| dc.description.abstract | Childhood cancer is a complex and poorly understood process. It is estimated that around 10%
of pediatric cancer cases are due to a genetic condition known as a cancer predisposition
syndrome (CPS). Variants in adult cancer predisposing genes (CPGs), BRCA1 and BRCA2, have
been found to be enriched in pediatric cancer patients and are often associated with breast and
ovarian cancer in adults. Suggestions are made that heterozygous germline variants in these
genes can increase the risk of developing brain and solid tumors in children, although the
relationship between heterozygous BRCA1 and BRCA2 germline variants and pediatric cancer is
not yet demonstrated.
This study aimed to examine the presence of a potential second genetic event in pediatric patients
with a heterozygous BRCA1 or BRCA2 germline variant. The study employed two approaches.
First, somatic mutational pattern analysis was conducted to assess the presence of homologous
recombination deficiency (HRD), which is associated with most cancers in adult patients with a
BRCA1 or BRCA2 germline variant. Hence, a comparison of HRD-related mutational signatures
and the use of CHORD aimed to assess the presence of HRD in pediatric patients with a
heterozygous BRCA1 or BRCA2 germline variant. Next, the study aimed to investigate the
relationship between expression quantitative trait loci (eQTLs) on the non-pathogenic allele of
the BRCA2 gene in pediatric patients and allelic imbalance by comparing germline variants of
patients with the presence of eQTLs.
Results showed that HRD was only observed in pediatric patients with a biallelic BRCA2 germline
variant or heterozygous BRCA2 germline variant and a somatic second hit. However, no relation
was found between heterozygous BRCA1 or BRCA2 germline variants and HRD, and therefore the
onset of pediatric cancer. Moreover, the study found a slightly higher percentage of cis-eQTLs
within patients with a BRCA2 germline variant compared to the healthy population, but not
compared to the AYAs patients with bladder cancer. Additionally, seven clusters of co-occurring
eQTLs were found. Accordingly, read-based phasing and RNA expression analysis are required to
validate whether combinations of cis-eQTL clusters are present on the non-pathogenic allele and
therefore could induce allelic imbalance leading to tumor development. Due to a limited sample
size, further research is required to better understand the findings. | |
