NEW YORK (GenomeWeb News) – In a genome-wide association study appearing online yesterday in Nature Genetics, an international research team identified genetic loci linked to kidney cancer risk — including SNPs in a gene coding for a key component in a known kidney cancer-related pathway.
"For most of the GWAS, when we study searching agnostically, the regions [detected] are in places that we don't really know anything about or wouldn't have predicted," co-corresponding author Stephen Chanock, chief of the laboratory of translational genomics in the National Cancer Institute's cancer epidemiology and genetics division, told GenomeWeb Daily News.
Consequently, he explained, researchers were surprised to find that some of the strongest SNP associations detected in the current study fell in a gene called EPAS1, which codes for a player in the von Hippel-Lindau, or VHL, pathway — a pathway implicated in highly penetrant, familial kidney cancer cases.
The researchers initially did a genome-wide association study involving nearly 3,800 individuals with renal cell carcinoma and more than 8,500 healthy controls before testing half a dozen of the top associations in thousands more cases and controls. Their search unearthed a pair of genetic loci on chromosomes 2 and 11 that are associated with renal cell carcinoma, as well as a third locus on chromosome 12 showing potential ties to the disease.
Although environmental factors such as smoking, obesity, and hypertension are all thought to up the risk of renal cell carcinoma, cancer that springs up in renal parenchyma tissue, the authors noted, past research indicates that genetics play a part as well. Even so, they added, the genetic contributors to renal cell carcinoma are poorly understood.
To hunt down such factors, the large international team — led by investigators at the National Institutes of Health, the International Agency for Research on Cancer in France, and the French Centre National de Genotypage — used a two-stage GWAS involving nearly 20,000 individuals.
"We recognized quite some time ago that, as we get into the less common cancers, the value is much greater if everyone gets together than if we try to have a series of under-powered studies," Chanock said.
For the first stage of this effort, the team used Illumina Infinium HumanHap 300, 500, 610, or 660w BeadChips to genotype 3,772 individuals with renal cell carcinoma and 8,505 healthy controls, all of European descent. The samples were genotyped in the US at the NCI Core Genotyping Facility, at France's CNG, and in Moscow at the Kurchatov Scientific Center.
The team then homed in on the six most suspicious SNPs, genotyping these in another 2,198 cases and 4,918 controls using TaqMan genotyping assays.
Two of the loci — a chromosome 2 locus involving the rs11894252 and rs7579899 SNPs in EPAS1 and a chromosome 11 locus consisting of a SNP called rs7105934 SNP that fell in non-gene-coding sequence — reached genome-wide significance.
The researchers were particularly intrigued that their search led them to EPAS1, Chanock explained, since the gene codes for a protein called hypoxia-inducible factor 2-alpha that's known to be a key player in the VHL pathway.
"GWAS pointed us to common variants right in the middle of that pathway," Chanock said, explaining that "mutations in VHL are responsible for a substantial proportion of the highly penetrant mutations in the familial pedigrees with renal cancer."
"An awful lot of the [kidney cancer] biology has come out of studying VHL and its downstream interactions," he added, noting that the pathway is also being studied in connection with processes such as oxygen deprivation and hypoxia stress, and smoking.
The association between kidney cancer and variants in EPAS1 also seemed to coincide with smoking behavior, the team found, since both current and former smokers carrying variants in the gene seemed to be at greater risk of the disease than those who were never smokers. The EPAS1 region signal was also slightly stronger in men than in women, researchers noted.
Even so, Chanock emphasized, more work is needed to verify and explore such connections. "I can't overestimate the value of replication in independent [sample] sets to really establish this," he said.
On the other hand, the chromosome 11 locus was not clearly tied to a particular gene or pathway, Chanock said, though mutations detected in the same 11q13.3 region have been implicated in other types of cancer.
Meanwhile, a third locus near the scavenger receptor class B, or SCARB1, gene on chromosome 12 was less firmly linked to renal cell carcinoma but is still considered a candidate risk region.
"We think [the SCARB1 association] is going to be real, but we just have to be careful because the evidence was not airtight," Chanock explained.
Researchers involved in the GWAS are currently putting together an even larger collection of case and control samples for additional association studies, Chanock said. They are also delving into the biology behind the associations already detected through mapping, re-sequencing, and other studies.
And, he added, future kidney cancer research are expected to include more in-depth studies aimed at unraveling interactions between genes and environmental risk factors and exposures.