5Ethical issues raised by whole genome sequencing
Introduction
In the last decade, the development of high-throughput and massively parallel DNA sequencing technologies, also known as next generation sequencing (NGS) technologies, has resulted in a substantial reduction in the cost and time needed to sequence an entire human genome. The Human Genome Project lasted over a decade, cost three billion USD and resulted in the sequencing of basically one human genome. Meanwhile, in January 2014 the company Illumina announced that it could sequence a human genome for the fabled price of 1000 USD (an albeit relatively arbitrary and likely more psychological price threshold) in less than a day [2]. Although Illumina's price tag is undoubtedly on the low side of the present range of prices, it is still in line with the costs presented by The National Human Genome Research Institute's yearly update on WGS costs, which was estimated at between 5000 and 10 000 USD in 2013 [3]. As highlighted by Dr. Euan Ashley, director of the Clinical Genome Service and the Center for Inherited Cardiovascular Disease at Stanford University (USA), this reduction in price would be similar to an expensive car with a price tag of 400 000 USD at the time of the Human Genome Project falling in price such that it cost only 40 cents today [4]. Such a dramatic drop in price obviously increases the accessibility of NGS so that whole genome sequencing (WGS) or whole exome sequencing (WES) are now within the reach of an exponentially growing number of researchers and physicians and by extension, patients and research subjects as well.
‘“Next-generation” and “massive-parallel” DNA sequencing are blanket terms used to refer collectively to the high-throughput DNA sequencing technologies available which are capable of sequencing large numbers of different DNA sequences in a single reaction (i.e., in parallel).’ [5] NGS tools allow for the sequencing of entire genomes, but they can also be used to sequence only targeted regions of the genome. For example, one can sequence only the protein coding regions of the genome (the exome), which is referred to as whole exome sequencing (WES),1 or one can sequence only certain gene families (e.g.: globin genes) or genes involved in a particular biological pathway or associated with a particular (set of) disorder(s) (e.g.: colon cancer). Hence the tools provide many new opportunities to sequence more DNA faster and cheaper, but they also allow us to perform more or less the same experiments or testing we performed previously but more efficiently. Furthermore, it is also important to note that NGS enables the study of more than just the DNA sequence and its variations: it also allows for the study of RNA sequences and hence the study of the transcriptome (the genes transcribed from DNA, which also includes untranslated regions) as well as the study of epigenetic phenomena including DNA methylation and chromatin analysis. Casey and coauthors [6] review these applications in the specific context of gastrointestinal (GI) malignancies including the identification of germ line DNA markers for disease risk assessment and diagnosis; the identification of germ line or somatic DNA changes in order to help classify GI malignancies and/or be an indicator of therapeutic response; and allowing for the sequencing and analysis of the gut microbiome, which could lead to novel drug targets. The applications for transcriptome and epigenetic studies also raise practical and ethical issues that are related to and overlap with germline DNA sequencing and the study of variations (which is, presently, the most popular subject of debate when it comes to discussing WGS) [7], however we will focus our discussion herein on issues related to the latter application, and specifically to whole genome and whole exome sequencing.
In the clinic, WGS has enabled a new approach to how to diagnose patients with an unclear clinical diagnosis and allow for the study of many more genes than a relatively small subset of genes traditionally associated with the patient's condition [8]. Furthermore, even if a targeted approach is adopted, the use of NGS may reduce the time and hassle of the ‘diagnostic odyssey’ by sequencing all genes known to be involved in a disorder at once instead of sequentially [6]. Hitherto, WGS has been most useful in the clinic, by aiding to diagnose diseases ‘that present with atypical manifestations, are difficult to confirm using clinical or laboratory criteria alone, or otherwise require extensive or costly evaluation’ and for which not all genetic variants are known [9]. These conditions tend to be genetically heterogeneous, and often have large variation in their phenotypic expression such as intellectual disability, congenital malformations and mitochondrial dysfunctions [9]. Targeted sequencing of cancer genes has also been used to help guide cancer treatment and a number of cancer centres are considering using whole genome or exome sequencing in the future [10].
