POT1 and Damage Response Malfunction Trigger Acquisition of Somatic Activating Mutations in the VEGF Pathway in Cardiac Angiosarcomas.

Background Mutations in the POT1 gene explain abnormally long telomeres and multiple tumors including cardiac angiosarcomas (CAS). However, the link between long telomeres and tumorigenesis is poorly understood. Methods and Results Here, we have studied the somatic landscape of 3 different angiosarcoma patients with mutations in the POT1 gene to further investigate this tumorigenesis process. In addition, the genetic landscape of 7 CAS patients without mutations in the POT1 gene has been studied. Patients with CAS and nonfunctional POT1 did not repress ATR (ataxia telangiectasia RAD3-related)-dependent DNA damage signaling and showed a constitutive increase of cell cycle arrest and somatic activating mutations in the VEGF (vascular endothelial growth factor)/angiogenesis pathway (KDR gene). The same observation was made in POT1 mutation carriers with tumors different from CAS and also in CAS patients without mutations in the POT1 gene but with mutations in other genes involved in DNA damage signaling. Conclusions Inhibition of POT1 function and damage-response malfunction activated DNA damage signaling and increased cell cycle arrest as well as interfered with apoptosis, which would permit acquisition of somatic mutations in the VEGF/angiogenesis pathway that drives tumor formation. Therapies based on the inhibition of damage signaling in asymptomatic carriers may diminish defects on cell cycle arrest and thus prevent the apoptosis deregulation that leads to the acquisition of driver mutations.

In vivo phosphoproteomics reveals kinase activity profiles that predict treatment outcome in triple-negative breast cancer.

Triple-negative breast cancer (TNBC) lacks prognostic and predictive markers. Here, we use high-throughput phosphoproteomics to build a functional TNBC taxonomy. A cluster of 159 phosphosites is upregulated in relapsed cases of a training set (n = 34 patients), with 11 hyperactive kinases accounting for this phosphoprofile. A mass-spectrometry-to-immunohistochemistry translation step, assessing 2 independent validation sets, reveals 6 kinases with preserved independent prognostic value. The kinases split the validation set into two patterns: one without hyperactive kinases being associated with a >90% relapse-free rate, and the other one showing ≥1 hyperactive kinase and being associated with an up to 9.5-fold higher relapse risk. Each kinase pattern encompasses different mutational patterns, simplifying mutation-based taxonomy. Drug regimens designed based on these 6 kinases show promising antitumour activity in TNBC cell lines and patient-derived xenografts. In summary, the present study elucidates phosphosites and kinases implicated in TNBC and suggests a target-based clinical classification system for TNBC.

Optimizing sharing of hospital biobank samples.

Implementing technical guidelines and standards as well as ways to boost cooperation should facilitate sharing of hospital biobank samples.

Cost model for biobanks.

Current economic conditions and budget constraints in publicly funded biomedical research have brought about a renewed interest in analyzing the cost and economic viability of research infrastructures. However, there are no proposals for specific cost accounting models for these types of organizations in the international scientific literature. The aim of this paper is to present the basis of a cost analysis model useful for any biobank regardless of the human biological samples that it stores for biomedical research. The development of a unique cost model for biobanks can be a complicated task due to the diversity of the biological samples they store. Different types of samples (DNA, tumor tissues, blood, serum, etc.) require different production processes. Nonetheless, the common basic steps of the production process can be identified. Thus, the costs incurred in each step can be analyzed in detail to provide cost information. Six stages and four cost objects were obtained by taking the production processes of biobanks belonging to the Spanish National Biobank Network as a starting point. Templates and examples are provided to help managers to identify and classify the costs involved in their own biobanks to implement the model. The application of this methodology will provide accurate information on cost objects, along with useful information to give an economic value to the stored samples, to analyze the efficiency of the production process and to evaluate the viability of some sample collections.

Preguntas y recomendaciones sobre integración de los archivos diagnósticos de los servicios de Anatomía Patológica en biobancos / Questions and recommendations on the integration of diagnostic files of the Anatomical-Pathology departments into biobanks

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Cyclooxygenase-2 expression in bladder cancer and patient prognosis: results from a large clinical cohort and meta-analysis.

