Unraveling the Genetic Threads: How Inherited Variants Heighten Pediatric Cancer Risks

Recent findings from the Dana-Farber Cancer Institute indicate that rare inherited genetic variations may heighten the risk of pediatric cancers such as neuroblastoma, Ewing sarcoma, and osteosarcoma. Together, these pediatric solid tumors represent roughly one-third of all new pediatric cancer diagnoses and are a prominent cause of childhood mortality due to illness in the United States. The results could enhance treatment options or screening processes for these childhood cancers. 

“The more effectively we comprehend the initial occurrences that trigger these ailments, the better positioned we are to devise improvements in treatment for these patients,” advocates co-first author Riaz Gillani, MD, a pediatric oncologist at Dana-Farber/Boston Children’s Cancer and Blood Disorders Center. 

The research was published in Science.

At present, primary treatments for these three pediatric malignancies significantly depend on chemotherapy, radiation, and surgical intervention. Not all patients achieve a cure, and those who do often face enduring health complications. 
In some adult cancers, recognition of inherited cancer risk genes has facilitated more advanced screening, diagnostics, and the development of more effective targeted therapies. The same principles may apply to pediatric cancers. Nevertheless, thus far, the risk factors associated with adult cancers, mainly genetic mutations known as single nucleotide variants, only account for a small fraction of pediatric cancer cases. 

In this investigation, Gillani and co-first author Ryan Collins, PhD, a computational biologist at Dana-Farber, both affiliated with the Dana-Farber lab of Eliezer Van Allen, MD, head of the Division of Population Sciences, aimed to conduct a broad analysis of the genomes of patients diagnosed with these pediatric cancers looking for variants that might raise cancer risk.

They evaluated whole-genome sequencing data from 1,766 children diagnosed with cancer, 943 cancer-free relatives, and 6,665 unrelated adults without a cancer diagnosis. Their research leveraged the Google Cloud Platform to execute millions of hours of computations across petabytes of data. 

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

They discovered three significant categories of germline genetic variants, inherited genetic changes that manifest in every cell from birth, which elevate the risk for these pediatric cancers. The variants identified by the team were all structural variants of genes, differing from mutations. A structural variant involves a segment of the genome that is either deleted, inverted, or extensively rearranged compared to its original sequence.

The initial discovery illustrated that substantial chromosomal abnormalities enhanced the risk of these three cancers by four times in patients with XY chromosomes, typically recognized as male children. Each cell contains 23 pairs of chromosomes holding the genetic instructions that cells utilize for operation. Each chromosome is made up of roughly 100 million nucleotides, the “letters” that constitute DNA instructions. A significant chromosomal abnormality corresponds to the loss of about one million of these nucleotides. 

“That’s a massive change for DNA,” remarks Collins. 

Close to 80% of the abnormalities identified were inherited from the child’s parents, yet the parents did not have cancer. This implies that each pediatric cancer case may reflect a blend of elements including one or more chromosomal anomalies, additional gene variants, and/or environmental factors.

“These variants offer a broader perspective of the factors that could relate to the emergence of pediatric cancers,” asserts Gillani. “We are illuminating these new elements that may push a child’s risk over the threshold leading to the emergence of a specific pediatric cancer.”

While current clinical settings cannot execute the types of analyses this team conducted on genomes, it may soon be feasible to integrate the detection of certain large chromosomal variants into germline genetic tests to identify more children at risk requiring enhanced cancer monitoring. 

The researchers also located inherited structural variants of protein-coding genes. These structural variants influenced three classes of genes: those vital for normal development; those involved in the repair mechanisms of damaged DNA; and those currently known to be associated with cancer. Additionally, they discovered that these structural variants are not only present, but also exert differential impacts on genes in the origin tissues related to the studied cancers. 

“Further research is essential to comprehend the biological mechanisms,” remarks Gillani. “However, the results imply that we might need to consider new treatment strategies, such as utilizing medications that target DNA repair pathways in treating these diseases.”

The research team also explored the remaining 98% of the genome that does not encode proteins. Here, they found additional inherited structural variants that may influence the expression of genes active in the cells associated with these cancers. Further studies are required to clarify their role in cancer susceptibility.

“These findings are truly exciting, bringing together specialists at Dana-Farber in pediatric oncology, genetics, and computational biology to examine deeply the potential that inherited risk genes have a more significant influence on pediatric cancers than previously understood,” comments Van Allen. “This work, which would not have been achievable without this type of interdisciplinary collaboration and the contributions of our patients and their families, has the potential to inspire innovative methods for early detection and intervention for these devastating cancers.”

This study was supported by the following organizations: Alex’s Lemonade Stand Foundation, the American Society of Clinical Oncology, Conquer Cancer Sarcoma Foundation of America, Boston Children’s Hospital, and Dana-Farber Cancer Institute.