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Genomic Analysis of Wilms Tumors Leads to Kidney Development-Related Pathways

NEW YORK (GenomeWeb) – By characterizing genetic, genomic, and epigenetic patterns in children with a form of pediatric kidney cancer known as Wilms tumor, members of an international research team have identified developmental pathways that are frequently disrupted in the disease.

For an effort led by the Children's Oncology Group and National Cancer Institute's Therapeutically Applicable Research to Generate Effective Treatments (TARGET) project, the researchers focused on 117 Wilms tumor cases, including 78 tumors with favorable histological features and 39 cases that relapsed or had histological features implicated in poor outcomes. With Complete Genomics whole-genome sequencing on 80 tumors and exome sequencing on samples from another 37 Wilms tumor patients — along with DNA methylation, gene expression, and/or CNV profiling with Illumina and Affymetrix arrays — they detected more than 1,800 somatic, non-synonymous mutations in the discovery set.

With targeted capture and Sanger sequencing on 37 genes, the team attempted to verify alterations identified in the original tumor set with a collection of 651 more Wilms tumors. Together, the analyses led to recurrent alterations in Wilms tumor contributors such as TP53, CTNNB1, DROSHA, and DICER1, as well as recurrent alterations affecting BCOR, BCORL1, ARID1A, and other new candidate genes. The findings appeared online today in Nature Genetics.

"We discovered that many of these genetic mutations converge into two developmental pathways that lead to cancer," senior author Elizabeth Perlman, a pathology and laboratory medicine researcher at the Ann and Robert H. Lurie Children's Hospital of Chicago, said in a statement.

Although they identified broad swathes of mutated genes, mutation combinations, and related epigenetic and expression shifts in the Wilms tumors, the researchers noted that the alterations tended to converge on pathways related to renal development or on regulatory pathways related to such processes.

"In Wilms tumors, one set of mutations promotes abnormal and continued proliferation of the undifferentiated cells. A second set of mutations impacts the differentiation switch itself," Perlman said. "Targeting these two different pathways in future studies might be more efficient than targeting individual gene mutations."

Along with the somatic mutations, the team uncovered suspicious germline mutations in genes such as TP53, WT1, DICWE1, DIS3L2, PALB2, and CHEK2 in roughly 10 percent of the Wilms tumor patients, suggesting that there may also be an inherited component to disease risk for a subset of the kidney cancer cases.