Aberrant overexpression of cyclooxygenase-2 (COX2) is observed in urothelial carcinoma of the bladder (UCB). Studies evaluating COX2 as a prognostic marker in UCB report contradictory results. We determined the prognostic potential of COX2 expression in UCB and quantitatively summarize the results with those of the literature through a meta-analysis. Newly diagnosed UCB patients recruited between 1998-2001 in 18 Spanish hospitals were prospectively included in the study and followed-up (median, 70.7 months). Diagnostic slides were reviewed and uniformly classified by expert pathologists. Clinical data was retrieved from hospital charts. Tissue microarrays containing non-muscle invasive (n=557) and muscle invasive (n=216) tumours were analyzed by immunohistochemistry using quantitative image analysis. Expression was evaluated in Cox regression models to assess the risk of recurrence, progression and disease-specific mortality. Meta-hazard ratios were estimated using our results and those from 11 additional evaluable studies. COX2 expression was observed in 38% (211/557) of non-muscle invasive and 63% (137/216) of muscle invasive tumors. Expression was associated with advanced pathological stage and grade (p<0.0001). In the univariable analyses, COX2 expression - as a categorical variable - was not associated with any of the outcomes analyzed. As a continuous variable, a weak association with recurrence in non-muscle invasive tumors was observed (p-value=0.048). In the multivariable analyses, COX2 expression did not independently predict any of the considered outcomes. The meta-analysis confirmed these results. We did not find evidence that COX2 expression is an independent prognostic marker of recurrence, progression or survival in patients with UCB.

Managing a biobank network.

Today's biomedical research of excellence is mainly seen as a global phenomenon around the study of large series of samples organized with well-defined and detailed criteria regarding the identification of patients, with the specific information required in each case. This justifies the growing interest in developing cooperative networks of biobanks to minimize biases arising from heterogeneity in the quality of biological samples by means of protocols for procedures, development of common quality assurance policies, and promotion of collaborative environments. This article focuses on some basic aspects of biobank networking, including design and management. It does not try to be an exhaustive analysis but a preliminary approach to the topic, based on the author's expertise in biobank networking in Spain.

New concepts of biobanks--strategic chance for uro-oncology.

Cancer, as well as other common diseases, is a complex condition that not only causes a major threat to human health, but also represents a huge burden to society in terms of healthcare cost and loss of economic productivity. Treatment improvements remain elusive, since the causes of cancer are due to a huge number of small and possibly additive effects arising from genetic susceptibility, lifestyle, and environmental conditions. Thus, progress in translational cancer research investigating these changes and their complex interaction is highly dependent on large series of cases (affected and unaffected individuals) including high quality samples and their associated data. Therefore, large and well-organized biobanks have been established, are underway, or are planned in many countries and institutions. The integration of these resources with powerful molecular and "omics" approaches, integrated bioinformatic tools hold the promise to further advance our knowledge of disease development, thus leading to better prevention and treatment strategies. However, these valuable and irreplaceable collections typically suffer from underutilization, due to fragmentation of the collections and their accessibility, lack of common management strategies, including consensus on standard operating procedures, unique policies of utilization, and distribution as well as missing input on a broad basis reflecting research needs on an interdisciplinary, multi-institutional fashion beyond project-driven interest. The uro-oncologic community has not yet contributed to these efforts to its full potential, and broad knowledge on the contemporary developments in the field of biobanking and input into these efforts are still missing. This review presents an overview on biobanking and may serve as an update to be integrated into future discussions on managing biobanks involving uro-oncology. It is based on the discussions at the last meeting of the International Bladder Cancer Network in Barcelona (Spain) in fall 2008 and has been also largely influenced by the works and discussions of the Marble Arch International Working Group on Biobanking for Biomedical Research.

A molecular risk score based on 4 functional pathways for advanced classical Hodgkin lymphoma.

