Unraveling predisposition to bilateral Wilms tumor

Children with bilateral Wilms tumor have a tumor in each of their kidneys — a condition that strongly suggests an underlying genetic or epigenetic predisposition driving the disease. Treating bilateral Wilms tumor is complicated. When Wilms tumor occurs in just one kidney, surgeons can remove the entire organ, but when the disease is bilateral, removing both kidneys is not the optimal approach, as it would eliminate renal function. Instead, patients with bilateral Wilms tumor first receive chemotherapy to shrink the tumors as much as possible and then undergo organ-sparing surgery to remove the tumors without removing the kidneys.  

“We see a lot of patients with bilateral Wilms tumor here at St. Jude, offering these organ-sparing surgeries so that patients do not become dependent on dialysis and require kidney transplants,” said co-corresponding author Andrew Murphy, MD, Department of Surgery. “This means we were also uniquely privileged to have access to patient tissue samples, which enables us to do this research to establish the relative frequencies of different modes of predisposition.” 

The researchers gathered the largest cohort reported for bilateral Wilms tumor and conducted whole-exome, whole-genome, R/content/web-sitNA-sequencing, and DNA-methylation analyses to unravel the factors involved in predisposition to this type of cancer. Published in Nature Communications, their study revealed the predominant genomic events predisposing patients to bilateral Wilms tumor. These include pre-zygotic (before fertilization) germline (inherited) variants detectable in blood samples, such as WT1, NYNRIN, TRIM28, and BRCA-related genes. 

The researchers also identified an epigenetic mechanism, post-zygotic (in the early embryo) hypermethylation at the gene location coordinates 11p15.5 H19/ICR1, that predisposes patients to bilateral Wilms tumor. DNA methylation is a fundamental biologic process in which methyl groups are added to the cytosine residues of DNA. The process guides the instructions for how gene expression is regulated. In this case, abnormal hypermethylation at chromosome 11p15.5 inherited from the mother leads to increases in gene expression. In bilateral Wilms tumor, this phenomenon, also called loss of imprinting at 11p15.5, leads to the increased expression of IGF2, one of the major genes previously implicated in cancer predisposition.  

The researchers also found evidence of hypermethylation at 11p15.5 on chromosomes in cells within the blood of patients with Wilms tumor, not just in the tumor or the non-diseased kidney. The hypermethylation signature in the bilateral disease was a higher level than that in unilateral Wilms tumor or in healthy individuals. 

“Realizing that a pair of bilateral tumors from the same patient shared almost no somatic mutations, we suspected there were several ways genomes predisposed patients to develop bilateral Wilms tumor, but it is essential to drive the research forward to holistically determine their frequency and interplay across a large cohort,” said co-corresponding author Xiang Chen, PhD, Department of Computational Biology. “We needed to study germline and post-zygotic factors by integrating analyses, and we have now thoroughly characterized the landscape of predisposing events.”   

The work has implications for counseling patient families, guiding treatment decisions, and informing the design of future clinical trials.