Three extraordinary papers in the Lancet provide a fascinating first glimpse at issues that will be the topic of discussion and debate for the next generation at least. For the first time, investigators at Stanford and Massachusetts General Hospital used a complete human genome of an individual patient to provide a clinical assessment of the patient, a 40-year-old asymptomatic man with a family history of coronary artery disease and sudden death.
The analysis of 2.6 million SNPs and 752 copy number variations found that the patient was at increased risk for MI, type 2 diabetes, and some cancers, the researchers reported. They also found three rare variants of genes that have been linked to sudden cardiac death. They also found an LPA variant associated with familial CAD and mutations linked to clopidogrel resistance and a positive response to lipid-lowering therapy. These were some of the more clinically relevant findings, but an important aspect of the Lancet report is the nearly overwhelming amount of information that can be obtained from the whole-genome approach.
The investigators discussed key issues with the patient during genetic counseling, including the possibility that the analysis might “uncover high risk of a serious disease, including some for which there is no treatment.” Also discussed were the “reproductive implications.” In addition:
We noted that most of the sequence information is difficult to interpret, and discussed error rates and validation processes. Additionally, we discussed that risk alleles might be discovered that have reproductive or familial importance rather than personal importance (such as those for breast or ovarian cancer). We addressed the possibility of discrimination on the basis of genetics.
In their discussion, the authors state that “although the methods that we used are nascent, the results provide proof of principle that clinically meaningful information can be derived about disease risk and response to drugs in patients with whole genome sequence data.”
The investigators write that by current ATP III guidelines the patient “does not currently have major risk factors for coronary artery disease” and would not be a candidate for lipid-lowering therapy. However, based on the assessment of genetic risk the patient’s physician recommended lipid-lowering therapy.
In an accompanying Comment, Nilesh Samani, Maciej Tomaszewski, and Heribert Schunkert write:
Even if the direct cost of sequencing whole-individual genomes becomes affordable, there are many practical challenges that will need to be overcome if the personal genome is going to enter clinical practice. Arguably of greater importance are ethical issues: who should have their genome sequenced, what counselling should be provided before and after testing and by whom, and who should have access to an individual’s genetic information. Whereas these issues are familiar in genetic testing, the scale of the data contained within each personal genome, and the potential implication for so many different aspects of an individual’s health (and the health of their relatives), mean that these issues will need to be even more carefully considered (and legislated on where necessary) to prevent misuse.
In addition to the Comment, the Lancet also published a Viewpoint in which several of the authors of the main paper explore some of the ethical and practical issues surrounding the topic. They observe that, compared to genetic testing as it is now performed, “whole-genome sequencing greatly expands the breadth of testing from genes associated with a particular disease to the whole genome and, potentially, all the information that the genome contains about diseases or traits.”
Not all patients want or are capable of absorbing this type of information, they note, and informed consent becomes a complex issue: “The vast amount of knowledge that is offered by whole-genome sequencing makes informed consent for this procedure more complex than that for existing genetic testing.”
The authors go on to write that the clinical relevance of most findings is unclear, and even when there is a clear message there may be no therapeutic option. And the knowledge obtained will undoubtedly have important implications for the patient and for society:
In view of the predicted frequency of recessive mutations in the population, every patient will learn that he or she is a heterozygous carrier of more than one serious or lethal autosomal recessive disease. This information might affect a patient’s reproductive decisions, and have implications for existing children or other relatives. Since whole-genome sequencing will show that every patient has an above-average risk for some disorders, and for having children with some genetic diseases, every patient could face some negative social consequences from those risks, whether in insurance, employment, stigma, or otherwise. Although, in the long run, recognition of the universality of risk might lead to improved social support, in the short term, the patient might suffer.
They also note the potential strain on the healthcare system of simply conveying the results to people: “We predict that an average person might need information about roughly 100 genetic risks discovered in their genome. Even if that information averaged only 3 min per disorder, this process would take more than 5 h of direct patient contact, after many hours of background research into the importance of the various genomic findings.”
Finally, they conclude:
We are optimistic about the value of whole-genome sequencing in medical practice, but implementation of such testing will be challenging. As academics, we often assume that information is good and more information is better. But more information can sometimes be counterproductive. We need to begin thinking about when and how to offer full genome sequencing for clinical use. This preparation is essential to achieve maximum benefits from this technology, while keeping the harms to a minimum.
Here is the Lancet press release:
PERSONAL GENETIC PROFILING CAN YIELD CLINICALLY RELEVANT INFORMATION
The complete genetic profile, or genome, of a person can now be rapidly and inexpensively sequenced. But how useful is this information? In an Article published in this week’s Lancet, researchers show that whole-genome sequencing can yield clinically relevant information such as increased risk of cardiovascular disease and increased susceptibility or resistance to certain drugs. The Article is written by Dr Euan A Ashley, Stanford University School of Medicine, CA, USA, and colleagues.