Despite improvement in the treatment of advanced classical Hodgkin lymphoma, approximately 30% of patients relapse or die as result of the disease. Current predictive systems, determined by clinical and analytical parameters, fail to identify these high-risk patients accurately. We took a multistep approach to design a quantitative reverse-transcription polymerase chain reaction assay to be applied to routine formalin-fixed paraffin-embedded samples, integrating genes expressed by the tumor cells and their microenvironment. The significance of 30 genes chosen on the basis of previously published data was evaluated in 282 samples (divided into estimation and validation sets) to build a molecular risk score to predict failure. Adequate reverse-transcription polymerase chain reaction profiles were obtained from 262 of 282 cases (92.9%). Best predictor genes were integrated into an 11-gene model, including 4 functional pathways (cell cycle, apoptosis, macrophage activation, and interferon regulatory factor 4) able to identify low- and high-risk patients with different rates of 5-year failure-free survival: 74% versus 44.1% in the estimation set (P < .001) and 67.5% versus 45.0% in the validation set (P = .022). This model can be combined with stage IV into a final predictive model able to identify a group of patients with very bad outcome (5-year failure-free survival probability, 25.2%).

The role of the pathologist in tissue banking: European Consensus Expert Group Report.

Human tissue biobanking encompasses a wide range of activities and study designs and is critical for application of a wide range of new technologies (-"omics") to the discovery of molecular patterns of disease and for implementation of novel biomarkers into clinical trials. Pathology is the cornerstone of hospital-based tissue biobanking. Pathologists not only provide essential information identifying the specimen but also make decisions on what should be biobanked, making sure that the timing of all operations is consistent with both the requirements of clinical diagnosis and the optimal preservation of biological products. This document summarizes the conclusions of a Pathology Expert Group Meeting within the European Biological and Biomolecular Research Infrastructure (BBMRI) Program. These recommendations are aimed at providing guidance for pathologists as well as for institutions hosting biobanks on how to better integrate and support pathological activities within the framework of biobanks that fulfill international standards.

Biobanking: old activity or young discipline?

Biobanking is a new concept with solid bases in traditional pathology, the development of which is mandatory to allow effective translational research to flourish. Biobank activity is developing as a progressively complex young discipline playing a central role in biomedical research. This review analyzes the role of disease-driven biobanks in translational research, focusing on some aspects considered to be crucial for the future development of these institutions and service providers, including dedicated designs, funding, personnel, and ethical and legal frameworks, which, coupled with networked functioning, can provide an endless source of samples and, ideally, associated clinical information for biomedical research.

Biobanking for better healthcare.

Translational cancer research is highly dependent of large series of cases including high quality samples and their associated data. Comprehensive Cancer Centers should be involved in networks to enable large-scale multi-center research projects between the centers [Ringborg, U., de Valeriola, D., van Harten, W., Llombart-Bosch, A., Lombardo, C., Nilsson, K., Philip, T., Pierotti, M.A., Riegman, P., Saghatchian, M., Storme, G., Tursz, T., Verellen, D, 2008. Improvement of European translational cancer research. Collaboration between comprehensive cancer centers. Tumori 94, 143-146.]. Combating cancer knows many frontiers. Research is needed for prevention as well as better care for those who have acquired the disease. This implies that human samples for cancer research need to be sourced from distinct forms of biobanking. An easier access to these samples for the scientific community is considered as the main bottleneck for research for health, and biobanks are the most adequate site to try to resolve this issue [Ozols, R.F., Herbst, R.S., Colson, Y.L., Gralow, J., Bonner, J., Curran Jr., W.J., Eisenberg, B.L., Ganz, P.A., Kramer, B.S., Kris, M.G., Markman, M., Mayer, R.J., Raghavan, D., Reaman, G.H., Sawaya, R., Schilsky, R.L., Schuchter, L.M., Sweetenham, J.W., Vahdat, L.T., Winn, R.J., and the American Society of Clinical Oncology, 2007. Clinical cancer advances 2006: major research advances in cancer treatment, prevention, and screening: a report from the American Society of Clinical Oncology. J. Clin. Oncol. 25, 146-162.]. However, biobanks should not be considered a static activity. On the contrary, biobanking is a young discipline [Morente, M.M., Fernandez, P.L., de Alava, E. Biobanking: old activity or young discipline? Semin. Diagn. Pathol., in press.], which need continuously evolve according to the permanent development of new techniques and new scientific goals. To accomplish current requirements of the scientific community biobanks need to face some essential challenges including an appropriate design, harmonized and more suitable procedures, and sustainability, all of them in the framework of their ethic, legal and social dimensions. This review therefore presents an overview on these issues, based on the works and discussions of the Marble Arch International Working Group on Biobanking for Biomedical Research, integrated by experts in biobanking from five continents.

