However, it could potentially have a significant effect on local industry and on consumer access.

Complexity of genome sequencing and reporting: Next generation sequencing (NGS) technologies and implementation of precision medicine in real life.

The finalization of the Human Genome Project in 2003 paved the way for a deeper understanding of cancer, favouring a faster progression towards "personalized" medicine. Research in oncology has progressively focused on the sequencing of cancer genomes, to better understand the genetic basis of tumorigenesis and identify actionable alterations to guide cancer therapy. Thanks to the development of next-generation-sequencing (NGS) techniques, sequencing of tumoral DNA is today technically easier, faster and cheaper. Commercially available NGS panels enable the detection of single or global genomic alterations, namely gene mutation and mutagenic burden, both on germline and somatic DNA, potentially predicting the response or resistance to cancer treatments. Profiling of tumor DNA is nowadays a standard in cancer research and treatment. In this review we discuss the history, techniques and applications of NGS in cancer care, under a "personalized tailored therapy" perspective.

The Genomics of Prostate Cancer: A Historic Perspective.

The genomics of prostate cancer (PCA) has been difficult to study compared with some other cancer types for a multitude of reasons, despite significant efforts since the early 1980s. Overcoming some of these obstacles has paved the way for greater insight into the genomics of PCA. The advent of high-throughput technologies coming from the initial use of microsatellite and oligonucleotide probes gave rise to techniques like comparative genomic hybridization (CGH). With the introduction of massively parallel genomic sequencing, referred to as next-generation sequencing (NGS), a deeper understanding of cancer genomics in general has occurred. Along with these technologic advances, there has been the development of computational biology and statistical approaches to address novel large data sets characterized by single base resolution. This review will provide a historic perspective of PCA genomics with an emphasis on the cardinal mutations and alterations observed to be consistently seen in PCA for both hormone-naïve localized PCA and castration-resistant prostate cancer (CRPC). There will be a focus on alterations that have the greatest potential to play a role in disease progression and therapy management.

Machine learning approaches to study glioblastoma: A review of the last decade of applications.

BACKGROUND: Glioblastoma (GB, formally glioblastoma multiforme) is a malignant type of brain cancer that currently has no cure and is characterized by being highly heterogeneous with high rates of re-incidence and therapy resistance. Thus, it is urgent to characterize the mechanisms of GB pathogenesis to help researchers identify novel therapeutic targets to cure this devastating disease. Recently, a promising approach to identifying novel therapeutic targets is the integration of tumor omics data with clinical information using machine learning (ML) techniques. RECENT FINDINGS: ML has become a valuable addition to the researcher's toolbox, thanks to its flexibility, multidimensional approach, and a growing community of users. The goal of this review is to introduce basic concepts and applications of ML for studying GB to clinicians and practitioners who are new to data science. ML applications include exploring large data sets, finding new relevant patterns, predicting outcomes, or merely understanding associations of the complex molecular networks presented within the tumor. Here, we review ML applications published between 2008 and 2018 and discuss ML strategies intending to identify new potential therapeutic targets to improve the management and treatment of GB. CONCLUSIONS: ML applications to study GB vary in purpose and complexity, with positive results. In GB studies, ML is often used to analyze high-dimensional datasets with prediction or classification as a primary goal. Despite the strengths of ML techniques, they are not fail-safe and methodological issues can occur in GB studies that use them. This is why researchers need to be aware of these issues when planning and appraising studies that apply ML to the study of GB.

A Decade of GWAS Results in Lung Cancer.

Genome-wide association studies (GWAS) were successful to identify genetic factors robustly associated with lung cancer. This review aims to synthesize the literature in this field and accelerate the translation of GWAS discoveries into results that are closer to clinical applications. A chronologic presentation of published GWAS on lung cancer susceptibility, survival, and response to treatment is presented. The most important results are tabulated to provide a concise overview in one read. GWAS have reported 45 lung cancer susceptibility loci with varying strength of evidence and highlighted suspected causal genes at each locus. Some genetic risk loci have been refined to more homogeneous subgroups of lung cancer patients in terms of histologic subtypes, smoking status, gender, and ethnicity. Overall, these discoveries are an important step for future development of new therapeutic targets and biomarkers to personalize and improve the quality of care for patients. GWAS results are on the edge of offering new tools for targeted screening in high-risk individuals, but more research is needed if GWAS are to pay off the investment. Complementary genomic datasets and functional studies are needed to refine the underlying molecular mechanisms of lung cancer preliminarily revealed by GWAS and reach results that are medically actionable. Cancer Epidemiol Biomarkers Prev; 27(4); 363-79. ©2018 AACRSee all articles in this CEBP Focus section, "Genome-Wide Association Studies in Cancer."

