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GWAS Uncovers New Wilms Tumor Risk Loci

NEW YORK (GenomeWeb News) – Two new loci have been linked to elevated risk for a childhood embryonal kidney cancer called Wilms tumor, according to a study appearing online yesterday in Nature Genetics.

Researchers from the UK, US, and Canada did a genome-wide association study involving thousands of individuals with or without Wilms tumor. After testing 10 candidate variants from the initial GWAS in replication groups from the UK and the US, they narrowed in on SNPs at chromosome 2 and chromosome 11 loci with significant ties to the childhood kidney cancer. Another three candidate sites remained associated with the disease in one of the two replication groups.

Based on their findings so far, corresponding author Nazneen Rahman, who heads the genetics and epidemiology division at the Institute of Cancer Research in the UK, and her co-authors argued that "multiple loci of equivalent or weaker effect are likely to exist and may be identified through follow-up analysis of additional SNPs showing evidence of association in this study and/or through further GWAS."

Prior to the new study, a few syndromes associated with elevated Wilms tumor risk had already been identified. Even so, researchers explained, familial features of the disease and varying prevalence rates in different populations hinted that there were other unidentified genetic factors contributing to the childhood kidney cancer.

In their effort to find these, Rahman and her co-authors started by looking at almost 600,000 SNPs in the genomes of 757 children with Wilms tumor and 1,879 unaffected controls from data generated at the Broad Institute using the Illumina HumanOmniExpress array. All of the children included in the discovery set were of European ancestry and enrolled at sites in North America.

After sifting through SNPs implicated in the GWAS and tossing out those in linkage disequilibrium with one another, the team was left with 10 candidate SNPs that it went on to test in another 769 cases and 2,814 controls from the UK and in 719 American Wilms tumor cases.

For the US replication analysis, researchers used information on 1,037 unaffected individuals from the dbGAP database as controls, since control samples were not available for direct gentotyping.

Variants at two loci — a site harboring the helicase gene DDX1 on chromosome 2 and a chromosome 11 locus containing the cell polarity protein coding gene DLG2 — remained associated with Wilms tumor at the end of this replication testing.

The DDX1 gene is believed to contribute to a range of processes that could conceivably be altered in cancer, including DNA repair, RNA splicing, and translation. It also falls in a region affected by copy number alterations in some other childhood cancers, researchers noted.

Meanwhile, the chromosome 11 association is of note, they explained, because the Drosophila homolog of DLG2 codes for a component of a cell polarity pathway. In fruit flies, that pathway contains the homolog of a human protein targeted by the protein product of WT1, a known Wilms tumor risk gene.

There were hints that the associated variant in this chromosome 11 region had stronger effects in females and in children diagnosed with Wilms tumor at older ages, the study's authors noted, though more testing is needed to determine whether such patterns hold up in additional cases.

Another three sites on chromosomes 5, chromosome 22, and the X chromosome that contained somewhat rarer SNPs also showed ties to the Wilms tumor risk in the discovery and US replication groups, but not in the UK replication group. At these three loci, study authors explained that "further replication studies are required to confirm these associations, as low-frequency variants in particular are subject to signal artifact when using different genotyping platforms for cases and controls."

Nevertheless, when the researchers used HapMap3 and 1000 Genomes Project data to impute SNPs at all five loci, they tracked down imputed variants at four of the loci that were more strongly associated with Wilms tumor than any of the SNPs assessed directly.

Although the imputed SNPs seemed to show similar risk frequency patterns as the SNPs directly tested by the array used, though, the team noted that it would be useful to direct genotype imputed SNPs in cases and controls as part of future efforts to narrow in on causative Wilms tumor variants.

"The next step is to determine exactly what it is about these regions of the genome that is causing the link with Wilms tumour," Rahman said in a statement. "This will lead to better understanding of the condition and, potentially, improved treatments."

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