"As more patients affected by congenital heart disease have been surviving to adulthood, it has become clear from studies performed by other clinical researchers that these patients face an increased risk of cancer at a younger age," Dr. Christine E. Seidman and Dr. Sarah U. Morton of Harvard Medical School, in Boston, told Reuters Health in a joint email.
"Molecular discoveries have identified mutated genes that cause congenital heart disease and mutated genes that cause cancer, as well as recognition that some genes contribute to both conditions," they explained. "Our study asked the broader question - whether mutations in any gene found in patients with congenital heart disease could contribute to the increased risk of cancer."
To address this question, the two researchers and their colleagues compared the frequency of damaging loss-of-function (LoF) variants in cancer-risk genes of 4,443 individuals with CHD and 9,808 control participants without CHD.
The frequency of LoF variants in regulatory cancer-risk genes was significantly higher in patients with CHD than in controls (3.2% vs. 1.7%), as was the frequency of CHD genes previously associated with cancer risk (1.3% vs. 0.18%), the researchers report in JAMA Cardiology.
Overall, the frequency of all cancer-risk variants was 34% higher among patients with CHD (642/4443) than among controls (1099/9808). Most CHD patients with cancer-risk variants (93.3%) had a single cancer-risk variant, 6.7% had two and 0.5% had three.
Damaging cancer-risk variants were significantly increased in individuals with developmental delays and were most frequent among patients with CHD and extracardiac anomalies (16.7%) and among those with CHD and neurodevelopmental defects (15.0%).
In contrast, the frequency of LoF in cancer-risk genes in patients with isolated CHD was comparable with that of controls.
Even among patients with CHD without pathogenic variants in CHD genes, there were significantly more LoF variants than among unaffected controls (13.4% vs. 11.0%).
The authors propose "that cancer risk (CR) is increased because the germline variant provides the first of 2 hits needed for cancer to emerge. Across this CHD cohort, 3.6% had LoF variants in recessive CR genes, while 1.8% had LoF variants in dominant CR genes. We speculate that high lifetime radiation doses might increase somatic variants that complement CHD LoF variants."
"There are two important clinical implications," Dr. Seidman and Dr. Morton noted. "First, genetic information can define patients with congenital heart disease who may be at increased risk for cancer risk. These patients may benefit from greater surveillance for cancers."
"Second," they said, "patients with congenital heart disease and increased rates of mutations in cancer-risk genes also had additional congenital anomalies. By contrast, patients with only heart malformations did not have increased rates of cancer gene mutations. These data indicate clinical findings can also help to define congenital-heart-disease patients with highest risk."
Dr. Lazaros Kochilas of Emory University, in Atlanta, who has researched various aspects of CHD, told Reuters Health by email, "We have noted in different settings that patients with CHD are at risk of developing cancer. The reasons can be multiple: iatrogenic, (including) exposure to radiation at a young age, chronic exposure to medications, some of them with carcinogenic potential, and sub- or total thymectomy that is required as part of most cardiac surgeries for CHD; high level of chronic stress decreasing immune response to carcinogenesis; and genetic predisposition due to shared pathways between cardiogenesis and tumor development."
"In many diseases and particularly of congenital nature, the study of developmental pathways is important for understanding the full breadth of implications of the presence of a certain defect," said Dr. Kochilas, who was not involved in the new study. "Closing a 'hole' like an atrial septal defect or ventricular septal defect does not cure the patient from the implications of the genetic predisposition that were responsible for the birth of the child with the specific congenital heart lesion."
"The subject still requires more investigation: LoF is only a small portion of possible genetic determinants," he added.
SOURCE: https://bit.ly/37Pf51O JAMA Cardiology, online October 21, 2020.
By Will Boggs MD
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