New Research Shows Inherited Genetic Variants Increase Risk of Certain Pediatric Cancers

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New research from Dana-Farber Cancer Institute has found that rare germline genetic abnormalities could increase the risk of childhood cancers such as neuroblastoma, Ewing sarcoma, and osteosarcoma. These and other pediatric solid tumors comprise approximately one-third of all new pediatric cancer cases and are a leading cause of childhood death by disease in the US. The findings could help improve treatments or screening for these pediatric cancers.

“The better we can understand the earliest events that cause these diseases, the better we’re able to think about how to improve treatment for these patients,” says co-first author Riaz Gillani, MD, a pediatric oncologist at Dana-Farber/Boston Children's Cancer and Blood Disorders Center.

The study was published in Science.

Currently, first-line treatments for these three pediatric cancers heavily rely on chemotherapy, radiation, and surgery. Not all patients are cured, and those who are, often end up with lifelong health challenges. In some adult cancers, an understanding of inherited cancer risk genes has led to more sophisticated screening and diagnostics and development of more effective targeted therapies. The same could hold for pediatric cancers. Yet so far, the risk factors implicated in adult cancer, which are predominantly misspellings of genes called single nucleotide variants, explain risk in only a minority of pediatric cancer cases.

In this study, Gillani and co-first author Ryan Collins, PhD, a computational biologist at Dana-Farber, both working in the Dana-Farber lab of Eliezer Van Allen, MD, chief of the Division of Population Sciences, set out to take a wide look at the genomes of patients with these pediatric cancers in search of variants that could increase cancer risk.

They analyzed the whole-genome sequencing of 1,766 children with cancer, 943 relatives without cancer, and 6,665 adults who were unrelated and did not have cancer. They employed the Google Cloud Platform to perform millions of hours of computations on petabytes of data.

“The dataset would not fit on 1000 laptops,” says Collins.

They found three important types of germline genetic variants, genetic changes that are inherited and appear in every cell of the body from birth, that increase the risk of these pediatric cancers. The variants the team identified were all structural variants of genes, which differ from misspellings. A structural variant is a segment of the genome that is deleted, inverted, or massively rearranged compared to its original.

The first finding was that large chromosomal abnormalities increased the risk of these three cancers four-fold in patients with XY chromosomes, children who are typically identified as males. Every cell contains 23 pairs of chromosomes, which contain the genetic instructions cells use to operate. Each chromosome has about 100 million nucleotides, the “letters” that form DNA instructions. A large chromosomal abnormality is missing about one million of these nucleotides.

“That’s a really big change for DNA,” says Collins.

About 80% of the abnormalities observed were inherited from the child’s parents, yet the parents did not develop cancer. This suggests that each pediatric cancer case might involve a combination of factors that could include one or more chromosomal abnormalities, other gene variants, and/or an environmental exposure.

“These variants provide a bigger picture of the factors that could be involved in the development of pediatric cancers,” says Gillani. “We’re shining a spotlight on these new factors that could tip a child’s risk over the edge leading to the development of a specific pediatric cancer.”

While it isn’t possible today to perform the kinds of analyses this team performed on genomes in a clinical setting, it could be possible in the near-term to incorporate detection of some of these large chromosomal variants into germline genetic testing to identify more children at risk and in need of monitoring for cancer.

The team also identified inherited structural variants of protein-coding genes. These structural variants influenced three categories of genes: those that are essential for normal development; those involved in the repair of damaged DNA; and those that are already known to be implicated in cancer. Moreover, they found that these structural variants are not just present, but also are differentially impacting genes in the tissue of origin for the cancers studied.

“More research is needed to understand the biological mechanisms,” says Gillani. “But the findings suggest we might want to think about new treatment ideas, such as how to use drugs that target DNA repair pathways in the treatment of these diseases.”

The team also looked at the other 98% of the genome, which does not code for proteins. There, they found more inherited structural variants that potentially impact the expression of genes known to be active in the cells related to these cancers. More research is needed to determine their role in cancer risk.

“These are really exciting findings that bring together experts at Dana-Farber in pediatric oncology, genetics, and computational biology to dive deeply into the possibility that inherited risk genes play a larger role in pediatric cancers than previously appreciated,” says Van Allen. “This work, which would not be possible without this kind of interdisciplinary collaboration and the help of our patients and their families, could inspire new approaches to early detection and intervention for these devastating cancers.”

This work was funded by the following sources: Alex’s Lemonade Stand Foundation, the American Society of Clinical Oncology, Conquer Cancer Sarcoma Foundation of America, Boston Children’s Hospital, Rally Foundation, the Department of Defense, the National Institutes of Health and Dana-Farber Cancer Institute.