By James Evans

from GeneWatch 28-1 | Jan-May 2015


Massively parallel sequencing is proving to be a potent clinical tool. The ability to sequence anywhere from dozens of genes to the entire exome of a patient can be critical to arriving at a diagnosis when confronted with an enigmatic clinical presentation that results from a primarily genetic etiology. Likewise, the application of massively parallel sequencing (MPS) to analyze a tumor's genome and guide targeted treatment shows great promise for improving cancer care.

Yet, while improving the care of the ill is a necessary and noble goal, our grandmothers had it right: "An ounce of prevention is worth a pound of cure." If we wish to gain the most possible benefit from any medical application, we should look for ways in which it may be used to prevent disease in the first place. When it comes to medical interventions, the successful application of public health measures holds the greatest promise for providing the greatest benefit to the greatest number of people. Stunning successes like vaccines and fluoridated water attest to the power of public health and dwarf the small good that I do in my medical office treating one sick patient at a time.

Thus, given the inherent power of public health to provide benefit, there has long been interest in applying genomics in this realm. Until recently, however, those efforts focused primarily upon genomic risk assessment in common disease. Unfortunately, these approaches have gained little traction so far, due to a variety of factors. We remain ignorant about the majority of the genomic contribution to common disease and genomic factors are only one of many etiologic contributors to the maladies we are most likely to develop. Moreover, the hope that the provision of genomic information would be a potent motivator to get people to change unhealthy lifestyles has, predictably, not been borne out.

But there does exist a highly promising potential application of genomics in the public health sphere. Millions of people in the US harbor mutations that predispose them to dramatically increased risk of severe but preventable disease. For example, given a population prevalence of about 1/400 for Lynch Syndrome, there exist close to a million individuals in this country who are at starkly elevated risk for colorectal cancer and could thus benefit from specifically targeted preventive modalities with already-proven efficacy. If one carefully compiles a list of genes that when mutated confer a high risk of preventable disease, roughly 1-2% of the US population carries such a mutation, making them candidates for robust prevention. The way we currently identify such individuals in routine clinical care is by their family history - bluntly put, we wait for family members to get sick or die to signal the presence of a potent genetic predisposition - arguably a rather grim and imperfect way to detect the presence of preventable disease risk in a family. However, with the advent of MPS it is now theoretically possible to identify those 1-2% of individuals in the population who are at high risk of preventable disorders and initiate preventive modalities in time to avert or greatly mitigate disease.

The investigation of such an approach is timely. Mary-Claire King recently called for all women in the US over 30 years of age to undergo BRCA1/2 sequencing and President Obama has called for a "Precision Medicine" initiative. But we must be careful before we rush head long to inflict our favorite medical interventions on those who are already healthy.  The healthy have less to gain from any medical intervention and more to lose than those who already suffer from disease and who come to us seeking help. And make no mistake, all medical interventions have the potential to do mischief, whether it be overt physical harm from treatment, over-diagnosis from a non-specific screening test or simply missed opportunity costs in which time and money could have been better spent.

A pilot study, GeneScreen (funded by the NHGRI) is currently underway at the University of North Carolina in which healthy individuals are being screened for mutations in a highly selected set of genes that when mutated result in a high risk of preventable disease, such as the Lynch Syndrome associated genes and BRCA1/2. There are many challenges to realizing the tantalizing potential of this approach, including how to adequately consent, educate and return results to vast numbers of people. But the time is ripe for investigating its promise. As in newborn screening, if one can target those conditions that are amenable to early treatment or prevention, much good could result. The current study will answer important questions about implementing such a program, but further questions will remain, such as the true penetrance and prevalence of high-risk mutations in the general, unselected population.

One could ask a rather obvious question: "Why focus on a set of highly selected genes? Given the plummeting costs and wealth of information to be discovered, why not just do whole genome sequencing (WGS) on everyone?" Cogent arguments against such a clinical approach are myriad. We are still far from understanding how to interpret the vast majority of the 4 million variants found upon WGS. Long experience in clinical care has taught us well that there is little point in generating massive amounts of information in the provision of an individual's medical care that we do not understand and that begs for mis- and over-interpretation.

Moreover, the notion that one's whole genome sequence is a "resource" that can be drawn upon for years ignores the reality that a whole genome sequence derived in 2015 will be vastly out of date by 2018, just as a genome sequence derived in 2012 would now not be relied upon. Until this rapidly advancing technology plateaus there is no point in depositing a vast, soon to be obsolete data set in your medical record. More to the point, the entire lesson of the new genomic landscape is that sequencing is getting cheap and easy. We can therefore sequence what we need to sequence when we need to do so as we understand it. This is not to argue that we shouldn't obtain whole genome sequence data on vast numbers of people. We should and we must if we ever hope to gain sufficient knowledge to interpret the human genome. But that endeavor falls squarely within the context of research - we must not conflate research with clinical care. WGS of vast numbers of people must be pursued in a context in which those individuals are appropriately consented and educated and in which we do not dilute their clinical care and squander opportunity costs by making them unwitting research subjects.

Finally, the issue of financial cost looms large. Medical care is phenomenally expensive. Even at today's relatively low cost of sequencing, providing a whole genome sequence (not to mention storing and interpreting it) costs more than $1,000. Moreover, the upfront cost of a test is only the tip of the iceberg in clinical medicine. An unwarranted test, even if free, is exorbitantly expensive if it generates downstream testing or overt harms. These costs cannot and should not be borne by the medical system until we show that the provision of such information to the healthy individual is clinically beneficial.

The time is right to aggressively investigate the promise of targeted sequencing of carefully selected genes to detect those members of the population who are at high risk of preventable disease. Critical, immediate tasks include determining which genes warrant sequencing in healthy individuals, how to do so in an affordable way, how to properly educate individuals about the implications of both a positive and negative result and how to effectively implement preventive care when such mutations are found. In the end, if we determine that such a program results in improved outcomes to individuals and their families, we will have begun to realize a promising vision of public health genomics.

James P. Evans, MD, PhD, is Bryson Distinguished Professor of Genetics and Medicine at the University of North Carolina School of Medicine and the Editor-in-Chief of Genetics in Medicine.

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