Can Whole-genome Sequencing Predict Cancer Risk and Improve Public Health?


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To me, the concept is not just about whether these mutations change your risk, but rather, is the knowledge of these mutations going to change your behavior, your medical actions, your preventive strategies?

—Timothy Rebbeck, PhD

If, as expected, the cost of whole-genome sequencing continues to drop, perhaps down to the $1,000 vicinity, it may become an alluring option for consumers who want to know about their risks for cancer and other diseases. But can genome sequencing really provide practical information about individual risks and influence risk-reduction strategies that could improve public health?

If consumers obtain whole-genome sequencing in hopes that “it will to alert them to a risk that they don’t necessarily know about, then they will likely be satisfied, because there are risks for which these tests can in fact alert them. We estimate that at least half of individuals, once all the research is done, will get such a result,” remarked Bert Vogelstein, MD, coauthor of a study published in Science Translational Medicine1 on the potential of personal genome sequencing to predict the risks of cancer and other diseases.

“However, if individuals want to get tested because they think that this will be a crystal ball to tell them what their medical history will be, they will be disappointed. It will not do that,” Dr. Vogelstein said. Updating the caveat, let the buyer beware, he said, “Let the buyer understand what they are paying for, what information they are going to get. How useful that information will be is up to the consumer.” Dr. Vogelstein, who presented the research findings at the American Association for Cancer Research (AACR) Annual Meeting, is Clayton Professor of Oncology at the Johns Hopkins Kimmel Cancer Center, Co-director of the Hopkins’ Ludwig Center for Cancer Biology Research in Baltimore, and investigator at the Howard Hughes Medical Institute in Chevy Chase, Maryland.

Important Distinction

While costs in excess of $10,000 are currently curbing demand for whole-genome sequencing, discussants at a press conference where Dr. Vogelstein presented his findings in advance of the AACR meeting, agreed that it is important to properly frame the issues concerning whole-genome sequencing in anticipation of increased demand.

“We have to implement genome technologies correctly and for the public good,” stated Olufunmilayo I. Olopade, MD. Dr. Olopade is Professor of Medicine and Human Genetics and Director of the Cancer Risk Clinic at the University of Chicago School of Medicine. Whole-genome sequencing and related issues of tumor heterogeneity and personalized medicine were also discussed by speakers at other sessions of the Annual Meeting, attended by nearly 17,000 physicians, researchers, health-care professionals, cancer survivors, and patient advocates.

“To me, the concept is not just about whether these mutations change your risk, but rather, is the knowledge of these mutations going to change your behavior, your medical actions, your preventive strategies? Does it change something about the way you will act as a result of having that knowledge? Then it presumably would have value in being tested,” said Timothy Rebbeck, PhD, Professor of Epidemiology, University of Pennsylvania Perelman School of Medicine in Philadelphia. “I think that the number of situations where that is the case right now is very small, but the number of situations where we can actually act on genetic information in a positive way by changing our behavior, by changing our prevention strategies, is extremely limited. As those grow, as we have more of those options available to us, based on genetic information, then these genetic tests will become more and more valuable.”

Thomas Sellers, PhD, MPH, Executive Vice President and Director of the Moffitt Research Institute in Tampa, Florida, noted that the article coauthored by Dr. Vogelstein made a very important distinction between genome sequencing to predict risk and for personalized medicine. “Once you have disease, having a full sequence could be extremely valuable,” Dr. Sellers stated. Identification of mutations can inform treatment, such as how a patient might respond to a particular drug, but to know if there is a mutation or not, “you need to know what the normal germline sequence is,” Dr. Sellers pointed out. “So in that situation, knowing the complete sequence of an individual is going to have to be part of the exercise of doing personalized treatment if we are going to provide proper therapy for a particular cancer.”

Quantitative Framework

The research findings reported by Dr. Vogelstein were based on data on the incidence of 24 diseases, including cancer, autoimmune, and other diseases, among 53,666 pairs of identical twins entered into registries worldwide. Johns Hopkins researchers developed mathematic models to predict minimum and maximum risk distributions compatible with the twin data and used these distributions to estimate the capacity of whole-genome sequencing to identify individuals at clinically significant risk for the 24 diseases.

“Identical twins share the same genome, and if the genome were the determining factor for common diseases, then the prevalence of a specific disease in an individual whose twin has that disease can be used to determine how well whole-genome sequencing could predict an individual’s disease risk. What we hope to do in this study is to put the debate about the value of whole-genome sequencing and its relevance to personalized medicine in a quantitative framework,” Dr. ­Vogelstein explained.

“Each of us contains about 4½ million variants that distinguish us one from another,” he said, and “trying to figure out the way these variants interact with one another to cause or reduce the risk of disease is really a Herculean task.” He added, “the functional significance of almost all these variants is currently unknown.”

