Pilar Nicolás

Whole-genome sequencing identifies recurrent mutations in chronic lymphocytic leukaemia

Chronic lymphocytic leukaemia (CLL), the most frequent leukaemia in adults in Western countries, is a heterogeneous disease with variable clinical presentation and evolution. Two major molecular subtypes can be distinguished, characterized respectively by a high or low number of somatic hypermutations in the variable region of immunoglobulin genes. The molecular changes leading to the pathogenesis of the disease are still poorly understood. Here we performed whole-genome sequencing of four cases of CLL and identified 46 somatic mutations that potentially affect gene function. Further analysis of these mutations in 363 patients with CLL identified four genes that are recurrently mutated: notch 1 (NOTCH1), exportin 1 (XPO1), myeloid differentiation primary response gene 88 (MYD88) and kelch-like 6 (KLHL6). Mutations in MYD88 and KLHL6 are predominant in cases of CLL with mutated immunoglobulin genes, whereas NOTCH1 and XPO1 mutations are mainly detected in patients with unmutated immunoglobulins. The patterns of somatic mutation, supported by functional and clinical analyses, strongly indicate that the recurrent NOTCH1, MYD88 and XPO1 mutations are oncogenic changes that contribute to the clinical evolution of the disease. To our knowledge, this is the first comprehensive analysis of CLL combining whole-genome sequencing with clinical characteristics and clinical outcomes. It highlights the usefulness of this approach for the identification of clinically relevant mutations in cancer.

Non-coding recurrent mutations in chronic lymphocytic leukaemia.

Chronic lymphocytic leukaemia (CLL) is a frequent disease in which the genetic alterations determining the clinicobiological behaviour are not fully understood. Here we describe a comprehensive evaluation of the genomic landscape of 452 CLL cases and 54 patients with monoclonal B-lymphocytosis, a precursor disorder. We extend the number of CLL driver alterations, including changes in ZNF292, ZMYM3, ARID1A and PTPN11. We also identify novel recurrent mutations in non-coding regions, including the 3′ region of NOTCH1, which cause aberrant splicing events, increase NOTCH1 activity and result in a more aggressive disease. In addition, mutations in an enhancer located on chromosome 9p13 result in reduced expression of the B-cell-specific transcription factor PAX5. The accumulative number of driver alterations (0 to ≥4) discriminated between patients with differences in clinical behaviour. This study provides an integrated portrait of the CLL genomic landscape, identifies new recurrent driver mutations of the disease, and suggests clinical interventions that may improve the management of this neoplasia.

Strategies to design clinical studies to identify predictive biomarkers in cancer research

The discovery of reliable biomarkers to predict efficacy and toxicity of anticancer drugs remains one of the key challenges in cancer research. Despite its relevance, no efficient study designs to identify promising candidate biomarkers have been established. This has led to the proliferation of a myriad of exploratory studies using dissimilar strategies, most of which fail to identify any promising targets and are seldom validated. The lack of a proper methodology also determines that many anti-cancer drugs are developed below their potential, due to failure to identify predictive biomarkers. While some drugs will be systematically administered to many patients who will not benefit from them, leading to unnecessary toxicities and costs, others will never reach registration due to our inability to identify the specific patient population in which they are active. Despite these drawbacks, a limited number of outstanding predictive biomarkers have been successfully identified and validated, and have changed the standard practice of oncology. In this manuscript, a multidisciplinary panel reviews how those key biomarkers were identified and, based on those experiences, proposes a methodological framework-the DESIGN guidelines-to standardize the clinical design of biomarker identification studies and to develop future research in this pivotal field.

Ethical and juridical issues of genetic testing: A review of the international regulation

The obtaining and use of genetic data have several particular implications for the rights of the patients and their relatives, and frequently practitioners and researchers face some new conflicts to which law and ethics try to give an answer. Some countries have enacted national laws related to genetic analysis. At the international level a great effort has been done to develop a common regulatory framework taking into account the rights of the patients/subjects of the research and other rights and interests. In the field of genetic analysis, both diagnostic and research purposes frequently go hand in hand. The scientific interest in the use of biological samples as a research tool has increased simultaneously with the knowledge of human genetics. The regulations related to the rights of the patients in the use of biological samples need to be abided.

The International Cancer Genome Consortium's evolving data-protection policies

519 In light of the re-identification possibilities presented in these recent scientific papers, several ICGC project members and the ICGC Ethics and Policy Committee decided to review the data sharing and confidentiality policies stipulated in the ICGC Access Policy and List of Data Elements (Access Policy) (http://www.icgc.org/icgc/goals-structurepolicies-guidelines/). To accomplish this review, ICGC created a Working Group on Identifiability and Privacy (WGIP). In addition to monitoring developments and reviewing the Access Policy, a key goal was to assess the risks of re-identification of research participants through their data and to make appropriate recommendations. This article highlights the key findings of the WGIP, which may provide a useful reference for other research consortia seeking to build and maintain secure genomic data sets. The methodological approach used by the WGIP was multidisciplinary and deliberative. It focused on a qualitative review of scientific, policy, ethical, legal and social scholarly publications related to the protection of genomic data. The WGIP considered issues such as re-identification probabilities4–10, potential risks to participants following reidentification6, informed consent, governance structure, monitoring and compliance frameworks (including sanctions)12, and communication of information on privacy risks and applicable policies to the participants. For example, the sanctions that can be sought by the database authority in case of a privacy breach or disrespect of the terms of the controlled access agreement, as well as the importance of implementing a robust compliance framework to quickly detect breaches, were also considered by a subgroup of the WGIP12. The Core Bioethical Principles of ICGC, which must be respected by all members of the ICGC consortium, include provisions on informed consent that require that some information on the privacy aspects of genomic data and associated clinical The International Cancer Genome Consortium’s evolving data-protection policies

A Role for Research Ethics Committees in Exchanges of Human Biospecimens Through Material Transfer Agreements

International transfers of human biological material (biospecimens) and data are increasing, and commentators are starting to raise concerns about how donor wishes are protected in such circumstances. These exchanges are generally made under contractual material transfer agreements (MTAs). This paper asks what role, if any, should research ethics committees (RECs) play in ensuring legal and ethical conduct in such exchanges. It is recommended that RECs should play a more active role in the future development of best practice MTAs involving exchange of biospecimens and data and in monitoring compliance.

Discussing options between patients and health care professionals in genetic diagnosis: ethical and legal criteria

The specific characteristics of genetic data lead to ethical-legal conflicts in the framework of genetic diagnosis. Several international organisations, including UNESCO and the Council of Europe, have enacted rules referring to the use of genetic information. This paper discusses possible legal and ethical criteria that could be used in genetic testing.

Spanish Regulation of Biobanks.

The Spanish legal framework for the processing of samples and data with biomedical research purposes has sought to encourage scientific research, protect the right to freedom of research, and guarantee the interests of donors. The pillars of this legal framework are firstly, the duty to inform the donor in order to ensure that he or she is aware of the importance and the consequences of the donation; secondly, the control by ethics committees (RECs and External Ethics Committees of biobanks); and third, the supplementary application of the general rules on data protection. There are three different possibilities for processing samples (project, collection, and biobanks) - each one reinforcing specific consent or requiring other added guarantees. This system, which is applied consistently in the entire national territory, is producing very satisfactory results. However, there are some issues that need further policies or legal development, as the specific conditions and procedures for the international transfer of samples and data with research purposes.