Childhood cancers are often considered genetically simple, containing few mutations. However, this notion has been challenged in a new study that found an unexpectedly high number of mutations in a pediatric kidney cancer. The findings open the door to rethinking treatment strategies, potentially including immunotherapies originally designed for adults.
The paper titled “High-resolution clonal architecture of hypomutated Wilms tumors” was published in Nature Communications.
The international team included researchers at the Wellcome Sanger Institute, the University of Cambridge, and the Princess Máxima Center for Pediatric Oncology. They used advanced genomic sequencing techniques to analyze Wilms tumor samples to better understand the foundations of this disease.
Wilms tumor primarily affects children under the age of five and is the most common type of pediatric kidney cancer. While survival rates are high with current treatments, which often include surgery, chemotherapy, and radiation, the risk of long-term side effects remains a pressing concern—making the search for more precise, less toxic therapies a top priority.
“Being able to trace the evolution of a tumor can uncover crucial information about how and why it develops,” said co-senior author Jarno Drost, PhD, researcher at the Princess Máxima Center for Pediatric Oncology and the Oncode Institute in the Netherlands.
Bulk whole genome sequencing methods are used to identify genetic changes common among tumor cells. This is often the case in adults, but pediatric tumors often have fewer shared genetic changes, and many mutations that are not shared between cells are not identified.
“Widespread sequencing methods are incredibly useful for a large number of cancer tumors, especially in adults. However, they fail to capture the true genetic complexity of cancers, particularly those that occur in the youngest children,” said Henry Lee-Six, PhD, co-first author and researcher at the Wellcome Sanger Institute.
To overcome this limitation, the team utilized two techniques: nanorate sequencing (nanoseq) and whole-genome sequencing of organoids derived from individual cancer cells. These tools allow scientists to detect genetic variants at the single cell level.
“With these latest genomic sequencing techniques, we can now see a much more detailed picture of Wilms tumor, which can occur in newborns,” said Lee-Six. “This could help us understand this condition in more detail, and may change the way we view and treat childhood tumors as a whole.”
Using tumor samples from four children under six months old, the team identified 72 to 111 additional mutations in single cancer cells beyond those previously detected by bulk whole genome sequencing.
“Our findings suggest that childhood tumors have at least four times more genetic changes per cell than expected, which adds millions more changes per tumor,” said Sam Behjati, PhD, pediatric oncologist at the Wellcome Sanger Institute and Cambridge University Hospitals NHS Foundation Trust. This highlights “that what we could see before was just the tip of the iceberg.”
In three of the four children, the team also uncovered a new mutation that causes Wilms tumor—a spontaneous mutation in the FOXR2 gene. This mutation appears to occur during fetal kidney development and is associated with a distinct histological appearance and RNA signature of the tumors.
“By understanding the genetic changes that cause tumors, and in this case, identifying different genetic subsets, it could lead to more targeted treatment options, something that every child deserves,” said Drost.
The implications of this work extend beyond understanding tumor development. The researchers suggest that a larger quantity of mutations could mean that pediatric tumors are more genetically adaptable than previously assumed, potentially explaining why some tumors become resistant to standard treatments.
“It has been a widely held belief that childhood tumors had much lower numbers of genetic changes than adult tumors,” said Behjati. “We have been able to show that, at least in these cases, it is not true.”
The increased genetic complexity and similarity to adult cancers’ genetic diversity could also present new therapeutic opportunities, suggesting that childhood tumors like Wilms could be responsive to immunotherapy approaches with limited use in pediatric oncology.
“This has implications for both childhood kidney cancer and possibly other childhood tumors,” concluded Behjati. “If we understand childhood cancer fully, we can develop new ways to treat it or repurpose existing treatments to get options to those who need them as quickly as possible.”
The post More Mutations in Childhood Cancer Might Mean More Therapy Options appeared first on GEN - Genetic Engineering and Biotechnology News.
The paper titled “High-resolution clonal architecture of hypomutated Wilms tumors” was published in Nature Communications.
The international team included researchers at the Wellcome Sanger Institute, the University of Cambridge, and the Princess Máxima Center for Pediatric Oncology. They used advanced genomic sequencing techniques to analyze Wilms tumor samples to better understand the foundations of this disease.
Wilms tumor primarily affects children under the age of five and is the most common type of pediatric kidney cancer. While survival rates are high with current treatments, which often include surgery, chemotherapy, and radiation, the risk of long-term side effects remains a pressing concern—making the search for more precise, less toxic therapies a top priority.
“Being able to trace the evolution of a tumor can uncover crucial information about how and why it develops,” said co-senior author Jarno Drost, PhD, researcher at the Princess Máxima Center for Pediatric Oncology and the Oncode Institute in the Netherlands.
Bulk whole genome sequencing methods are used to identify genetic changes common among tumor cells. This is often the case in adults, but pediatric tumors often have fewer shared genetic changes, and many mutations that are not shared between cells are not identified.
“Widespread sequencing methods are incredibly useful for a large number of cancer tumors, especially in adults. However, they fail to capture the true genetic complexity of cancers, particularly those that occur in the youngest children,” said Henry Lee-Six, PhD, co-first author and researcher at the Wellcome Sanger Institute.
To overcome this limitation, the team utilized two techniques: nanorate sequencing (nanoseq) and whole-genome sequencing of organoids derived from individual cancer cells. These tools allow scientists to detect genetic variants at the single cell level.
“With these latest genomic sequencing techniques, we can now see a much more detailed picture of Wilms tumor, which can occur in newborns,” said Lee-Six. “This could help us understand this condition in more detail, and may change the way we view and treat childhood tumors as a whole.”
Using tumor samples from four children under six months old, the team identified 72 to 111 additional mutations in single cancer cells beyond those previously detected by bulk whole genome sequencing.
“Our findings suggest that childhood tumors have at least four times more genetic changes per cell than expected, which adds millions more changes per tumor,” said Sam Behjati, PhD, pediatric oncologist at the Wellcome Sanger Institute and Cambridge University Hospitals NHS Foundation Trust. This highlights “that what we could see before was just the tip of the iceberg.”
In three of the four children, the team also uncovered a new mutation that causes Wilms tumor—a spontaneous mutation in the FOXR2 gene. This mutation appears to occur during fetal kidney development and is associated with a distinct histological appearance and RNA signature of the tumors.
“By understanding the genetic changes that cause tumors, and in this case, identifying different genetic subsets, it could lead to more targeted treatment options, something that every child deserves,” said Drost.
The implications of this work extend beyond understanding tumor development. The researchers suggest that a larger quantity of mutations could mean that pediatric tumors are more genetically adaptable than previously assumed, potentially explaining why some tumors become resistant to standard treatments.
“It has been a widely held belief that childhood tumors had much lower numbers of genetic changes than adult tumors,” said Behjati. “We have been able to show that, at least in these cases, it is not true.”
The increased genetic complexity and similarity to adult cancers’ genetic diversity could also present new therapeutic opportunities, suggesting that childhood tumors like Wilms could be responsive to immunotherapy approaches with limited use in pediatric oncology.
“This has implications for both childhood kidney cancer and possibly other childhood tumors,” concluded Behjati. “If we understand childhood cancer fully, we can develop new ways to treat it or repurpose existing treatments to get options to those who need them as quickly as possible.”
The post More Mutations in Childhood Cancer Might Mean More Therapy Options appeared first on GEN - Genetic Engineering and Biotechnology News.