Pathogenic Germline Variants Correlate With Worse Survival Outcomes in Neuroblastoma

Germline variants in cancer predisposition genes were associated with worse event-free and overall survival in patients with neuroblastoma.

Recent findings from the Gabriella Miller Kids First (GMKF) neuroblastoma X01 cohort study showed that the presence of pathogenic or likely pathogenic germline variants in cancer predisposition genes, which were identified in approximately 1 in 5 patients with neuroblastoma and were mostly inherited, was shown to correlate with worse event-free survival (EFS) and overall survival (OS) vs the absence of germline variants,

The results, presented ahead of the AACR Annual Meeting 2021, showed that 16% of the cohort (n = 90) harbored 93 pathogenic or likely pathogenic germline variants across 197 predefined cancer predisposition genes. The presence of a pathogenic or likely pathogenic germline variant in a cancer predisposition gene was associated with worse EFS (n = 82; P = .0107) and OS (P = .0015) compared with the absence of a germline variant (n = 421). The association between a pathogenic or likely pathogenic germline variant and high-risk and high-stage disease trended towards significance.

“The GMKF neuroblastoma cohort provides a rich and unique dataset that is allowing unanswered questions to be addressed,” said Emily Blauel-Bocko, MD, lead study author and a clinical fellow at the Children’s Hospital of Philadelphia, during a virtual presentation of the data.

Neuroblastoma is an embryonal tumor arising from the sympathetic nervous system. The solid tumor comprises 8% of childhood cancers and 12% to 15% of childhood cancer deaths.

Neuroblastoma is characterized by diverse clinical behavior, ranging from spontaneous regression to aggressive progression. Additionally, only 1% to 2% of patients have a family history of the disease, and the remainder of cases are believed to develop sporadically.

Within familial neuroblastoma, ALK mutations are responsible for 75% to 80% of pedigrees, and PHOX2B mutations are responsible for 5% to 10% of pedigrees. In sporadic neuroblastoma, genome wide association studies have aided in the discovery of susceptibility loci.

However, gaps in knowledge remain because of insufficient parental data, resulting in an inability to definitively determine heritability.

To that end, investigators worked with the GMKF program, which supports large-scale genomic research in the fields of childhood cancer and structural birth defects.

“The neuroblastoma cohort is a large-size cohort, which allowed us to identify rare germline variants. The cohort included germline data from patients and parents, allowing for establishment of heritability patterns of these germline variants. Additionally, the dataset included paired DNA and RNA, which allowed us to evaluate the role of these germline variants in tumor development or propagation,” said Blauel-Bocko.

The cohort included a total of 556 patients accompanied by germline data from the patient and both parents in the majority of cases. Approximately two-thirds of patients had matched tumor data.

The clinical characteristics of the neuroblastoma cohort generally mirrored that of the general neuroblastoma population, although there was a slight skew toward low-risk patients owing to the point of entry into the study, said Blauel-Bocko.

Additional results from the data collection indicated that one canonical ALK mutation in R1275Q was identified, and no evidence of a PHOX2B mutation was found. All pathogenic or likely pathogenic germline variants were identified in the tumor.

Enrichment was also seen in patients with identified pathogenic or likely pathogenic variants (P = .0006) overall, in genes associated with DNA repair defects (P < .0001), and in cancer predisposition genes, including BARD1 (P = .0024), CHEK2 (P = .0005), NSD1 (P = .0002), and RMRP (P < .0001) compared with control individuals,

Moreover, 94% of germline variants were inherited. Of the inherited variants, an equal percentage of maternal and paternal inheritance patterns were reported, at 47% each.

Furthermore, de novo variants (6%) were identified in syndromes predisposing to neuroblastoma, including Costello syndrome, Noonan syndrome, and Sotos syndrome.

“Our current work is focused on deeper investigations of the role of the role of these germline variants in tumor development and/or propagation in understanding the differing phenotype and genotype relationship between patients who have the disease and parents who do not have the disease despite the known inheritance patterns,” concluded Blauel-Bocko.


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. Presented at: AACR Annual Meeting 2021; April 9-14; Virtual. Abstract 3030.