Clinically Actionable Results

A positive test result, “something that we thought was clinically actionable,” Dr. Vogelstein explained, was defined as a 10% risk of disease, meaning 1 in 10 people would develop the disease from all factors combined. “A negative test result and its usefulness is in the eye of the beholder, but in order to be really useful—that is, actionable to change people’s behavior or their medical care—you probably want to have that risk much less than the general population,” Dr. Vogelstein added.

The study found that most patients would receive negative tests for most diseases, and the predictive value of the negative tests would be small. “On the positive side,” the researchers wrote, “our results show that, at least in the best-case scenario, the majority of patients might be alerted to a clinically meaningful risk for at least one disease through whole-genome sequencing.”

As an example, Dr. Vogelstein presented the study data for ovarian cancer. “At most, 1 in 50 women will get a positive result. That could be very useful to those women, because it would suggest that they should be candidates for intense surveillance, he said. But for the 49 out of 50 who test negative, the result “is not that informative,” Dr. Vogelstein stated. “It shows only that they have a risk that is slightly lower than the general population.” Instead of the estimated 1.4% risk of ovarian cancer for women in the United States today, having a negative test would mean the risk “is somewhere about 1.3% or 1.2% at best,” he noted.

“The point about medically actionable information is critical,” Dr. Rebbeck stated. “We have often been treating genetic risk equally across all diseases, but some diseases and some genetic risks are going to be more medically actionable than others,” he said. “A 10% increased risk where there is no medical intervention might be thought of very differently than a 10% increased risk that could be easily addressed” by preventive actions, such as staying out of the sun, he said. “So we may need to think about whether a particular level of risk has a medically actionable intervention and not treat all of these increased risks the same.”

Dr. Olopade pointed out that receiving a positive result predicting a high risk for ovarian cancer can be “an actionable item” or an anxiety-creating dilemma, depending on a woman’s circumstances. A woman who is done having children may choose to have her ovaries removed, but a woman in her 20s concerned about marriage and future childbearing could have “so much anxiety over that information that it in fact does more harm than good.”

Strong Family History

Whole-genome sequencing can be extremely valuable for identifying the genetic basis of monogenetic diseases—those caused by a single defect in a single gene—and management of families with a strong history of these diseases, Dr. Vogelstein said. “That will of course be dependent on understanding all the kinds of variations that occur and what their influence is, but on monogenetic diseases, that certainly is a good possibility for many families,” he added.

“I agree completely that that is where the greatest value will be,” Dr. Sellers said, “but there are limitations.” Some people may not know their family history either because of adoption, separation, or lack of communication. Another limitation is that “family history is not a static event. It’s dynamic,” he noted. A person may not have a family history, then suddenly a family member develops cancer and the other family members are now in a different risk category. “That raises the question about when you do sequencing for family history,” Dr. ­Sellers said.

In her AACR Presidential Address, Judy E. Garber, MD, MPH, noted that genome sequencing may reveal alterations in genes that were not suspected based on the patient’s history. “One of the issues that comes up in this context concerns how good our history-taking is—we have certainly relied on such interviews to identify individuals and families for testing—and whether it is important to use family history as it gets easier and easier to identify alterations using these specific technologies,” Dr. Garber said. “Clinically, most of us would still argue that it is critically important to have context for your analysis.”

Dr. Garber, who completed her term as AACR President during the Annual Meeting, is Director of the Center for Cancer Genetics and Prevention at Dana-Farber Cancer Institute and Associate Professor of Medicine at Harvard Medical School in Boston.

Genes, Environment, and Bad Luck

“Cancer is a mixture of genetic and nongenetic effects,” Dr. Vogelstein explained, but many people think nongenetic effects refer only to the lifestyle and environmental factors. “That’s only a small part of the picture. Much more important in some cases are stochastic, or random, influences. Cancers, as we now know, are caused by the sequential accumulation of mutations, almost all of them occurring after birth. These mutations occur strictly by chance as cells divide,” he explained.

“We do know that when it comes to cancer, it is genes, it is the environment, and it is also bad luck,” Dr. Sellers agreed. He said that the study by Dr. Vogelstein and colleagues emphasizes the relative contributions of those three components.

“For the vast majority of individuals, whole-genome sequencing will never be a crystal ball that can reliably predict future health,” Dr. Vogelstein said. He explained that for males in the United States, a negative test would reduce their risk of developing some type of cancer from 45% to between 32% and 42%; for females, the risk would be reduced from 38% to between 27% and 36%. “A fortune teller with a crystal ball this precise would soon go out of business,” he said.

For those who test positive, meaning they have a 10% risk for disease, “this does not imply that the disease will be the person’s major health problem,” Dr. Vogelstein added. “Perhaps most important, from a public health perspective, whole-genome sequencing can certainly be useful in certain patients but cannot substitute for conventional risk management strategies, including routine checkups, lifestyle optimization, and so forth.”

