Researchers Find Inherited Genetic Condition Raises Risk of Developing Two Rare Pediatric Cancers

Led by a faculty member at Roswell Park Comprehensive Cancer Center, an international team of experts has identified a genetic condition that raises the risk of developing two rare pediatric cancers — Wilms tumor and pineoblastoma. Their findings appear today in Clinical Cancer Research, a journal of the American Association for Cancer Research.

Wilms tumor, also called nephroblastoma, is the most common type of pediatric kidney cancer and occurs mostly in children younger than five. Pineoblastoma, a rare and aggressive type of malignant brain tumor, mostly affects those 10 and younger, and has a poor prognosis.

Kenan Onel, MD, PhD, Chief of Clinical Genomics and Director of the Center for Precision Oncology and Cancer Prevention at Roswell Park Comprehensive Cancer Center, served as Principal Investigator of the study, which focused on the regulation of microRNAs — molecules that are important in normal development and can prevent tumors from forming. However, when microRNAs don’t function properly, they can become oncogenes, increasing cancer risk and helping tumors grow.

Three genes play a key role in controlling microRNA processing — DICER1, DGCR8 and DROSHA. These genes are found to be mutated in a number of different cancers, including pineoblastoma and Wilms tumor. Previous studies revealed that increased tumor risk was linked to inherited changes called germline pathogenic variants (GPVs) in DICER1 and DGCR8, but this study marks the first time the connection has been identified with DROSHA GPVs.

Unexpectedly, the research team found that about 20% of all cases of pineoblastoma may be caused by DROSHA GPVs — especially a pineoblastoma subtype, PB-microRNA1, which is associated with abnormal microRNA processing. Because PB-microRNA1 is associated with older age at diagnosis and better outcomes than other subtypes, this information could help better gauge prognosis.

“This study is a great example of how Roswell Park’s new Department of Clinical Genomics partners with our patients and families to discover and give back answers that matter to them — especially answers to their fundamental questions, such as ‘Why me?’ and ‘What does this mean for my family?’ ” notes Dr. Onel, who is senior author on the new publication. “More broadly, this study demonstrates that even one family may hold the key that unlocks the mystery of cancer risk for many other families. Knowledge is power!”

The study investigated both families and large pediatric and adult cancer datasets. To look for inherited GPVs, researchers used whole-exome sequencing to analyze the DNA of every gene from every study participant, in both germline samples — that is, normal DNA typically isolated from blood cells and which can be passed on from parent to child — and tumor samples.

This study is the second major publication produced by the Department of Clinical Genomics in less than a year. Dr. Onel also led the first study, published in fall 2024, which showed that up to 10% of multiple myeloma cases are linked to an inherited genetic trait, and that genetic testing could help point the way to more effective therapies for affected patients.

Peter Fiorica, predoctoral trainee in Cancer Prevention & Control, is first author on the newly published study.

The Department of Clinical Genomics at Roswell Park focuses on diagnosing and caring for patients and families whose genetics or family medical history increase their risk of cancer.