[Cancer: three eras of personalized medicine]. / Cancer : les trois époques de la médecine personnalisée - Chroniques génomiques.

Since the completion of the first human DNA sequence, genomic approaches have penetrated into cancer research and therapy: first through expression profiling for diagnostic, prognostic and predictive purposes, then by sequencing of tumour DNA in order to define and apply targeted therapies. These overlapping changes occurred quite rapidly and are now overshadowed by immuno-oncology approaches that show much promise. There is however still much left to understand to make this more widely applicable, and the extreme cost of these therapies is a serious concern.

On the shoulders of Hubrecht: From embryos to stem cells.

One hundred years of the Hubrecht Institute were celebrated in May 2016 with the organization of a one-day symposium "From embryos to stem cells" on the Uithof Campus, Utrecht, the Netherlands. Nine distinguished speakers were invited. They all represent a research branch originating from the passion of Institute founder, Ambrosius Hubrecht, for embryology:, regulation of gene expression, genome structure and function, embryonic and adult stem cells, nuclear reprogramming, and understanding cancer and other diseases using model organisms. The centennial symposium not only retraced the history of the Institute and of modern developmental biology, but was also a tribute to basic research. From there, avenues to therapeutics are being developed and implemented. The symposium was organized, introduced and chaired by Jeroen den Hertog and Alexander van Oudenaarden, the present Directors of the Institute, who also stand on Hubrecht's shoulders.

Radiogenomics - current status, challenges and future directions.

Radiogenomics designates a scientific field that addresses possible associations between genetic germline alterations and normal tissue toxicity after radiotherapy. The ultimate aim of this research is to establish a gene-based predictive test for normal tissue radiosensitivity. During the last 5 years, substantial progress has been achieved in this field. Several compelling associations for SNPs have been demonstrated in large candidate gene studies as well as genome wide association studies. These findings shed new light on radiobiology and expand our understanding of the processes that lead to side effects after radiotherapy. Despite this, certain fundamental challenges still relate to genomic approaches. Based on the latest insights into complex trait genetics and molecular genetics, we provide an analysis of these challenges and propose putative strategies to further advance the field. These strategies include 'big data approaches' and collaborative research within international consortia. Furthermore, research that combines the study of radiation-induced gene expression and genome-wide SNP genotype may discover genetic alterations that regulate the biological response to ionizing radiation. Thus, such integrative approaches may lead to genetic alterations that affect risk of normal tissue toxicity.

TILLING in extremis.

Targeting induced local lesions in genomes (TILLING), initially a functional genomics tool in model plants, has been extended to many plant species and become of paramount importance to reverse genetics in crops species. Because it is readily applicable to most plants, it remains a dominant non-transgenic method for obtaining mutations in known genes. The process has seen many technological changes over the last 10 years; a major recent change has been the application of next-generation sequencing (NGS) to the process, which permits multiplexing of gene targets and genomes. NGS will ultimately lead to TILLING becoming an in silico procedure. We review here the history and technology in brief, but focus more importantly on recent developments in polyploids, vegetatively propagated crops and the future of TILLING for plant breeding.

Insights from next generation sequencing of the cancer genome.

This detailed review provides a history and update of the complex field of cancer genetics. Using examples of progress such as the development of imatinib for chronic myeloid leukemia (which stemmed from the recognition of the Philadelphia chromosome in the 1960s), Michael Stratton, Director of the Sanger Institute in Cambridge is confident that we are now entering the end game of cancer genome sequencing. This has led to other drug therapies, based on knowledge of the molecular changes in some cancers, lung and breast cancers for example.

Roles of mutation and selection in speciation: from Hugo de Vries to the modern genomic era.

One of the most important problems in evolutionary biology is to understand how new species are generated in nature. In the past, it was difficult to study this problem because our lifetime is too short to observe the entire process of speciation. In recent years, however, molecular and genomic techniques have been developed for identifying and studying the genes involved in speciation. Using these techniques, many investigators have already obtained new findings. At present, however, the results obtained are complex and quite confusing. We have therefore attempted to understand these findings coherently with a historical perspective and clarify the roles of mutation and natural selection in speciation. We have first indicated that the root of the currently burgeoning field of plant genomics goes back to Hugo de Vries, who proposed the mutation theory of evolution more than a century ago and that he unknowingly found the importance of polyploidy and chromosomal rearrangements in plant speciation. We have then shown that the currently popular Dobzhansky-Muller model of evolution of reproductive isolation is only one of many possible mechanisms. Some of them are Oka's model of duplicate gene mutations, multiallelic speciation, mutation-rescue model, segregation-distorter gene model, heterochromatin-associated speciation, single-locus model, etc. The occurrence of speciation also depends on the reproductive system, population size, bottleneck effects, and environmental factors, such as temperature and day length. Some authors emphasized the importance of natural selection to speed up speciation, but mutation is crucial in speciation because reproductive barriers cannot be generated without mutations.

