A very small percentage of the population carries pathogenic variants that significantly increase their risk for certain cancers and cardiovascular disease. And according to new research, this increased risk was not reliably detected by family history.
Lead study author Aniruddh Patel, MD, a cardiology fellow at MGH and Harvard Medical School, said in a press release that the study idea came about to determine “how outcomes were affected for pathogenic variant carriers within the context of contemporary care.”
The researchers assessed three genomic conditions: familial hypercholesterolemia, hereditary breast and ovarian cancer syndrome, and Lynch syndrome. They collected gene-sequencing data from 49,738 patients spanning 22 sites in the UK from the UK Biobank. Data were collected between March 21, 2006, and Oct. 1, 2010, and included inpatient hospital data (dating back to 1977), cancer registry data (dating back to 1957), and death registry data (dating back to 2006). The primary exposures were pathogenic or likely pathogenic DNA variants, as classified by a clinical laboratory geneticist. The main outcome measure was the composite end point specific to each condition: atherosclerotic cardiovascular disease events for familial hypercholesterolemia, breast or ovarian cancer for hereditary breast and ovarian cancer syndrome, and colorectal or uterine cancer for Lynch syndrome.
Pathogenic Variants Increase Disease Risks
A total of 49,738 patients were included (mean age, 57 years; 55% were female), of whom 441 (0.9%) had a pathogenic or likely pathogenic variant associated with one of the three genomic conditions: familial hypercholesterolemia, n=131 (0.3%); hereditary breast and ovarian cancer syndrome, n=235 (0.5%); and Lynch syndrome, n=76 (0.2%). Patients with the variants had a greater risk for the associated disease: familial hypercholesterolemia, 21.4% of carriers versus 9.4% of noncarriers developed atherosclerotic cardiovascular disease; hereditary breast and ovarian cancer syndrome, 27.6% of female carriers versus 7.7% of female noncarriers developed associated cancers; and Lynch syndrome, 22.4% of carriers versus 1.9% of noncarriers developed colorectal or uterine cancer. At age 75 years, carriers receiving contemporary clinical care had a predicted probability of 45.3% for familial hypercholesterolemia, 41.1% for hereditary breast and ovarian cancer syndrome, and 38.3% for Lynch syndrome. For all three conditions, 39.7% of carriers versus 23.2% of noncarriers reported a family history of the disease.
The study was published in JAMA Network Open.
According to senior author Amit V. Khera, MD, 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, “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.”
“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,” lead author Dr. Patel said.