Nearly 1% of the population carry certain pathogenic variants that put them at high risk of cancer or cardiovascular disease (CVD), according to a new study led by investigators at Massachusetts General Hospital (MGH). The study also showed that individuals at markedly increased risk could not be reliably identified based solely on family history. Instead, genetic testing was needed to identify them. The MGH group’s paper was recently published in JAMA Network Open.
“What was really striking was that simply taking a family history—as I currently do in my clinical practice—would have failed to identify most of the high-risk individuals,” said senior author Amit V. Khera, M.D., a medical director of the MGH Preventive Genomics Clinic and leader of a research group at MGH and the Broad Institute of MIT and Harvard.
The researchers studied data from 49,738 middle-aged adults in the UK Biobank, which recruited individuals across the United Kingdom. The MGH study used whole exome sequencing to look for three genetic conditions: familial hypercholesterolemia, which predisposes to cardiovascular disease; hereditary breast and ovarian cancer; and Lynch syndrome, which predisposes to colorectal and uterine cancers. According to the U.S. Centers for Disease Control and Prevention, identifying individuals carrying these pathogenic variants can be particularly useful.
Working with geneticists at Partners HealthCare Personalized Medicine, the scientists determined that 441 (0.9%) of the UK Biobank participants carried a pathogenic variant, including 0.3% for familial hypercholesterolemia, 0.5% for hereditary breast and ovarian cancer, and 0.2% for Lynch syndrome.
For all three conditions, risk of associated diseases was substantially higher: 21% for familial hypercholesterolemia variant carriers vs. 9% of noncarriers, 28% of hereditary breast and ovarian variant carriers of variants vs. 8% of noncarriers, and 22% of Lynch syndrome variant carriers vs. 2% of noncarriers.
Across the three conditions, only 40% of individuals who carried a pathogenic variant noted that a parent or sibling had been affected by the associated disease. “What’s more is that the information was complementary–those who had both a family history and a pathogenic variant were at the highest risk,” Khera said.
“Genetic testing is currently used predominantly in those already affected by disease, but these data really speak to the potential of doing it in much broader populations,” said lead author Aniruddh Patel, M.D., a cardiology fellow at MGH and Harvard Medical School. The cost of testing has decreased dramatically, and is now about $200. If such variants are identified, risk can be reduced by interventions such as cholesterol-lowering medications, earlier screening with mammograms or colonoscopy, or surgical procedures such as a mastectomy and ovary removal.
The approach currently recommended by clinical guidelines has focused on genetic testing only for individuals affected by disease and their family members. However, this phenotype-first process may give way to a genotype-first future, the MGH scientists suggest in their paper. In this paradigm, population-based genomic screening would be used to identify high-risk individuals before disease onset, enabling targeted screening or prevention.
Population genomic screening has become increasingly feasible because of rapid decreases in the cost of gene sequencing and is already underway or planned in several health care systems and national biobanks. There are currently more than 120 biobanks in the world.
As next steps, the researchers are performing genetic testing via an NIH research study on thousands of MGH patients who volunteered for the Partners HealthCare Biobank, aiming to identify the 1% of patients who harbor pathogenic variants and offer to work with patients and their health care teams to prevent disease before it starts.
