Researchers identify pathogenic germline variants in children with sporadic neuroblastoma
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Approximately 16% of children with sporadic neuroblastoma harbored rare pathogenic or likely pathogenic variants in a cancer predisposition gene, most of which were inherited, according to study results.
The findings, presented at the virtual American Association for Cancer Research Annual Meeting, also showed children with these variants had poorer outcomes.
Only around 1% to 2% of children with neuroblastoma have a family history of disease with underlying causal germline mutations in ALK or PHOX2B.
Although the remainder of cases have been thought to arise sporadically, data from next-generation sequencing studies led to estimates that 8% to 10% of children across cancer types harbor a rare pathogenic or likely pathogenic germline variant in a cancer predisposition gene. But, without parental data, the heritability of these germline variants had been unknown.
“This research was done on the heels of decades of work by my mentors and principal investigators of the study, John M. Maris, MD, and Sharon J. Diskin, PhD, whose labs focus on understanding the genomic landscape of neuroblastoma,” Emily Blauel, MD, attending physician at Children’s Hospital of Philadelphia, told Healio. “Knowledge gained from recent genome-wide association studies in sporadic neuroblastoma cases, such as the identification of numerous susceptibility loci, has led us to think of susceptibility as more of a spectrum. This study is unique in that — for the first time — we have a large cohort with paired parental germline data, which allows us to definitively determine heritability.”
Blauel and colleagues assessed for the presence of rare variants in a predefined set of 197 cancer predisposition genes by conducting whole-genome sequencing of germline DNA from 556 children (male, 54%; white, 85%; aged younger than 12 months at diagnosis, 42%) with neuroblastoma and at least one of their parents (both biological parents, n = 457; one biological parent, n = 99). Researchers also performed whole-genome and exome sequencing on 336 matched tumor DNA samples and RNA sequencing on 207 matched tumor RNA samples.
Overall, 90 children (16%) harbored 93 pathogenic or likely pathogenic germline variants in known cancer predisposition genes.
Researchers observed enrichment of such variants in genes associated with DNA repair defects and in several cancer predisposition genes, including CHEK2, BARD1, NSD1 and RMRP. They identified one canonical ALK mutation, but no patients harbored PHOX2B mutations.
That 16% rate of children harboring these variants is within the range of what researchers expected to find, Blauel said.
“Several studies have reported similar statistics, across many cancer types,” she told Healio. “There is a growing interest in evaluating germline variants in cancer predisposition genes throughout pediatric oncology at large. We are just starting to understand what this means and the magnitude of the importance.”
Sequencing data of 85 parents showed 94% of the germline variants had been inherited, with equal distribution between maternal (47%) and paternal (47%) inheritance patterns. Six percent of variants were de novo, all of which occurred in genes related to syndromes associated with neuroblastoma development, such as Costello syndrome, Noonan syndrome and Sotos syndrome.
Children who harbored pathogenic or likely pathogenic germline variants in cancer predisposition genes had poorer 10-year EFS (66.9% vs. 79.7%) and 10-year OS (76.5% vs. 89.4%) than children without these variants.
This finding warrants further discussion within the neuroblastoma community, according to Blauel.
“This absolutely heightens our concern for patients with such germline variants,” she said. “However, as this is a new finding, the application to risk assignment, treatment decisions and general counseling has yet to be evaluated. Additionally, we do not yet fully understand the function of many of these variants.”
Researchers plan to use this data set to conduct sequencing analyses of additional genes beyond cancer predisposition genes and noncoding regions of the genome.
They also plan to further study why parents with these variants did not develop neuroblastoma.
“Our hypothesis is that modifying factors are contributing to the tumorigenic process, and that it's the interplay of rare pathogenic germline variant and these modifying factors that lead to the development of neuroblastoma,” Blauel said. “We are currently working to understand how this cumulative risk might explain the difference between genotype and phenotype that we are observing.”
Perspective
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Ajay Gupta, MD, MS
Blauel and colleagues’ rich analysis of familial trios will help determine whether hitherto unrecognized variants of familial neuroblastoma will be identified as causative, potentially altering care and genetic counseling for many families with a child with neuroblastoma. If these data are eventually paired with detailed outcome data associated with each patient, the correlation between pathogenesis and germline enrichment of currently unknown variants may be elucidated. Further, the team plans to both expand its sequencing studies to whole-genome analysis and to study parents with known pathogenic or likely pathogenic variants to better understand why a proband developed disease, but the parent did not.
Having such data sets publicly available will additionally enhance the ability to mine for information. The future standard of care for neuroblastoma may include the targeted sequencing of such a panel of familial neuroblastoma genes, the results of which may inform clinical practice and outcomes.
Perspective
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Antoni Ribas, MD, PhD, FAACR
This is an important study because of the number of patients analyzed and the significance of the results.
Investigators evaluated a cohort of 556 patients with neuroblastoma, a common childhood malignancy. It has been known for years that some neuroblastomas have an inherited pattern, but the majority do not. It has been though that fewer than 10% of cases are inherited.
By studying these patients genetically, and having information from both parents, the investigators were able to document that inheritability of neuroblastoma is probably more common than previously thought, because 16% had germline variants that were also in the parents, suggesting the neuroblastoma would have been inherited. The patients who had these variants also had worse outcomes.
This is very important information because it could allow genetic counseling for these families to prevent some of these cases. It also opens the door for future studies of the function of these genes to determine how they can be used therapeutically to treat neuroblastoma.
UCLA Health
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Blauel E, et al. Abstract 3030. Presented at: American Association for Cancer Research Annual Meeting (virtual meeting); April 10-15, 2021.
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