Researchers identify pathogenic germline variants in children with sporadic neuroblastoma

According to the results of the study, about 16% of children with sporadic neuroblastoma had rare pathogenic or possibly pathogenic variants of a cancer predisposition gene, most of which were hereditary.

The results, presented at the American Association for Cancer Research’s virtual annual meeting, also showed that children with these variants performed worse.

Only about 1% to 2% of children with neuroblastoma have a family history of the disease with underlying germline mutations in them. ALK or PHOX2B.

Although the rest of the cases are thought to occur sporadically, data from next-generation sequencing studies have led to estimates that 8% to 10% of children of all cancer types harbor a variant of the pathogenic germline. rare or probably pathogenic in a gene predisposing to cancer. But, without parental data, the heritability of these germline variants was unknown.

“This research was conducted as a result of decades of work by my mentors and the lead investigators of the study, John M. Maris, MD, and Sharon J. Diskin, PhD, whose laboratories focus on understanding the genomic landscape of neuroblastoma, ” Emily Blauel, MD, attending physician at Philadelphia Children’s Hospital, Healio said. “Knowledge gained from recent genome-wide association studies in cases of sporadic neuroblastoma, such as the identification of many susceptibility loci, has led us to view susceptibility as more of a spectrum. This study is unique in that – for the first time – we have a large cohort with matched parental germline data, which allows us to definitively determine heritability.

Emily blauel

Blauel and colleagues assessed the presence of rare variants in a predefined set of 197 cancer predisposition genes by performing whole genome sequencing of germ DNA from 556 children (male, 54%; white, 85%; aged less 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). The 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 possibly pathogenic germline variants in known cancer predisposition genes.

The researchers observed an enrichment of these variants in genes associated with DNA repair defects and in several cancer predisposition genes, including CHEK2, BARD1, NSD1 and RMRP. They identified a canonical ALK mutation, but no patient hosted PHOX2B mutations.

That 16% rate of children harboring these variants is within the range of what the researchers expected to find, Blauel said.

“Several studies have reported similar statistics on many types of cancer,” she told Healio. “There is increasing interest in pediatric oncology throughout pediatric oncology evaluating germline variants in cancer predisposition genes. We are only now beginning to understand what this means and the extent of the importance. ”

Sequencing data from 85 parents showed that 94% of germline variants were inherited, with an equal split between maternal (47%) and paternal (47%) inheritance patterns. Six percent of the variants were de novo, all occurring in genes linked to syndromes associated with the development of neuroblastoma, such as Costello syndrome, Noonan syndrome and Sotos syndrome.

Children who harbored pathogenic or possibly pathogenic germline variants in cancer predisposition genes had SES at 10 years (66.9% vs. 79.7%) and OS at 10 years (76.5% vs. 89.4%) weaker than children without these variants.

This finding warrants further discussion within the neuroblastoma community, according to Blauel.

“This absolutely reinforces our concern for patients with such germline variants,” she said. “However, as this is a new discovery, the application to risk attribution, treatment decisions and general advice has yet to be evaluated. Additionally, we do not yet fully understand the function of many of these variations. “

The researchers plan to use this dataset to perform additional gene sequencing analyzes beyond cancer predisposition genes and non-coding regions of the genome.

They also plan to study in more detail why parents with these variants did not develop neuroblastoma.

“Our hypothesis is that modifying factors contribute to the tumorigenic process, and that it is the interaction of the rare pathogenic germ line variant and these modifying factors that lead to the development of neuroblastoma,” said Blauel. “We are currently working to understand how this cumulative risk could explain the difference between the genotype and the phenotype that we observe.”

Perspective

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Antoni Ribas, MD, PhD, FAACR

This is an important study because of the number of patients analyzed and the importance of the results.

The researchers evaluated a cohort of 556 patients with neuroblastoma, a common childhood malignancy. It has been known for years that some neuroblastomas have a hereditary pattern, but the majority do not. However, less than 10% of cases are hereditary.

By studying these patients genetically and obtaining information from both parents, the researchers were able to document that heritability of neuroblastoma is probably more common than previously thought, as 16% had germline variants that were also in parents, suggesting that the neuroblastoma was inherited. Patients who had these variants also had worse outcomes.

This is very important information because it could allow genetic counseling for these families in order to prevent some of these cases. It also opens the door to future studies on the function of these genes to determine how they can be used therapeutically to treat neuroblastoma.

Antoni Ribas, MD, PhD, FAACR

President of the AACR
UCLA Health

Disclosures: No product or company that would require financial disclosure is mentioned in this perspective.

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American Association for Cancer Research Annual Meeting