Population sciences, translational research, and the opportunities and challenges for genomics to reduce the burden of cancer in the 21st century.

Advances in genomics and related fields are promising tools for risk assessment, early detection, and targeted therapies across the entire cancer care continuum. In this commentary, we submit that this promise cannot be fulfilled without an enhanced translational genomics research agenda firmly rooted in the population sciences. Population sciences include multiple disciplines that are needed throughout the translational research continuum. For example, epidemiologic studies are needed not only to accelerate genomic discoveries and new biological insights into cancer etiology and pathogenesis, but to characterize and critically evaluate these discoveries in well-defined populations for their potential for cancer prediction, prevention and response to treatment. Behavioral, social, and communication sciences are needed to explore genomic-modulated responses to old and new behavioral interventions, adherence to therapies, decision making across the continuum, and effective use in health care. Implementation science, health services, outcomes research, comparative effectiveness research, and regulatory science are needed for moving validated genomic applications into practice and for measuring their effectiveness, cost-effectiveness, and unintended consequences. Knowledge synthesis, evidence reviews, and economic modeling of the effects of promising genomic applications will facilitate policy decisions and evidence-based recommendations. Several independent and multidisciplinary panels have recently made specific recommendations for enhanced research and policy infrastructure to inform clinical and population research for moving genomic innovations into the cancer care continuum. An enhanced translational genomics and population sciences agenda is urgently needed to fulfill the promise of genomics in reducing the burden of cancer.

[Next generation sequencing technologies (NGST) -- development and applications]. / Következo generációs szekvenálási technológiák kifejlodése és alkalmazásai.

In the past ten years the development of next generation sequencing technologies brought a new era in the field of quick and efficient DNA sequencing. In our study we give an overview of the methodological achievements from Sanger's chain-termination sequencing in 1975 to those allowing real-time DNA sequencing today. Sequencing methods that utilize clonal amplicons for parallel multistrand sequencing comprise the basics of currently available next generation sequencing techniques. Nowadays next generation sequencing is mainly used for basic research in functional genomics, providing quintessential information in the meta-analyses of data from signal transduction pathways, onthologies, proteomics and metabolomics. Although next generation sequencing is yet sparsely used in clinical practice, cardiology, oncology and epidemiology already show an immense need for the additional knowledge obtained by this new technology. The main barrier of its spread is the lack of standardization of analysis evaluation methods, which obscure objective assessment of the results.

Between clinical medicine and the laboratory: medical research funding in France from 1945 to the present.

By focusing on funding methods, this paper considers the way in which medical research eventually led to the science-based medicine that is prevalent in France today. This process seems to have taken place in three stages during the second half of the twentieth century. In the 1940s and 1950s, two major events occurred. The first was the creation of a national health insurance fund in France, which opened up new reasons for, and ways of, funding medical research. The second was the development of antibiotics, which triggered a revival of clinical medicine. In the 1960s and 1970s, a proactive government science policy allowed the life sciences and medical research to come together in the wake of a burgeoning new science: molecular biology. Thus, in 1964, the creation of the National Health and Medical Research Institute (Institut national de la santé et de la recherche médicale or INSERM), destined to "molecularize" medical research, was seen as the fulfillment of the government's ambitious research policy. Today, with medicine irreversibly embedded in scientific and technical rationality, health has become a major issue in modern societies. This paper therefore touches on some of the key features of biomedical research, including the revival of funding systems for clinical research and the development of a system of research grants that was made possible by patient organizations and the creation of new funding agencies.

Genomics of medulloblastoma: from Giemsa-banding to next-generation sequencing in 20 years.

Advances in the field of genomics have recently enabled the unprecedented characterization of the cancer genome, providing novel insight into the molecular mechanisms underlying malignancies in humans. The application of high-resolution microarray platforms to the study of medulloblastoma has revealed new oncogenes and tumor suppressors and has implicated changes in DNA copy number, gene expression, and methylation state in its etiology. Additionally, the integration of medulloblastoma genomics with patient clinical data has confirmed molecular markers of prognostic significance and highlighted the potential utility of molecular disease stratification. The advent of next-generation sequencing technologies promises to greatly transform our understanding of medulloblastoma pathogenesis in the next few years, permitting comprehensive analyses of all aspects of the genome and increasing the likelihood that genomic medicine will become part of the routine diagnosis and treatment of medulloblastoma.