Annelien L. Bredenoord

Ethical, Legal, and Counseling Challenges Surrounding the Return of Genetic Results in Oncology

In the last decade, an overwhelming number of genetic aberrations have been discovered and linked to the development of treatment for cancer. With the rapid advancement of next-generation sequencing (NGS) techniques, it is expected that large-scale DNA analyses will increasingly be used to select patients for treatment with specific anticancer agents. Personalizing cancer treatment has many advantages, but sequencing germline DNA as reference material for interpreting cancer genetics may have consequences that extend beyond providing cancer care for an individual patient. In sequencing germline DNA, mutations may be encountered that are associated with increased susceptibility not only to hereditary cancer syndromes but also to other diseases; in those cases, disclosing germline data could be clinically relevant and even lifesaving. In the context of personal autonomy, it is necessary to develop an ethical and legal framework for how to deal with identified hereditary disease susceptibilities and how to return the data to patients and their families. Because clear legislation is lacking, we need to establish guidelines on disclosure of genetic information and, in the process, we need to balance privacy issues with the potential advantages and drawbacks of sharing genetic data with patients and their relatives. Importantly, a strong partnership with patients is critical for understanding how to maximize the translation of genetic information for the benefit of patients with cancer. This review discusses the ethical, legal, and counseling issues surrounding disclosure of genetic information generated by NGS to patients with cancer and their relatives. We also provide a framework for returning these genetic results by proposing a design for a qualified disclosure policy.

Preimplantation genetic diagnosis for mitochondrial DNA disorders: ethical guidance for clinical practice.

Although morally acceptable in theory, preimplantation genetic diagnosis (PGD) for mitochondrial DNA (mtDNA) disorders raises several ethical questions in clinical practice. This paper discusses the major conditions for good clinical practice. Our starting point is that PGD for mtDNA mutations should as far as possible be embedded in a scientific research protocol. For every clinical application of PGD for mtDNA disorders, it is not only important to avoid a ‘high risk of serious harm’ to the future child, but also to consider to what extent it would be possible, desirable and proportional to try to reduce the health risks and minimize harm. The first issue we discuss is oocyte sampling, which may point out whether PGD is feasible for a specific couple. The second issue is whether one blastomere represents the genetic composition of the embryo as a whole – and how this could (or should) be investigated. The third issue regards the cutoff points below which embryos are considered to be eligible for transfer. We scrutinize how to determine these cutoff points and how to use these cutoff points in clinical practice – for example, when parents ask to take more or less risks. The fourth issue regards the number of cycles that can (or should) justifiably be carried out to find the best possible embryo. Fifth, we discuss whether follow-up studies should be conducted, particularly the genetic testing of children born after IVF/PGD. Finally, we offer the main information that is required to obtain a truly informed consent.

Clarifying assent in pediatric research

Assent is a relatively young term in research ethics, but became an often mentioned ethical requirement in current pediatric research guidelines. Also, the European Society of Human Genetics considers assent an important condition for the inclusion of children in biobanks. However, although many emphasize the importance of assent, few explain how they understand the concept and few have elaborated on the underlying grounds. In this paper, we will discuss the different underlying ethical principles of assent. In the first category, assent appears to be derived from informed consent. This understanding is grounded in respect for autonomy and protection against harm. We conclude that this interpretation of assent is not of added value as a majority of children cannot be considered competent to make autonomous decisions. In addition, other safeguards are more appropriate to protect children against harm. The grounds from the second category can be classified as engagement grounds. These grounds do justice to the specifics of childhood and are of added value. Furthermore, we argue that it follows that both the content and the process of assent should be adjusted to the individual child. This can be referred to as personalized assent. Personalized assent is an appeal to the moral responsibility and integrity of the researcher.

Big Data in medical research and EU data protection law: challenges to the consent or anonymise approach

Medical research is increasingly becoming data-intensive; sensitive data are being re-used, linked and analysed on an unprecedented scale. The current EU data protection law reform has led to an intense debate about its potential effect on this processing of data in medical research. To contribute to this evolving debate, this paper reviews how the dominant ‘consent or anonymise approach’ is challenged in a data-intensive medical research context, and discusses possible ways forwards within the EU legal framework on data protection. A large part of the debate in literature focuses on the acceptability of adapting consent or anonymisation mechanisms to overcome the challenges within these approaches. We however believe that the search for ways forward within the consent or anonymise paradigm will become increasingly difficult. Therefore, we underline the necessity of an appropriate research exemption from consent for the use of sensitive personal data in medical research to take account of all legitimate interests. The appropriate conditions of such a research exemption are however subject to debate, and we expect that there will be minimal harmonisation of these conditions in the forthcoming EU Data Protection Regulation. Further deliberation is required to determine when a shift away from consent as a legal basis is necessary and proportional in a data-intensive medical research context, and what safeguards should be put in place when such a research exemption from consent is provided.

Avoiding transgenerational risks of mitochondrial DNA disorders: a morally acceptable reason for sex selection?

