Pathogenic Germline Variants Identified in Children with Neuroblastoma

TOP - September 2021 Vol 14, No 5 - Genetic Counseling

Researchers have identified 2 inherited pathogenic genetic variants in patients with pediatric neuroblastoma, according to results from a study presented at the 2021 virtual American Association for Cancer Research annual meeting. Both variants—the ALK gene and loss of function in PHOX2B—are associated with worse outcomes.

“The observed association of pathogenic/likely pathogenic germline variants with worse outcomes suggests that we need a more thorough evaluation of patients with neuroblastoma than is currently performed as standard of care,” said Emily Blauel-Bocko, MD, Attending Physician, Children’s Hospital of Philadelphia, PA, and lead investigator of the study.

“This study is very important. It opens the door to genetic counseling for these families and the possibility of preventing some of these cases,” she continued.

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

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

Although recent studies estimate that approximately 8% to 10% of pediatric patients spanning all cancer types harbor a rare pathogenic or likely pathogenic germline variant in a cancer predisposition gene, the heritability of such germline variants remains largely unknown because of limited parental data.

Study Details

The research was conducted with the support of the Gabriella Miller Kids First Pediatric Research Program. Dr Blauel-Bocko and colleagues studied paired samples from children and parents using whole-genome sequencing of germline DNA from 556 patients with neuroblastoma and 1 or both of their biologic parents (457 samples from patients and both parents and 99 patients with 1 biologic parent).

The investigators sampled tumor DNA in 336 samples and tumor RNA in 207 samples. They found 93 pathogenic/likely pathogenic variants in known cancer predisposition genes in 90 patients, or 16% of the cohort.

Two main pathogenic/likely pathogenic genes were identified: ALK, which accounts for 75% to 80% of neuroblastoma, and loss of function in PHOX2B, accounting for 5% to 10% of neuroblastoma.

Compared with controls, enrichments in genes associated with repair defects were observed in patients with identified pathogenic/likely pathogenic variants. In addition, 95% of the identified germline variants were inherited, with a distribution of 54% maternal and 46% paternal inherited patterns (6% were de novo).

Importantly, the presence of these germline variants correlated with worse event-free survival (P = .0107) and worse overall survival (P = .0015).

“The association between pathogenic/likely pathogenic germline variants and high-risk and high-stage trended toward significance,” Dr Blauel-Bocko noted.

Further research will analyze host–tumor interactions and modifying factors of disease. One important focus is to understand the genotype and phenotype relationship in children who have neuroblastoma and parents who never developed it despite the presence of genetic alterations.

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Last modified: September 13, 2021