Blood group type as a risk factor for pancreatic cancer

5 August 2009

Pancreatic cancer, a complex disease involving both genetic and environmental risk factors, has one of the lowest cancer survival rates worldwide. Prognosis is poor, with a median survival of less than 12 months, and an estimated 5-year relative survival rate of less than 5%. There is also currently no effective screening test for pancreatic cancer, and by the time a diagnosis is made, the cancer has often spread. Despite these difficulties, established risk factors include a positive family history (2- to 4-fold increased risk for a first-degree relative), obesity, type 2 diabetes, and smoking, with genetic factors proving more difficult to replicate. With the emergence of high-throughput genotyping technology, the genome-wide association study design carries high hopes of uncovering genetic factors involved in the aetiology of pancreatic cancer.

A new study published in the journal Nature Genetics, reports a genome-wide association study (GWAS) to identify common variants associated with pancreatic cancer. In their GWAS, Amundadottir et al. [Amundadottir L et al. (2009) Nat Genet 2 August doi:10.1038/ng.429] genotyped over half a million SNPs in 1,896 pancreatic cases and 1,939 controls collated from twelve prospective cohorts and one hospital-based case-control study. This was followed-up by a ‘fast-track replication phase’ which involved genotyping ten of the most promising SNPs identified by the initial GWAS across 3 chromosomal regions (7q36, 9q34, and 15q14) in a further 2,457 cases and 2,654 controls from eight case-control studies. The strongest association with pancreatic cancer in the combined analysis across both phases in participants of European background was for the locus marked by rs505922, located within the first intron of the ABO gene (per allele OR = 1.20, 95% CI 1.12-1.28; P = 5.37 x 10-8), which determines the major antigens found on the surface of red blood cells. This finding replicates work conducted in the 1950s and 1960s, which first reported the association between ABO blood type and gastrointestinal cancers (such as gastric cancer and pancreatic cancer) [Aird I et al. (1953) BMJ 1:799-801; Marcus D (1969) N Engl J Med 280:994-1006]. Interestingly, the protective T allele of rs505922 is in complete linkage disequilibrium with the O allele of the ABO gene, which is consistent with the earlier reports showing an increase in risk of gastric and pancreatic cancer for A and B blood group individuals. To determine whether this observed association is due to the O allele of the ABO gene would require further more detailed genotyping.

Although the mechanism underlying the association between blood type and pancreatic cancer risk is unknown, there is also an increased risk of venous thrombosis in non-O blood type individuals and patients with pancreatic cancer, and a possible mechanism via aberrant blood coagulation has been proposed [Maisonneuve et al. (2009) JNCI 10 July doi:10.1093/jnci/djp198].

Comment: Pancreatic cancer has one of the highest mortality rates with a very poor prognosis. Few known risk factors exist that have been well replicated and improved diagnostics as well as a finer understanding of the molecular pathogenesis is needed to improve early detection, risk stratification and to develop novel therapeutic approaches. Approaches such as GWAS offer a powerful tool for dissecting the genetic basis of disease and for uncovering genes that might not otherwise emerge from classical epidemiological studies; in this case, however, it has primarily served to support a 50 year old association with blood type, which is both simple and reliable to measure without the need for a genetic test.

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