Tumor microenvironment and mitotic checkpoint are key factors in the outcome of classic Hodgkin lymphoma.

Around 20% to 30% of patients with Hodgkin lymphoma (HL) do not benefit from standard therapies and finally succumb to their disease. The factors that influence the outcome of HL have not been elucidated, underscoring the demand for the identification of biologic risk factors and new therapeutic targets. We analyzed the gene expression profiles of samples from 29 patients with advanced classic HL treated with standard therapy and compared the expression profiles of patients with favorable and unfavorable clinical outcome. Using supervised methods, we identified 145 genes associated with outcome, which were grouped into 4 signatures representing genes expressed by either the tumoral cells (genes involved in the regulation of mitosis and cell growth/apoptosis) or the tumor microenvironment. The relationship between the expression of 8 representative genes and survival was successfully validated in an independent series of 235 patients by quantification of protein expression levels on tissue microarrays. Analysis of centrosomes and mitotic checkpoint confirmed the existence of an abnormal transition through mitosis in HL cells. Therefore, genes related to tumor microenvironment, cell growth/apoptosis, and regulation of mitosis are associated with treatment response and outcome of patients with HL.

Current challenges of human tumour banking.

Tumour Banks (TB) are called upon to play a central role in Oncological translational research. TB have been existing since Pathology Departments started storing blocks of tissue samples, but in keeping this role they must face some urgent challenges including: an updated definition of hospital TB, integration into clinical trials and projects of excellence, networking and a new framework for ethics and laws. Current TB definition includes not only tissue storage, but also a series of hospital protocols that allow molecular studies of tumour and normal samples. The real value of these protocols and samples appears with scientific projects of excellence and integrated in clinical trials. Most of these trials need for a large number of cases with homogeneously treated tissue samples in the context of multicentre and multinational projects. Thereby, networking appears the best solution for TB to expand. Networking implies standardised technical procedures, a strict quality control programme, homogeneous ethic requirements and an open mentality for sharing. In the international setting the major challenge for networking is the various laws and customs in the different countries. To bring these diverse legislation together is, perhaps, the most important challenge for TB Networking in the very close future.

Influence of biologic markers on the outcome of Hodgkin's lymphoma: a study by the Spanish Hodgkin's Lymphoma Study Group.

PURPOSE: Current therapies fail to cure a significant proportion of patients with Hodgkin's lymphoma (HL). Predictive systems for stratification of the disease and selection of treatment based on sets of clinical variables, such as the international prognostic score (IPS), are of relatively small practical value. The predictive use of biologic parameters has so far provided limited and inconsistent results. Here we explore the influence of a set of molecular markers on the outcome of HL. PATIENTS AND METHODS: Forty molecular markers involved in B-cell differentiation and activation, signal transduction, cell cycle, and apoptosis control were analyzed in 259 classic HL patient cases by using tissue microarrays. Univariate analysis was performed to evaluate the influence of markers on favorable outcome (complete remission of > 12 months). Significant variables were included in a multivariate logistic regression analysis, and the probability of favorable outcome was estimated. RESULTS: Univariate analysis revealed four molecular markers that predicted outcome, and the multivariate analysis showed p53, Bcl-X(L), and terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate-biotin nick-end labeling (TUNEL) to have independent significance. The combination of these factors determined two groups of patients (group I, zero to one factor; group II, two to three factors) with a probability of a favorable outcome of.948 and.687, respectively. A multivariate Cox's model shows that these biologic risk groups have special predictive power in low-IPS patients. CONCLUSION: The data from this exploratory study suggest that the accumulation of molecular events seems to influence the outcome of HL, particularly in the low-IPS group.