NEW YORK – New research is revealing the role that rare structural variants (SVs) in the germline can play in the predisposition to several pediatric solid cancer types, particularly Ewing sarcoma, neuroblastoma, and osteosarcoma.
"Overall, our results demonstrate that rare germline SVs that span coding and noncoding loci are important risk factors for pediatric solid tumors," senior and co-corresponding author Eliezer Van Allen, a medical oncology and cancer genomics researcher affiliated with the Broad Institute, Harvard Medical School, and the Dana-Farber Cancer Institute, and his colleagues wrote in Science on Thursday, adding that the study "supports the integration of germline SVs into clinical practice and research efforts related to pediatric solid tumor predisposition."
For their analyses, the investigators used a cloud-based pipeline called GATK-SV to search for rare pediatric cancer-related germline SVs with whole-genome sequence profiles for 1,765 pediatric cancer patients, including 789 children with Ewing sarcoma, 690 pediatric neuroblastoma cases, and 286 cases of osteosarcoma. The analyses were helped along by whole-genome sequence data for 943 cancer-free parents and 6,665 adult control individuals.
The team uncovered dozens of rare, relatively large, de novo SVs in the germlines of pediatric cancer patients. Together, the analyses suggested that such variants account for an estimated 1.1 percent to 5.6 percent of pediatric cancer risk.
"Our findings indicate that rare germline SVs explain a modest but meaningful component (1.1 to 5.6 percent) of an individual's total liability for childhood cancer," the authors explained, "which lays the groundwork for the eventual incorporation of germline SV analyses into routine diagnostic screening and clinical practice."
The germline SVs tended to be enriched in genes involved in DNA damage repair, RAS-receptor tyrosine kinase signaling, and tissue of origin-related pathways, the investigators explained, as well as genes such as PHOX2B and FANCA that have been implicated in cancer predisposition in the past.
Along with ultrarare gene-disrupting SVs as well as SVs affecting noncoding variants, the researchers uncovered large, unbalanced germline chromosomal alterations that appeared to contribute to solid tumor risk in male children specifically.
Such sex-biased SVs were particularly prevalent in pediatric cancer cases involving neuroblastoma, where the investigators also highlighted higher-than-usual rates of rare de novo duplication copy number variants and alterations affecting known cancer risk genes. On the other hand, Ewing sarcoma cases were more often marked by complex de novo SVs, de novo inversion-mediated SVs, and germline changes that impacted Fanconi anemia- or DNA damage repair-related genes.
"Ongoing germline WGS efforts in other pediatric cancer populations will enable further generalization and replication of our findings, as well as the discovery of additional disease-specific risk factors," the authors suggested.
In addition, they added, future work focused on integrated genome-wide evaluation of SVs with single-nucleotide variants and small insertions and deletions in the same patients will enable a more complete understanding of germline factors that contribute to the development of pediatric cancer and, in turn, "a better understanding of the central oncogenic programs that give risk to these malignancies."
In a corresponding perspectives article in Science, the Spanish National Cancer Research Center's Geoff Macintyre and Jayne Hehir-Kwa of the Princess Maxima Center for Pediatric Oncology in Utrecht, Netherlands, said the results "suggest that germline SVs may contribute to early genome instability in these [pediatric extracranial solid] cancers and could inform the design of targeted therapies."
"Adopting a more precise, targeted approach against pediatric extracranial solid tumors may not only enhance treatment outcomes," Macintyre and Hehir-Kwa suggested, "but could also reduce the late effects seen in pediatric patients that result from long-term toxicities as well as lower the risk of secondary malignancies associated with traditional therapies."