Although it is still unknown exactly how often WES or WGS approaches have lead to a diagnosis, reports for different disorders and cohort sizes, most of which are highly selected, range from 19% [8] to 40% [10] respectively. How many of these diagnoses lead to changes and/or improvement in care, treatment or management of the disease remains largely unknown but seem to be rare [8], [10]. However, even if sequencing identifies a mutation and a molecular diagnosis for which there are no treatment options, it could still provide the benefit of saving the patient, family, and the medical community the time and effort of continuing to do tests in vain [10].
As stated above NGS as a tool, and WGS as an approach have the potential to help further the understanding of the causes and the natural history of diseases and to help to diagnose diseases in patients and/or inform on specific treatment or therapies [11]. This being said, the use of WGS as a widespread approach still has its share of challenges, including a number of issues that may be viewed as more practical in nature than ethical (although admittedly the former are often linked, on some level, to the latter). Before delving into the focal ethical discussion concerning informed consent, handling of data and return of results, we briefly mention below some of these more practical barriers in order to give a broader picture of where WGS stands at present.
Given the reality of limited health care budgets, cost is an important factor to address when considering the responsible and widespread implementation of a novel tool or approach. As such, it is important to note that although it is clear that the costs of technically sequencing a genome and obtaining the raw data have dropped dramatically in the last decade, the total costs of using WGS, including safe storage of the data/results, interpretation and the return of results still remain unknown. As stated by Frank et al who conducted a review of cost calculations for WGS, ‘The real costs for the whole sequencing workflow, including data management and analysis, remain unknown.’ [12] Furthermore, at present, the ‘economic evidence for whole genome sequencing is quite poor’ [12] and as some have noted, given the team of experts needed to analyse the data and return the results to patients, we may have to seriously consider ‘The $1000 genome’ and ‘the $100 000 analysis’ [13]. Indeed, the very characteristics that make NGS-based testing so powerful and attractive, namely the large amount of genomic data produced relatively quickly, also, in a sense, create further difficulties: ‘NGS reactions generate huge sequence data sets in the range of megabases (millions) to gigabases (billions), the interpretation of which is no trivial task. Moreover, the scale and nature of data produced by all NGS platforms place substantial demands on information technology at all stages of sequencing, including data tracking, storage, and quality control.’ [5] Furthermore, the general background education and training for physicians to properly manage genomic results is also lacking [1]. The dilemmas for genetic counselling involve not only the large amount of time it is expected to take to explain the nature of the technology and its consequences to patients, but also on how to actually communicate the information so that patients understand [14].
With respect to the wide(r) implementation of WGS in the clinic, indeed, many of the challenges stem from, or are at least related to the fact that NGS as a technology, and WGS as an approach are still, in essence, ‘in translation’ from the research laboratory to the clinic. This means that many of the aspects related to all stages of the testing procedure are still being ‘tried out’, assessed and evaluated. Furthermore, in the context of WGS, the study of the entire genome may be the last resort to get to a diagnosis. The outcome of such a journey is unpredictable, and in this sense ‘every patient becomes a major research endeavour.’ [1] Although patients in this situation may not be part of the typical formally designed and systematic research context we usually envisage, there is no doubt that the use of a novel tool and approach (still in a translational phase) to address their diagnosis, places them in a particular situation between purely clinical aims, and purely research aims. This should be kept in mind as the issues surrounding WGS are discussed.