In this article, we discuss sex selection not intended to help a couple avoid having a child with a severe genetic disorder, but to avoid possible health risks further along the line of generations. Sex selection may be put to this use in the context of preventing mitochondrial DNA disorders by means of preimplantation genetic diagnosis (PGD) and possibly in the future also through nuclear transfer (NT; also known as mitochondrial gene replacement). A relevant analogy can be found in the context of PGD for X-linked diseases, where sex selection against healthy female carrier embryos would have the same 2-fold purpose of (i) avoiding difficult reproductive decisions for the future child and (ii) avoiding transmission of the mutation to a possible third generation. Because sex selection would still be done for reasons of health, this application should not give rise to the moral concerns associated with sex selection for non-medical reasons. However, the proportionality of adding the relevant procedures to PGD or NT is a relevant concern. We discuss post- and preconceptional sex selection strategies. We conclude that if PGD is already part of the procedure, either as the central technology or as a back-up test after NT, preferentially transferring male embryos could in principle be a morally acceptable way of reducing possible burdens and risks. To start an IVF/PGD-cycle especially for this purpose would be disproportional. The alternative approach of preconceptional sex selection may be morally justified as a means to increase the chances of obtaining male embryos.

Reproductive decision-making in the context of mitochondrial DNA disorders: views and experiences of professionals.

Bredenoord AL, Krumeich A, De Vries MC, Dondorp W, De Wert G. Reproductive decision‐making in the context of mitochondrial DNA disorders: views and experiences of professionals.

Unsolicited findings of next-generation sequencing for tumor analysis within a Dutch consortium: clinical daily practice reconsidered

Cancer patients participating in studies involving experimental or diagnostic next-generation sequencing (NGS) procedures are confronted with the possibility of unsolicited findings. The Center for Personalized Cancer Treatment (CPCT), a Dutch consortium of cancer centers, is offering centralized large-scale NGS for the discovery of somatic tumor mutations with their germline DNA as reference. The CPCT aims to give all cancer patients with advanced disease stages access to tumor DNA analysis in order to improve selection for experimental therapy. In this article, our experiences at the CPCT will serve as an example to discuss the ethical and practical aspects regarding the management of unsolicited findings in personalized cancer research and treatment. Generic issues, relevant for all researchers in this field are discussed and illustrated by description of three patients faced with an unsolicited DNA finding, while they intended to be candidate for future anticancer treatment by participating in a trial that included NGS of both somatic and germline DNA. As options for DNA analysis expand and costs decrease rapidly, more and more patients are offered large-scale NGS testing. After reviewing current recommendations in literature, we conclude that classical informed consent procedures need to be adapted to become more explicit in asking patients if they want to be informed about unsolicited findings and if so, what level of detail of genetic risk information exactly they want to be returned after the analysis.

Consent procedures in pediatric biobanks

The inclusion of children’s samples in biobanks brings forward specific ethical issues. Guidelines indicate that children should be involved in the consent procedure. It is, however, unclear how to allocate an appropriate role for children. Knowledge of current practice will be helpful in addressing this issue. Therefore, we conducted an international multiple-case study on the child’s role in consent procedures in pediatric biobanks. Four biobanks were included: (1) LifeLines, (2) Prevention and Incidence of Asthma and Mite Allergy (PIAMA), (3) Young-HUNT3 and (4) the Oxford Radcliffe Biobank contribution to the Children’s Cancer and Leukaemia Group tissue bank (ORB/CCLG). Four themes linked to the child’s role in the consent procedure emerged from the multiple-case study: (1) motives to involve the child, (2) informing the child, (3) the role of dissent, assent and consent and (4) voluntariness of children to participate. We conclude that biobank characteristics influence the biobank’s motives to include children in the consent procedure. Moreover, the motives to include children influence how the children are involved in the consent procedure, and the extent to which children are able to make voluntary decisions as part of the consent procedure. This insight is valuable when designing pediatric biobank governance.

Broad Consent Is Consent for Governance.

ISSN: 1526-5161 (Print) 1536-0075 (Online) Journal homepage: http://www.tandfonline.com/loi/uajb20 Broad Consent Is Consent for Governance Sarah N. Boers, Johannes J. M. van Delden & Annelien L. Bredenoord To cite this article: Sarah N. Boers, Johannes J. M. van Delden & Annelien L. Bredenoord (2015) Broad Consent Is Consent for Governance, The American Journal of Bioethics, 15:9, 53-55, DOI: 10.1080/15265161.2015.1062165 To link to this article: http://dx.doi.org/10.1080/15265161.2015.1062165

Preferences for genetic testing for colorectal cancer within a population-based screening program: a discrete choice experiment

This study explored individuals’ preferences for genetic testing for colorectal cancer (CRC) in a screening situation and their willingness to participate in genetic testing for Lynch syndrome, familial adenomatous polyposis (FAP), and familial colorectal cancer (FCC). For that purpose, 532 respondents aged 55–65 years completed a Discrete Choice Experiment. Using panel latent class models, the preferences for two screening situation characteristics (the probability of being genetically predisposed and the probability of developing CRC) and screening test characteristics (the frequency of preventive colonoscopies and CRC survival) were estimated. Based on these preferences, respondents’ willingness to participate in the three screening initiatives was estimated. Lower-educated respondents and respondents who express serious anxiety and worries found colonoscopy frequency and the probability of developing CRC relatively more important and survival relatively less important compared with higher-educated respondents and respondents who express no anxiety and worries. These differences in preferences resulted in opposite preferences for participation in FCC and FAP screening. In conclusion, the general population is willing to participate in genetic screening for CRC. If individuals are suspected of genetic or familial CRC, they should at least be informed about their increased risk of being genetically predisposed and about the importance of participating in all preventive follow-up colonoscopies in order to maximize survival.