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DeCode-led Team Taps Icelandic Population Data to Find Rare Gastric Cancer Risk Variants

NEW YORK (GenomeWeb) – In Nature Genetics, a DeCode Genetics-led team described alterations in the DNA damage response-related gene ATM that seem to boost the odds of developing gastric cancer for individuals with European ancestry.

The researchers considered array-based genotypes and imputed SNPs in 2,500 individuals from Iceland with gastric cancer and more than 205,000 individuals without. The search pointed to a gastric cancer-associated tandem repeat in MUC1, a gene previously implicated in the disease.

But along with associations with MUC1 and other genes linked to gastric cancer in the past, the team detected several independent loss-of-function variants in ATM that were over-represented in those who developed gastric cancer.

"The association between mutations in ATM and gastric cancer is intriguing, as it has been shown that [Helicobacter pylori] can induce double-strand breaks in target cells and trigger a DNA damage response that involves upregulation of ATM expression," senior author Kari Stefansson, DeCode's CEO and co-founder and a researcher at the University of Iceland, and colleagues wrote.

The ulcer-causing bacteria H. pylori has been incriminated in gastric cancer, though some past studies hint that the presence of this bug may portend more favorable patient outcomes. The disease also seems somewhat more common in smokers, individuals who consume lots of red or processed meat, and/or those with a history of gastric reflux, the team noted.

But gastric cancer is at least partly heritable as well. Genome-wide association studies have started untangling potential genetic contributors to the disease, though so far fewer risk loci have been found in Europeans than in Asian populations.

For the current study, Stefansson and colleagues focused on patterns at some 25 million SNPs in 400 gastric cancer cases identified through the Icelandic Cancer Registry who were directly genotyped and 2,100 more individuals with gastric cancer whose genotypes were imputed.

Compared to directly genotyped and imputed variant patterns in 205,652 individuals from the same population, the gastric cancer cases were marked by an over-representation of rare mutations in MUC1, including a tandem repeat in the gene that appeared to elevate gastric cancer risk in the Icelandic population.

The team's search for other rare loss-of-function variants linked to gastric cancer also led to new variants in ATM that were independently associated with gastric cancer.

This association appeared to span gastric cancer as a whole, the researchers noted, and did not show specific ties to any one of the four known gastric cancer subtypes.

Despite having tracked down the association with imputed SNPs, though, the team is confident in the associations, having directly genotyped individuals from a large collection of Icelanders to ensure that ATM variant imputations were accurate.

Moreover, the researchers detected three more loss-of-function version of the gene in four other individuals when they sifted through their whole-genome sequence data for more than 2,600 individuals from Iceland.

Finally, to further flesh out the list of gastric cancer associations, the team did targeted testing on half a dozen loci that have been linked to the disease in other populations.

That analysis provided evidence for gastric cancer risk at two of the loci in the Icelandic population, including sites in and around the PSCA gene that were associated with diffuse and intestinal gastric cancer subtypes and a SNP in the vicinity of a PRKAA1-PTGER4 locus linked to gastric cancer in the Han Chinese population.