Chicago, IL—For the individual at average risk for disease, whole-genome sequencing (WGS)—mapping the sequence of one’s full set of genetic material—is not a crystal ball to reliably predict future health, according to a study presented at the 2012 American Association for Cancer Research meeting.
WGS “cannot substitute for conventional risk management strategies, including routine checkups and lifestyle optimization,” said coinvestigator Bert Vogelstein, MD, Clayton Professor of Oncology and Pathology, Johns Hopkins Kimmel Cancer Center. WGS, however, may be extremely valuable for individuals with a strong family history of disease, Dr Vogelstein said.
The researchers estimated the maximum capacity of WGS to identify individuals at significant risk for 24 different diseases, including cancer, Alzheimer’s disease, heart disease, and stroke, based on 53,666 monozygotic twin pairs worldwide (Roberts NJ, et al. Sci Transl Med. 2012 Apr 2). Monozygotic twins share the same genome and therefore have identical genetic risk factors.
The potential scope of data is overwhelming. Every individual has 4.5 million variants in DNA sequence, and the significance of almost any given variant is yet unknown. Furthermore, the number of potential interactions between variants, which may cause, enhance, or even reduce disease risk, is “astronomical,” he said.
Within the more narrow confines of the study, for each disease in twin 1, the prevalence of that disease in twin 2 was assumed to yield the genetic risk for the twins’ genome. The investigators used a model to predict minimum and maximum risk distributions and used these to estimate the capacity of WGS to provide useful clinical information.
A positive test result was defined as an actionable (at least a 10% disease risk), meaning that 1 in 10 would develop the disease from all factors combined. Getting a positive test result would therefore make someone a candidate for intense surveillance. A negative, by contrast, result on the other hand would suggest that the individual had a slightly lower risk than the general population.
Why does WGS have such limited predictive power in cancer? “Because cancer is a mixture of genetic and nongenetic effects….Cancers are caused by the sequential accumulation of mutations, almost all occurring after birth. These things occur by chance; as cells divide, they make mistakes. If they occur in a cancer gene, that represents one step toward cancer. Cancer is a bad side effect of evolution,” Dr Vogelstein said.
WGS could, however, be extremely valuable for identifying the genetic basis of monogenic diseases. “If the consumer is purchasing the test because he or she hopes it will alert them to a risk that they don’t necessarily know about, then they will likely be satisfied, because these are risks for which these tests can in fact alert them. We estimate that at least one half of individuals, once all the research is done, will get such a result. However, if the individual wants to get tested because he or she thinks that this will be able to be a crystal ball, so to speak, to tell them what their medical history will be, they will be disappointed. It will not do that,” Dr Vogelstein said.
