Study highlights limits of whole genome sequencing

Genome gradient

CHICAGO—A large study casts doubt on whether whole genome sequencing can reliably predict the risk of cancer and other diseases for most individuals.

Researchers studied thousands of identical twins and found evidence to suggest that whole genome sequencing cannot accurately predict the risk of developing cancer in individuals without a family history of that cancer.

In fact, those who undergo whole genome sequencing and receive a negative test result for a certain malignancy may still develop that disease, the investigators said.

The negative result simply implies that the individuals’ risk of developing that cancer is similar to that of the general population.

Bert Vogelstein, MD, of the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins in Baltimore, and his colleagues reported these findings in Science Translational Medicine and at the AACR Annual Meeting 2012.

To investigate the predictive potential of whole genome sequencing, Dr Vogel and his colleagues used data recorded on thousands of identical twins entered into registries in Sweden, Denmark, Finland, Norway, and the National Academy of Science’s National Research World War II Veterans Twins Registry.

“Identical twins share the same genome,” Dr Vogelstein pointed out. “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.”

So the researchers collected information on the incidence of 24 diseases among the twin-pair groups, including autoimmune, cardiovascular, genitourinary, neurological, and obesity-associated diseases, as well as cancer.

The team used mathematical models to calculate the capacity of whole genome sequencing to predict the risk of each disease based on typical thresholds physicians use to initiate preventive or therapeutic measures.

The analysis revealed that whole genome sequencing could alert most individuals to an increased risk of at least one disease, signaled by a positive test result.

But most individuals would get negative test results for the majority of diseases studied, even though they might ultimately develop these diseases.

“As many as 2% of women undergoing whole genome sequencing could receive a positive test result for ovarian cancer, alerting them that they have at least a 1-in-10 chance of developing that cancer over their lifetime,” said Kenneth Kinzler, PhD, of the Johns Hopkins McKusick-Nathans Institute of Genetic Medicine.

“The other 98% of women who receive a negative test for ovarian cancer will not be guaranteed a lifetime free of ovarian cancer because their risk of developing it is very similar to that of the general population. So a negative test is not a ‘free pass’ to discount the chance of acquiring any particular disease.”

The investigators said their analysis shows that whole-genome-based tests are not highly informative for predicting cancer in most individuals without a strong family history of the disease.

“In families with strong histories of cancer, whole genome sequencing can still be very informative for identifying inherited genes that increase cancer risk,” said Victor Velculescu, MD, PhD, also of the McKusick-Nathans Institute of Genetic Medicine.

“But hereditary cancers are rare. Most cancers arise from mutations acquired through environmental exposures, lifestyle choices, and random mistakes in genes that occur when cells divide.”

On the other hand, the data suggested that genetic tests could theoretically identify more than three-quarters of individuals who may develop 4 of the diseases studied: coronary heart disease in men, thyroid autoimmunity, type 1 diabetes, and Alzheimer’s disease.

Discussion

Notify me when a comment is posted for this article