The researchers assessed a 40-year-old man who presented with a family history of coronary artery disease and sudden death. His own medical history was not clinically significant and the patient exercised regularly without symptoms. He was taking no prescribed medications and appeared well. Clinical assessment included analysis of this patient’s full genome sequence, risk prediction for coronary artery disease, screening for causes of sudden cardiac death, and genetic counselling. This counselling included preparing the patient for the possibility that a serious disease could be uncovered for which there is no treatment, and also other possibilities such as the reproductive ramifications if he was carrying the gene for conditions such as cystic fibrosis, something that might not show up in his family history. The difficulties of translating the information into clear risk values was also explained in full.
Genetic analysis included the development of new methods for the integration of whole genome and clinical risk including environmental influences. This included creating one of the largest databases of genetic variants and their association with disease. Many other databases were also queried, including another hosted at Stanford that includes all the known information on genetic variants affecting drug responses (PharmGKB). For variants that had never been seen before, the team developed new computer prediction methods to estimate the importance of variants. The emphasis was on the practical application of the information so the team then put these risks together in the form of a report card that could be used by the patient’s physician or by the patient himself. The report card incorporated the patient’s baseline risk for many diseases based on age and sex and overlaid the genetic risk.
The results showed that the man was at increased risk of heart attack, type 2 diabetes, and some cancers. He also had rare variants in three genes associated with sudden cardiac death. Another variant was consistent with the family history of coronary artery disease. Consistent with a variant in a gene previously associated with osteoarthritis, there was a family history of osteoarthritis and the patient reported chronic knee pain without a formal diagnosis.
In terms of reaction to drugs, the patient had several variants that are associated with good response to statins (including reduced risk of myopathy) and one variant suggesting that he might need a raised dose to achieve a good response. One variant uncovered suggested he could be resistant to the antiplatelet drug clopidogrel and might need higher doses of that drug or one with a different mechanism should he need antiplatelet treatment. He also had variations suggesting he required lower maintenance dosing of warfarin if that treatment was required in the future.
The authors say: “The results provide proof of principle that clinically meaningful information can be derived about disease risk and response to drugs in patients with whole genome sequence data.”
They add: “Important limitations remain in our ability to comprehensively integrate genetic information into clinical care. For example, a comprehensive database of rare mutations is needed. Since risk estimates change as studies are completed, a continually updated pipeline is necessary.”
They conclude: “As whole-genome sequencing becomes increasingly widespread, availability of genomic information will no longer be the limiting factor in application of genetics to clinical medicine. Development of methods integrating genetic and clinical data will assist clinical decision making and represent a large step towards individualised medicine. The transition to a new era of genome informed medical care will need a team approach incorporating medical and genetics professionals, ethicists, and health-care delivery organisations.”
In an accompanying Comment, Dr Nilesh J Samani, University of Leicester and NIHR Biomedical Research Unit in Cardiovascular Disease, Leicester, UK, and colleagues, point out the logistical challenges of whole genome sequencing, including the importance of accuracy and the mammoth task of training doctors and pharmacists on how to translate genetic profiling into meaningful information for patients.
They say: “Arguably of greater importance are ethical issues: who should have their genome sequenced, what counselling should be provided before and after testing and by whom, and who should have access to an individual’s genetic information. Whereas these issues are familiar in genetic testing, the scale of the data contained within each personal genome, and the potential implication for so many different aspects of an individual’s health (and the health of their relatives), mean that these issues will need to be even more carefully considered (and legislated on where necessary) to prevent misuse.”
They conclude: “Notwithstanding these challenges, today’s elegant analysis shows the huge potential this approach could have for clinical care and takes the notion of personalised medicine one big step forward.”
In an linked Online First Viewpoint, Professor Henry T Greely, Stanford Law School, CA, USA, and colleagues, delve deeper into the implications of complete genome sequencing for medicine. They say: “Although there is no doubt room for automated assistance in the interpretation, a knowledgeable human being will need to sit down with patients to explain, patiently and sensitively, the meanings of their genomes. Who will provide skilled interpretation of whole-genome sequence to millions of patients?”
They add: “Even if individual professionals or groups of professionals with the relevant knowledge were available, they would need to be paid. We predict that an average person might need information about roughly 100 genetic risks discovered in their genome. Even if that information averaged only 3 min per disorder, this process would take more than 5 h of direct patient contact, after many hours of background research into the importance of the various genomic findings. Although evolving analysis and visualisation methods will undoubtedly help, how we can provide that much information in a meaningful way—and who will pay for it—is unclear.”
They conclude: “Whole-genome sequencing is already occurring. Before very long all patients might have their genomes sequenced for medical use. We are optimistic about the value of whole-genome sequencing in medical practice, but implementation of such testing will be challenging. As academics, we often assume that information is good and more information is better. But more information can sometimes be counterproductive. We need to begin thinking about when and how to offer full genome sequencing for clinical use. This preparation is essential to achieve maximum benefits from this technology, while keeping the harms to a minimum.”
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