Researchers have made progress in unravelling the genetic underpinnings of pediatric neuroblastoma. Two main inherited pathogenic genetic variants have been identified and appear to be associated with worse outcomes: the ALK gene and loss of function in PHOX2B. The research, conducted with the support of the Gabriella Miller Kids First Pediatric Research Program, was presented at the virtual edition of the American Association for Cancer Research (AACR) Annual Meeting 2021 and featured in the opening press conference.¹

An important finding is that the heritability of pathogenic or likely pathogenic germline variants accounts for about 16% of neuroblastomas, whereas previous estimates were less than 10%. “The observed association of pathogenic or likely pathogenic germline variants with worse outcomes suggests we need a more thorough evaluation of patients with neuroblastoma than is currently performed as standard of care,” stated lead author Emily Blauel-Bocko, MD, an attending physician at the Children’s Hospital of Philadelphia.

Speaking about the main resource for this research, Dr. Blauel-Bocko commented: “The Gabriella Miller Kids First Pediatric Research Program has a neuroblastoma cohort with a rich and unique data set that is allowing unanswered questions to be addressed. We found that 16% of the pediatric neuroblastoma cohort harbored a pathogenic or likely pathogenic germline variant in a cancer predisposition gene and that the vast majority of these germline variants were inherited. Importantly, the presence of a pathogenic or likely pathogenic germline variant correlated with worse outcomes.”

Ongoing research efforts will be aimed at further understanding the host-tumor interactions and modifying factors of disease. One important area of research is to understand the genotype and phenotype relationship in children who have the disease and parents who do not, despite the parents having the genetic alterations.

Background

Neuroblastoma is a childhood cancer that arises from the sympathetic nervous system. It accounts for 8% of childhood cancers and 12% to 15% of childhood cancer mortality.

“Neuroblastoma is characterized by highly diverse clinical behavior—from spontaneous regression to relentless disease progression,” explained Dr. Blauel-Bocko. “Only 1% to 2% have a family history of disease (ie, familial neuroblastoma). The remainder are thought to arise spontaneously [sporadic],” she added.

Previous research allowed estimation that 8% to 10% of pediatric patients with cancer (all types) harbor a rare pathogenic or likely pathogenic germline variant in a cancer predisposition gene. Due to limited data from parents, the heritability of these germline variants remains largely unknown. “Despite the richness of prior studies, they were unable to definitively determine whether the germline variants were inherited due to the scarcity of parental germline data,” Dr. Blauel-Bocko stated.

“Recent genome-wide studies in sporadic neuroblastoma cases aid in the discovery of multiple susceptibility loci. With this in mind, we think of neuroblastoma as a spectrum of diseases. Although we have discovered valuable knowledge about the underpinnings of neuroblastoma, gaps in knowledge exist due to a lack of parental data and the inability to definitively determine heritability,” she elaborated.

Treasure Trove of Genomic Data

The Gabriella Miller Kids First Pediatric Research Program provides a treasure trove of large-scale genomic data from children with pediatric cancers and structural birth defects. Working with support from the Kids First Program, Dr. Blauel-Bocko and fellow researchers performed whole-genome sequencing from germline DNA from paired samples from 556 patients with neuroblastoma and one or both biologic parents (457 samples from patients and both parents and 99 patients with a single biologic parent).

“Working with these germline data from both parents and children allowed for the establishment of heritability patterns,” Dr. Blauel-Bocko told listeners. “Nearly two-thirds have matched tumor data.”

Dr. Blauel-Bocko and her colleagues identified two main pathogenic or likely pathogenic genes: ALK, which accounts for 75% to 80% of neuroblastomas, and loss of function in PHOX2B, which accounts for 5% to 10% of neuroblastomas. “Compared to the general neuroblastoma population, these genes have a slight skewing toward lower-risk patients, which is probably due to selection bias related to entry to the study. Results in the cohort mirror that of the general neuroblastoma population, allowing us to generalize findings,” she commented.

Study Details

The researchers sampled tumor DNA from 336,326 samples and tumor RNA from 207 samples. They found 93 pathogenic or likely pathogenic variants in known cancer predisposition genes in 90 patients, or 16% of the cohort. “The 16% is higher than previous estimates,” noted Dr. Blauel-Bocko.

One canonical ALK mutation and no PHOX2B mutations were identified. Sequencing data from biologic parents were available for 85 of the 90 patients. Compared to controls, enrichments in genes associated with repair defects were observed in patients with identified pathogenic or likely pathogenic variants. The second major finding was that 94% of the identified germline variants were inherited, with an equal distribution between maternal and paternal inherited patterns (47% each, 6% de novo).

Next, they looked at correlations between the presence of a pathogenic or likely pathogenic germline variant and outcome. They found that having a germline variant correlated with worse event-free survival (P = .0107) and worse overall survival (P = .0015). “The association between pathogenic or likely pathogenic germline variants and high-risk and high-stage disease trended toward significance,” noted Dr. Blauel-Bocko. “The observed associations…with worse outcomes suggest we need a more thorough genetic evaluation of patients with neuroblastoma than is currently performed as standard of care,” she added.

The study is limited in that the functional relevance to neuroblastoma remains to be understood for many of the pathogenic or likely pathogenic variants identified here. 

DISCLOSURE: Dr. Blauel-Bocko reported no conflicts of interest.

REFERENCE

1. Blauel E, Vaksman Z, Lee A, et al: Heritability of cancer predisposition gene mutations in 556 neuroblastoma patients with paired parental DNA whole genome sequences. AACR Annual Meeting 2021. Abstract 3030. Presented April 10, 2021.