Wilms tumor, also known as nephroblastoma, is a rare kidney cancer that mainly affects children. The average age of diagnosis of Wilms tumor in children depends upon whether one or both kidneys are affected. If one kidney is affected, unilateral Wilms tumor, the age at diagnosis usually is 42–47 months. If both kidneys are affected, bilateral Wilms tumor, the age at diagnosis usually is 30–33 months. Most cases of Wilms tumor occur by chance. They are the result of mutations in cells in the kidneys that usually occur after birth. Now scientists at St. Jude Children’s Research Hospital identified genetic and epigenetic mechanisms driving predisposition to bilateral Wilms tumor.
The study was published in Nature Communications in an article titled, “Genetic and epigenetic features of bilateral Wilms tumor predisposition in patients from the Children’s Oncology Group AREN18B5-Q.”
“Developing synchronous bilateral Wilms tumor suggests an underlying (epi)genetic predisposition,” the researchers wrote. “Here, we evaluate this predisposition in 68 patients using whole exome or genome sequencing (n = 85 tumors from 61 patients with matched germline blood DNA), RNA-seq (n = 99 tumors), and DNA methylation analysis (n = 61 peripheral blood, n = 29 non-diseased kidney, n = 99 tumors).”
When Wilms tumor occurs in just one kidney, surgeons can remove the entire organ. But with bilateral Wilms tumor, removing both kidneys would eliminate renal function. Instead, patients first need chemotherapy to shrink the tumors as much as possible, followed by organ-sparing surgery to remove the tumors without removing the whole kidney.
“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, St. Jude department of surgery. “This means we were also uniquely privileged to have access to patient tissue samples to enable us to do this research, to establish the relative frequencies of different modes of predisposition.”
The researchers gathered a cohort of bilateral Wilms tumor samples from patients treated at St. Jude as well as on the Children’s Oncology Group study AREN18B5-Q. This cohort allowed the researchers to conduct whole exome, whole genome, RNA-sequencing, and DNA methylation analyses to unravel the factors involved in predisposition.
Through their analyses, the researchers determined the predominant genomic events predisposing patients to bilateral Wilms tumor. These include pre-zygotic germline (inherited) variants detectable in blood samples, such as WT1, NYNRIN, TRIM28, and BRCA-related genes.
The researchers also identified an epigenetic mechanism causing predisposition. They found postzygotic (forming in the early embryo) hypermethylation at 11p15.5 H19/ICR1 predisposes patients to bilateral Wilms tumor.
The researchers also found evidence of hypermethylation at 11p15.5 in the blood of patients with bilateral Wilms tumor, not just the tumor or in the non-diseased kidney. This hypermethylation signature was found at higher levels than in unilateral Wilms tumor or 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’ tumors, 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, St. Jude department of computational biology. “We needed to study germline and postzygotic factors by integrating analyses, and we have now thoroughly characterized the landscape of predisposing events.”
The St. Jude team’s work provides support for the concept of mosaicism, where these predisposing genetic or epigenetic abnormalities are found in some, but not all, cells in the body. Based on this new finding, researchers are already exploring ways to incorporate these findings in the design of the next co-operative group clinical trial for Wilms tumor.
“We hope that once these data are established, these findings will become prospective biomarkers for treatment response or prognosis and can be included in the next generation of clinical trials,” said Murphy.
