Germline 16p11.2 Microdeletion Predisposes to Neuroblastoma

Abstract

Neuroblastoma is a cancer of the developing sympathetic nervous system. It is diagnosed in 600-700 children per year in the United States and accounts for 12% of pediatric cancer deaths. Despite recent advances in our understanding of this malignancy's complex genetic architecture, the contribution of rare germline variants remains undefined. Here, we conducted a genome-wide analysis of large (>500 kb), rare (<1%) germline copy number variants (CNVs) in two independent, multi-ethnic cohorts totaling 5,585 children with neuroblastoma and 23,505 cancer-free control children. We identified a 550-kb deletion on chromosome 16p11.2 significantly enriched in neuroblastoma cases (0.39% of cases and 0.03% of controls; p ¼ 3.34 3 10 À9 ). Notably, this CNV corresponds to a known microdeletion syndrome that affects approximately one in 3,000 children and confers risk for diverse developmental phenotypes including autism spectrum disorder and other neurodevelopmental disorders. The CNV had a substantial impact on neuroblastoma risk, with an odds ratio of 13.9 (95% confidence interval ¼ 5.8-33.4). The association remained significant when we restricted our analysis to individuals of European ancestry in order to mitigate potential confounding by population stratification (0.42% of cases and 0.03% of controls; p ¼ 4.10 3 10 À8 ). We used whole-genome sequencing (WGS) to validate the deletion in paired germline and tumor DNA from 12 cases. Finally, WGS of four parent-child trios revealed that the deletion primarily arose de novo without maternal or paternal bias. This finding expands the clinical phenotypes associated with 16p11.2 microdeletion syndrome to include cancer, and it suggests that disruption of the 16p11.2 region may dysregulate neurodevelopmental pathways that influence both neurological phenotypes and neuroblastoma.

Assessment of Birth Defects and Cancer Risk in Children Conceived via In Vitro Fertilization in the US

“… 23 Germline de novo variants have been reported to cause several genetic diseases, including birth defects (eg, congenital heart disease) and some childhood cancers, including neuroblastoma. 24 , 25 , 26 While more work is warranted to understand the role of de novo germline genetic variants in the interface between birth defects and childhood cancer, this remains a plausible mechanism as these events are also more likely in children conceived via IVF. 27 …”

Sex-specific recombination predicts parent of origin for recurrent genomic disorders

“…Females, on average, have more crossovers per genome, and when observing the frequency of CNVs in the population with known parental biases, a pattern emerges. 22q11.2 and 16p11.2 have a maternal bias and a prevalence of 1 in 4,000 and 1 in 3,000 [30,84] respectively, while 3q29 and 5q35.3 have paternal biases and a prevalence of 1 in 30,000 and 1 in 14,000 respectively [85]. While prevalence could be confounded by severity of the disorders, our data suggest the sex speci c frequency of meiotic recombination may also in uence the incidence of these genomic disorders.…”

Sex-specific recombination predicts parent of origin for recurrent genomic disorders

“…22q11.2 and 16p11.2 have a maternal bias and a prevalence of 1 in 4,000 and 1 in 3,000 6,80 respectively, while 3q29 and 5q35.3 have paternal biases and a prevalence of 1 in 30,000 and 1 in 14,000 respectively 81 . While prevalence could be confounded by severity of the disorders, our data suggest the sex specific frequency of meiotic recombination may also influence the incidence of these genomic disorders.…”