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Team IDs Pancreatic Cancer-Associated Loci in Chinese Population

NEW YORK (GenomeWeb News) – At least five newly identified genomic loci contribute to pancreatic cancer risk in Chinese populations, according to a study appearing online yesterday in Nature Genetics.

Researchers from China and Inner Mongolia found the five new loci through genome-wide association and replication studies involving thousands of Han Chinese individuals with and without pancreatic cancer. The search also uncovered a known chromosome 13 locus that appears to be a common pancreatic cancer risk region in the Chinese population and in previously studied European populations.

"These results advance our understanding of the development of pancreatic cancer and highlight potential targets for the prevention or treatment of this cancer," Chinese Academy of Medical Sciences and Peking Union Medical College researchers Chengfeng Wang and Dongxin Lin, co-senior authors on the new study, and their colleagues wrote.

Prior GWAS have detected distinct pancreatic cancer-associated loci in European and Japanese populations — patterns that may be related to variable pancreatic cancer prevalence rates in different parts of the world, the study authors explained, noting that "[p]ancreatic cancer incidence rates are substantially different among populations of distinct ancestry, possibly reflecting differences in genetic susceptibility to this cancer."

In their search of variants influencing pancreatic cancer risk in the Chinese population, researchers used the Affymetrix GeneChip Human Mapping 6.0 chip to genotype more than 1,000 Chinese individuals with pancreatic cancer enrolled at hospitals in Beijing and Shanghai over more than a decade.

To detect potential pancreatic cancer-associated variants, the team compared SNPs in the genomes of these pancreatic cancer cases with those in the genomes of around 2,000 unaffected individuals from the same population who were participating in community cancer screening or nutritional survey programs.

After the quality control stages of the study, the researchers were left with information at around 666,000 SNPs for 981 of the cases and 1,991 controls.

The 23 most suspicious SNPs found in that discovery group were then tested in more than 2,600 additional pancreatic cancer cases and almost 2,900 controls from 16 Chinese provinces or cities.

And at the end of that replication stage of the study, the team was left with five new pancreatic cancer-linked loci: two on chromosome 21 and one each on chromosomes 5, 10, and 22.

Variants at these sites fell in and around genes with functions that could theoretically relate to pancreatic cancer, at least at first blush. Among them were a suspected tumor suppressor gene, DAB2, a BACH1 gene that codes for a transcription repressor regulating the oxidative stress and inflammation related gene HMOX1, and a lactation and energy metabolism-related gene called PRLHR.

Moreover, at least one of the SNPs identified is suspected of influencing BACH1 expression, based on the team's initial analyses of published expression quantitative trait loci information.

The Chinese GWAS also pointed to ties between pancreatic cancer and SNPs in the same chromosome 13 locus implicated in elevated risk of the disease in Europeans. Though the precise variants identified differed between the populations, likely as a consequence of the arrays used for discovery phase testing, the authors noted that the variants found in the Chinese population are in linkage disequilibrium with those reported in past studies of pancreatic cancer in the Europeans.

In their follow-up analyses, the researchers found evidence that the disease-associated SNPs might have a cumulative effect on pancreatic cancer risk in the Chinese population, though they noted that those findings are still somewhat preliminary.

Along with additional studies to explore whether combinations of risk variants define sub-groups at different risk of pancreatic cancer within the population, researchers involved in the Chinese study also emphasized the need for research into other risk factors that could interact with the genetic variants.

"Further studies should be performed to address the interaction between risk variants and lifestyle risk factors, such as smoking, obesity, and diabetes mellitus," they wrote.