Abstract
In the past years, genome wide association studies (GWAS) have provided evidence that inter-individual susceptibility to diverse pathological conditions can reveal a common genetic architecture. Through the analysis of congenital heart disease (CHD) and neuroblastoma (NB) GWAS data, we aimed to dissect the genetic susceptibility shared between these conditions, which are known to arise from neural crest cell (NCC) migration or development abnormalities, via identification and functional characterization of common regions of association. Two loci (2q35 and 3q25.32) harbor single nucleotide polymorphisms (SNPs) that are associated at a p-value < 10−3 with conotruncal malformations and ventricular septal defect respectively, as well as with NB. In addition, the lead SNP in 4p16.2 for atrial septal defect and the lead SNP in 3q25.32 for tetralogy of Fallot are less than 250 Kb distant from the lead SNPs for NB at the same genomic regions. Some of these shared susceptibility loci regulate the expression of relevant genes involved in NCC formation and developmental processes (such as BARD1, MSX1, and SHOX2) and are enriched in several epigenetic markers from NB and fetal heart cell lines. Although the clinical correlation between NB and CHD is unclear, our exploration of a possible common genetic basis between NB and a subset of cardiac malformations can help shed light on their shared embryological origin and pathogenetic mechanisms.
Highlights
Neuroblastoma (NB) is an embryonic tumor arising from the sympathetic nervous tissue and is among the most frequent cancers diagnosed in early infants, accounting for 13% of all deaths due to childhood malignancies [1]
To evaluate the genome-wide shared genetic signals between NB and congenital heart disease (CHD), we selected a subset of independent single nucleotide polymorphisms (SNPs) in approximate linkage equilibrium with each other and evaluated for each condition the number of SNPs with association p-value above and below different thresholds
We used Fisher exact test and simulation analysis to evaluate whether NB and each CHD condition in turn share more SNPs above and below the p-value thresholds than expected by chance [37]
Summary
Neuroblastoma (NB) is an embryonic tumor arising from the sympathetic nervous tissue and is among the most frequent cancers diagnosed in early infants, accounting for 13% of all deaths due to childhood malignancies [1]. Complex genetic mechanisms underlie cardiac development and its anomalies, and a number of different defects could be the cause—such as migration defects, reduced specification or overproduction of neural crest-derived mesenchymal cell types—and efforts have been made to try and elucidate causative variants affecting these conditions [9,10,11,12]. Neural crest cells (NCC) development and migration abnormalities have been conjectured to be implicated in the genesis of both CHD and NB [13,14,15,16], and there are case reports in the literature of patients affected with both of these conditions simultaneously [17]. George and colleagues [18]
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