Association of Damaging Variants in Genes With Increased Cancer Risk Among Patients With Congenital Heart Disease.
Morton SU, Shimamura A, Newburger PE, Opotowsky AR, Quiat D, Pereira AC, Jin SC, Gurvitz M, Brueckner M, Chung WK, Shen Y, Bernstein D, Gelb BD, Giardini A, Goldmuntz E, Kim RW, Lifton RP, Porter GA Jr, Srivastava D, Tristani-Firouzi M, Newburger JW, Seidman JG, Seidman CE.
JAMA Cardiol. 2020 Oct 21:e204947. doi: 10.1001/jamacardio.2020.4947. Online ahead of print.
Take Home Points:
- There is a significant genetic component to the known increased rates of cancer in patients with congenital heart disease compared to the background population.
- There is no association between a particular cancer risk gene and specific congenital heart disease sub-type.
Commentary from Dr. Helen Parry (Leeds UK), section editor of ACHD Journal Watch:
Objective of the study:
To analyse the frequency of rare loss of function (LoF) cancer risk genes in a large cohort of patients with congenital heart disease
Genetic analysis was performed on participants in the Paediatric Cardiovascular Genetics consortium (n=4443) and controls (n=9808). Their genetic data were analysed for 723 genes associated with cancer risk, 38 of these were previously associated with congenital heart disease and 227 were LoF variants. These genes were previously identified and held on the Catalogue of Mutations in Cancer- Cancer-Gene consensus database.
Frequency of the above genetic variants were analysed in the cohort with congenital heart disease and compared with the control cohort. Binomial testing was performed and significance was taken as p value < 0.05. A separate sub-analysis was performed for 7 genes with multiple LoF variants associated with extra cardiac anomalies in patients with congenital heart disease.
The table shows analysis of the frequency of the above genetic variants in the congenital heart disease cohort versus controls.
|Number of gene variants
|Odds ratio 95% CI
|Cancer risk genes
|2.31 × 10−11b
|Cancer risk genes also associated with CHD
|<2.2 × 10−16b
|1.58 × 10−7
There was no association between a particular cancer risk gene and specific congenital heart disease sub-type. The prevalence of seven cancer risk genes with multiple LoF variants associated with extra cardiac anomalies in patients with congenital heart disease was also tabulated (not replicated here as sub-analysis with very small numbers).
There is a significant genetic component to the known increased rates of cancer in patients with congenital heart disease compared to the background population.
Large cohort available for genetic analysis.
Genes identified and validated by a well-recognised and independent database were used to form the basis of the study.
Comprehensive cover of the genes of interest.
Provides some insight into an topic with relatively little research.
There was almost no reference to potential confounding factors: were any of the gene variants also more common in individuals with particular behaviours also associated with cancer, e.g. smoking or substance misuse?
The study was limited to patients of European extraction.
There were no real details regarding the potential clinical relevance. There was a comment at the end of the paper that this may help guide screening programmes in the future but without any expansion on whether this will be limited to specific cancers or how this might work in a practical sense.
The analysis looking at multiple LoF variants associated with extra cardiac anomalies in patients with congenital heart disease had such small numbers it would be very difficult to draw any conclusions, this has been largely omitted from this review as a result.