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  • Posted: 08/02/2009

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Risk of Pancreatic Cancer Linked to Variation in Gene that Determines Blood Type

Common variants of the gene that determines human blood type are associated with an increased risk of pancreatic cancer, according to a study by scientists at the National Cancer Institute (NCI), part of the National Institutes of Health, and colleagues from many universities and research institutions. The study, published online Aug. 2, 2009, in Nature Genetics, is consistent with an observation first made more than 50 years ago.

In the study, the researchers discovered that genetic variation in a region of chromosome 9 that contains the gene for ABO blood type was associated with pancreatic cancer risk. Individuals with the variant that results in blood types A, B, or AB were at an increased risk of pancreatic cancer, compared to those with the variant for blood type O. This finding is consistent with previous research, some of it dating back to the 1950s and 1960s, that had shown increased risks of gastric and pancreatic cancer among individuals of the A and B blood groups (i.e., blood types A, B, and AB). The latest results provide a genetic basis for those earlier observations.

A person's blood type depends on which form or forms of the ABO gene they inherit from their parents. The protein produced by the ABO gene determines the type of carbohydrates (complex sugars) that are present on the surface of red blood cells and other cells, including cells of the pancreas. The proteins encoded by the A and B forms of the gene transfer different carbohydrates onto the cell surfaces to make A and B blood types. The O form encodes a protein that is unable to transfer carbohydrates. Studies by other researchers have shown that ABO protein encoding in pancreatic tumor cells is different than in normal pancreatic cells.

Genotyping chip with raw data -- red or green indicates identical copies of DNA inherited from both parents and yellow indicates copies from each parent are different.

To discover genetic variations that contribute to pancreatic cancer risk, the research team conducted a genome-wide association study (GWAS). In a GWAS, researchers analyze common variants, called single-nucleotide polymorphisms (SNPs), in the genomes of people with a disease and people without the disease. Initially, the research team studied the genomes of 1,896 patients with pancreatic cancer and 1,939 control subjects to identify SNPs with a strong association with pancreatic cancer. The team then verified its findings by studying the genomes of another 2,457 people with pancreatic cancer and 2,654 people without the disease. In the end, they identified several SNPs on the long arm of chromosome 9 that were associated with pancreatic cancer risk and mapped to the ABO gene.

"Only by working across disciplines and with more than a dozen research groups were we able to make this important discovery of the potential role of the ABO gene in pancreatic cancer risk," said co-author Patricia Hartge, Sc.D., of NCI's Division of Cancer Epidemiology and Genetics (DCEG). "Although it will take much more work, this finding may lead to improved diagnostic and therapeutic interventions that are so desperately needed."

Pancreatic cancer is the fourth leading cause of cancer death in the United States. It is difficult to detect, and in many people it is not diagnosed until after the disease has spread to other parts of the body. Less than five percent of Americans with pancreatic cancer survive five years past diagnosis. Risk factors include smoking, diabetes, race, and a family history of the disease.

"Pancreatic cancer is the newest beneficiary of so-called high-throughput genotyping that, over the past two years, has yielded scores of genetic hot-spots linked to risk for cancer and other diseases," said co-author Stephen J. Chanock, M.D., chief of NCI's Laboratory of Translational Genomics in DCEG. "As more variants are discovered and follow-up studies are conducted to examine the biological effects of these variants, a better understanding will emerge of the inherited risk factors and mechanisms that lead to the development of pancreatic cancer."

The study was part of PanScan, a GWAS of pancreatic cancer conducted by the Pancreatic Cancer Cohort Consortium, composed of 14 academic centers. The investigators are conducting whole-genome scans to identify common genetic variants that may be markers of susceptibility to pancreatic cancer.

Analyses and data from PanScan will be available through NCI's caBIG (Cancer Biomedical Informatics Grid). The summary results for similar data on breast and prostate cancer are already freely available to other researchers at this Web site.

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For more information on Dr. Hartge's research, please go to http://dceg.cancer.gov/about/staff-bios/hartge-patricia.

For more information on Dr. Chanock's research, please go to http://dceg.cancer.gov/about/staff-bios/chanock-stephen.

For more information about PanScan, please go to http://epi.grants.cancer.gov/PanScan.

NCI leads the National Cancer Program and the NIH effort to dramatically reduce the burden of cancer and improve the lives of cancer patients and their families, through research into prevention and cancer biology, the development of new interventions, and the training and mentoring of new researchers. For more information about cancer, please visit the NCI Web site at http://www.cancer.gov or call NCI's Cancer Information Service at 1-800-4-CANCER (1-800-422-6237).

Reference: Amundadottir L., et al. Genome-wide association study identifies ABO Blood Group Susceptibility Variants for Pancreatic Cancer. Nature Genetics. Online August 2, 2009.