New research has explored how childhood cancers, specifically Wilms tumor—a type of kidney cancer—develop in genetically predisposed children, which may help in predicting tumor formation before they completely develop.
Customized treatment plans for kids with a specific type of kidney cancer could provide the most effective care while minimizing side effects.
Researchers from various institutions, including the Wellcome Sanger Institute, Cambridge University Hospitals NHS Foundation Trust, Great Ormond Street Hospital, and the University of Würzburg, have examined the genetic differences among children diagnosed with Wilms tumor.
Approximately 30% of children with Wilms tumor have an inherited genetic alteration that heightens their risk of developing this disease. This study, published today (23 January) in Cancer Discovery, a journal associated with the American Association for Cancer Research, indicates that these inherited genetic alterations shape tumor development, affect treatment responses, and determine whether patients are at a greater risk for secondary cancers later in life.
The researchers highlighted that various genetic predispositions lead to distinct tumor development pathways and kidney structures, identifying factors that limit tumor growth. They also noted that Wilms tumors evolve differently in children without genetic predispositions.
These insights imply that personalizing treatment and screening based on a child’s genetic profile could ensure optimal care for every patient. This research may eventually aid in creating new treatments for specific genetic alterations and help identify children who might benefit from less invasive surgical options.
Wilms tumor primarily affects children younger than five years old, with about 85 new cases diagnosed annually in the UK1.
While these tumors can occasionally arise from spontaneous genetic changes during fetal development, around 30% of cases are linked to a genetic predisposition that elevates the risk for Wilms tumor. Typically, children showing specific characteristics, such as tumors in both kidneys, are screened for predisposition1.
Currently, treating Wilms tumor in genetically predisposed children involves a careful balance between removing sufficient tumor tissue to decrease the chance of secondary tumors and preserving vital kidney function. Methods to protect normal kidney tissue include chemotherapy, select surgical procedures, prolonged postoperative chemotherapy, and vigilant monitoring for recurrence.
The clinical approach for children with an established predisposition differs from that of those with spontaneous genetic changes due to the heightened risk involved. By gaining insights into how genetics influences Wilms tumor development, researchers could pinpoint individuals at lower risk for secondary tumors, informing surgical methods and screening protocols, ultimately leading to new therapeutic options.
In their recent study, the researchers created a genetic map from several hundred tissue samples of 137 children with Wilms tumor, which included 71 children who had a genetic predisposition, some of whom showed early signs of the disease.
The findings revealed variations in tumor development among children with genetic predispositions, which depended on which specific gene was affected and when during fetal development it was activated—that is, its developmental timing.
Different genetic predispositions were linked to unique DNA changes that contributed to tumor development in childhood, referred to as driver mutations. Some of these mutations also heightened the children’s risk for secondary cancers alongside Wilms tumor. Notably, mutations in genes like WT1 and TRIM28 led to the accumulation of additional driver mutations in particular pathways, which could be targeted in future drug therapies.
Moreover, the genetic predispositions affected the architectural structure of the kidneys, potentially explaining why some children develop benign kidney growths prior to cancerous tumors.
Overall, the findings suggest that genetic predisposition may determine the trajectory of Wilms tumor development, with distinct patterns corresponding to specific genetic changes. Researchers propose that in the future, treatment and screening programs could be customized based on a child’s genetic predisposition, ensuring they receive the most effective care available.
Dr. Taryn Treger, co-first author at the Wellcome Sanger Institute, stated: “Certain genetic changes that children are born with can set the stage for Wilms tumor. Our research shows that cancers can develop through different pathways depending on the underlying genetic factor. This allows us to predict which genetic changes can lead to cancer development, guiding the discovery of treatments that might prevent cancer from forming in the first place.”
Phil Brace, Chief Executive of The Little Princess Trust, which supported this research, expressed: “Treating childhood cancer can lead to significant negative effects for both the child and their family. We believe it’s vital to fund research aimed at enhancing survival rates while also reducing treatment-related side effects. We are optimistic that this study may assist in customizing future treatments.”
Professor Sam Behjati, co-senior author at the Wellcome Sanger Institute and Cambridge University Hospitals NHS Foundation Trust, commented: “Our research showcases the significance of collaborative genomic studies in addressing crucial clinical challenges. Currently, we apply the same treatment to all children with predispositions, which may lead to some receiving excessive treatments while others receive inadequate care. Our discoveries signify a potential for personalizing treatment based on genetic data. Furthermore, knowing the precise sequence of genetic changes that lead from predisposition to cancer could enhance tumor screening and even open up possibilities for prevention.”
