by Researchers at St. Jude Children’s Research Hospital have conducted a comprehensive analysis to unravel the factors contributing to the predisposition of bilateral Wilms tumor—a condition characterized by the development of tumors in both kidneys—in children. This groundbreaking work not only has implications for counseling patient families but also for guiding treatment decisions and informing the design of future clinical trials. The study, published in Nature Communications, sheds light on the genetic and epigenetic abnormalities that drive the development of the disease.
Treating bilateral Wilms tumor is more complicated compared to when the tumor occurs in just one kidney, as removing both kidneys would eliminate renal function. Instead, patients usually undergo chemotherapy to shrink the tumors before opting for organ-sparing surgery to remove the tumors without removing the entire kidney. The researchers at St. Jude, in collaboration with the Children’s Oncology Group study, were able to gather a large cohort of bilateral Wilms tumor samples, making it the largest reported cohort for this disease. They then conducted various analyses such as whole exome sequencing, whole genome sequencing, RNA-sequencing, and DNA methylation analyses to identify the factors contributing to the predisposition.
Through their analysis, the researchers identified several genomic events that predispose patients to bilateral Wilms tumor. These include pre-zygotic germline (inherited) variants, such as WT1, NYNRIN, TRIM28, and BRCA-related genes, which are detectable in blood samples. Additionally, the researchers also discovered an epigenetic mechanism that causes predisposition. They found post-zygotic hypermethylation at 11p15.5 H19/ICR1 to be associated with bilateral Wilms tumor. DNA methylation is a biological process where methyl groups are added to DNA, influencing gene expression. In this case, abnormal hypermethylation on the copy of chromosome 11p15.5 inherited from the mother leads to increased gene expression, specifically the IGF2 gene, which has been previously implicated in predisposition.
Interestingly, the researchers observed the hypermethylation at 11p15.5 in the blood of patients with bilateral Wilms tumor, not just in the tumor or non-diseased kidney. This hypermethylation signature was found at higher levels than in patients with unilateral Wilms tumor or healthy individuals. Furthermore, the researchers also found that a pair of bilateral tumors from the same patient shared very few somatic mutations, indicating that there are multiple ways in which genomes predispose patients to develop bilateral Wilms tumor. This highlights the importance of conducting further research to determine the frequency and interplay of these predisposing events across a larger cohort.
Wilms tumor is the most common kidney cancer in children, but only a small percentage of patients (5-7%) are diagnosed with bilateral Wilms tumor. These patients are diagnosed at a younger age and often have precursor lesions called nephrogenic rests. For years, researchers have suspected that bilateral Wilms tumor occurs due to a convergence of pre- and post-zygotic genomic effects—two or more genetic hits that collectively drive predisposition. The work done by the St. Jude team provides support for the concept of mosaicism, where these predisposing genetic or epigenetic abnormalities are present in some cells but not all cells in the body.
Based on these groundbreaking findings, researchers are already exploring ways to incorporate this knowledge in the design of future clinical trials for Wilms tumor. The hope is that these findings will become prospective biomarkers for treatment response and prognosis, improving the outcomes for patients with bilateral Wilms tumor.
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1. Source: Coherent Market Insights, Public sources, Desk research
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