Prevention and Detection Interventions

Dr. Vogelstein cited a review article by Colditz el al,2 also published in Science Translational Medicine, “showing that over half of cancers can be prevented by applying the knowledge that we have today,” he reported. “Effective risk management will have to involve the entire population, not just a genetically predisposed subset in order to make a real dent in disease incidence,” he said.

Going back to his ovarian cancer example, he noted that while the estimated percentage of women in the United States who will develop ovarian cancer is only 1.4%, this represents about 2.2 million women. If every woman had whole-genome sequencing, “you could conceivably identify a predisposition in 500,000 of them,” Dr. Vogelstein said. “That leaves 1.7 million of the 2.2 million who will get the disease unalerted to their condition. We have to make surveillance and early detection available to all, not just those who are at high risk.” It’s similar with pancreatic cancer, he said. Whole-genome sequencing conducted among all men and women in the United States could at best identify a predisposition among just 230,000 of the 4.5 million who will eventually develop the disease.

“We’re specifically not trying to say that whole-genome sequencing will or won’t be useful,” Dr. Vogelstein replied in response to a question. “We are simply trying to do a reality check. How many people benefit? How many people will get information that won’t really help them understand their risk?”

Also citing the Colditz article,2 Dr. Sellers stressed the importance of cancer prevention, particularly by reducing smoking, obesity, and use of tanning beds. “We are not doing a good enough job convincing the public that they need to do these things. We need to create the incentives to adopt those healthy lifestyles,” he said.

“We now have vaccines that can prevent human papillomavirus (HPV) infection, which would have a very large impact on eliminating cancers, and the only behavior change there—much easier than the others—is just to get the vaccine, but the uptake is nowhere near where it should be,” he added. Dr. Sellers noted that the HPV vaccine was important for both males and females.

Clinician’s Perspective

“I am the clinician in the room,” said Dr. Olopade, explaining her perspective and focus on the individual patient. “What I think the genome has really allowed us to appreciate is how each individual’s genome is different from every other person’s,” she said. “Unless we actually do a lot more sequencing of genomes, we’re not going to know the different variations of the genomes that explain the heterogeneity that we see among patients who come into the clinic,” she added. “For those of us who are doctors and have to prevent or treat illness, the more understanding we have of individual genomes, the better.”

Reading the study reported by Dr. Vogelstein, Dr. Olopade said, “I remembered the arguments and the discussions we had almost 20 years ago, when we started talking about the clinical implications of genetics for regular oncology practice. The debate at that time was about whether we were going to offer BRCA1 and BRCA2 testing and whether anyone would want to know that information because there was nothing they could do about it. We had passionate discussions and debate among ethicists, among patient advocates, and among geneticists who thought nothing good could come out of that sort of research. But 20 years later, the oncology community in fact has adopted widespread testing for BRCA1 and BRCA2 because we came to realize there were many women who died of ovarian cancer unnecessarily, and we could have prevented that if we knew they had the genetic mutation.”

Preparing Patients

Dr. Garber had also addressed early BRCA1 and BRCA2 testing in her talk the previous day. “We found that most people who sought to learn the results handled the information fine, as long as it was provided carefully,” she said. Whole-genome sequencing “may not be different, but preparing patients for what they may learn is a much more complicated task.” Dr. Garber noted that there has already been a shift from testing for BRCA1 and BRCA2 to testing for a panel of mutations that might indicate increased risk of ovarian cancer. “Individuals will say, ‘If you are going to look at some of my genes, why not all of them?’ So why not all of them?”

Dr. Olopade called on her medical colleagues to embrace the challenge of genome sequencing, to look at lifestyle, social, and cultural influences that can alter the genome, “and then we’ve got to figure out those so-called stochastic events.” Perhaps patients who knew that they were at increased cancer risk due to genetic and random events might be more motivated to make healthy lifestyle changes.

“What I always ask my patients is, ‘Are you asking about the risk of dying from cancer or risk of being diagnosed with cancer?’ I think from a public health perspective, the better our tools to help patients survive cancer and not have untoward side effects, the more the public will adopt public health interventions that will help them beat the odds of dying or suffering from cancer.” ■

Disclosure: Drs. Vogelstein, Olopade, Rebbeck, Sellers, and Garber reported no potential conflicts of interest.

References

1. Roberts NJ, Vogelstein JT, Parmigiani G, et al: The predictive capacity of personal genome sequencing. Sci Transl Med 4:133ra58, 2012.

2. Colditz GA, Wolin KY, Gehlert S: Applying what we know to accelerate cancer prevention. Sci Transl Med 4:127rv4, 2012.


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