American Association for Cancer Research Annual Meeting

American Association for Cancer Research Annual Meeting

Perspective from Ajay Gupta, MD, MS
Perspective from Antoni Ribas, MD, PhD, FAACR
Source:

Blauel E, et al. Abstract 3030. Presented at: American Association for Cancer Research Annual Meeting (virtual meeting); April 10-15, 2021.



Disclosures: Blauel reports no relevant financial disclosures. Please see the abstract for all other researchers’ relevant financial disclosures.
April 10, 2021
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Researchers identify pathogenic germline variants in children with sporadic neuroblastoma

Perspective from Ajay Gupta, MD, MS
Perspective from Antoni Ribas, MD, PhD, FAACR
Source:

Blauel E, et al. Abstract 3030. Presented at: American Association for Cancer Research Annual Meeting (virtual meeting); April 10-15, 2021.



Disclosures: Blauel reports no relevant financial disclosures. Please see the abstract for all other researchers’ relevant financial disclosures.
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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.

10-year survival outcomes
Data were derived from Blauel E, et al. Abstract 3030. Presented at: American Association for Cancer Research Annual Meeting (virtual meeting); April 10-15, 20201.

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.”

Emily Blauel, MD
Emily Blauel

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.”