Section snippets
Ethical issues in whole genome sequencing: informed consent, data handling, and return of results
The ethical issues raised by WGS are not completely new compared to those related with previous work in genetics and genomics. However, unique features of NGS and WGS, such as the amount and quality of data and the open-ended opportunities for future analysis render the detailed view and magnitude of ethical issues somewhat different for WGS compared to other tools and strategies. Given that most of the existing ethical frameworks created to guide biomedical research and diagnostic practice
Conclusion
We have focused the discussion herein on ethical issues that arise in the context of WGS; namely issues related to informed consent, data handling and return of results. As made evident throughout this article, many important questions regarding these ethical issues and how best to address them remain unanswered at the moment. Given this state of affairs, it may be wise to progress with some caution, particularly in the face of proposals to widely implement WGS in screening programmes; for
Conflict of interest
None.
Acknowledgements
The authors would like to thank Emilia Niemiec for her valuable comments and suggestions.
References (45)
Opportunities and challenges for the integration of massively parallel genomic sequencing into clinical practice: lessons from the ClinSeq project
Genet Med
(2012)- et al.
ACMG recommendations for reporting of incidental findings in clinical exome and genome sequencing
Genet Med
(2013) - et al.
Return of results: not that complicated?
Genet Med
(2012) - et al.
Personal genome research: what should the participant be told?
Trends Genet
(2010) - et al.
Return of individual research results from genome-wide association studies: experience of the Electronic Medical Records and Genomics (eMERGE) Network
Genet Med
(2012) - et al.
Recommendations for returning genomic incidental findings? We need to talk!
Genet Med
(2013) - et al.
Subjects matter: a survey of public opinions about a large genetic cohort study
Genet Med
(2008) - et al.
Exploring concordance and discordance for return of incidental findings from clinical sequencing
Genet Med
(2012) The clinical implementation of whole genome sequencing: a conversation with seven scientific experts
J Inherit Metab Dis
(2012)- ...
DNA sequencing costs; data from the NHGRI genome sequencing program (GSP)
Key principles and clinical applications of “next-generation” DNA sequencing
Cancer Prev Res
Next generation sequencing and a new era of medicine
Gut
Exome and whole-genome sequencing as clinical tests: a transformative practice in molecular diagnostics
Clin Chem
The promise and challenges of next-generation genome sequencing for clinical care
JAMA Intern Med
Sequencing set to alter clinical landscape
Nature
Next-generation sequencing: ready for the clinics?
Clin Genet
Genome sequencing: a systematic review of health economic evidence
Health Econ Rev
The $1,000 genome, the $100,000 analysis?
Genome Med
From genetic counseling to genomic counseling
Mol Genet Genomic Med
Research ethics recommendations for whole-genome research: consensus statement
PLoS Biol
Cited by (51)
Communication skills training for healthcare professionals in providing genetic counseling: A scoping literature review
2021, Patient Education and CounselingEthical issues related to research on genome editing in human embryos
2020, Computational and Structural Biotechnology JournalCitation Excerpt :These ELSI commonly revolve around issues of privacy and confidentiality of the genomic data; how to obtain fully informed consent from research subjects; the possibility of subjects to withdraw from research; as well as issues regarding the return of research results, including the right not to know. While going into depth into each of these issues is beyond the scope of this article (see Pinxten and Howard 2014 for a review) [50], we provide an example of the complexity of some ELSI by explaining the challenges of obtaining informed consent below. We also highlight that in general, the ELSI surrounding the use of WGS and WES in research is still being debated and the logistics and policies needed to be implemented to offer responsible genomic sequencing are still being developed.
«Genethics» and public health genomics
2019, Applied Genomics and Public HealthConsenting patients to genome sequencing
2019, Clinical Genome Sequencing: Psychological ConsiderationsWhole Exome Sequencing: Applications in Prenatal Genetics
2018, Obstetrics and Gynecology Clinics of North AmericaCitation Excerpt :Genetic professionals have an ethical obligation to follow appropriate protocols for patient consent60 and interpretation of variants. It is particularly important to discuss the options of opting in or out of receiving information on secondary/incidental findings and VOUS.61 In the case of trio analysis, it is essential to consent the mother separately from the father to discuss that nonpaternity may be disclosed from prenatal WES.