Genetically Determined ABO Blood Group, Secretor Status, Lewis Antigens, and panNENs Risk

Pancreatic neuroendocrine neoplasms (panNENs) are rare endocrine malignancies with poorly defined risk factors, in contrast to the more common pancreatic ductal adenocarcinoma (PDAC), for which non-O ABO blood group is a well-established susceptibility marker. To determine whether ABO and related glycosylation markers associated with PDAC risk extends to panNENs, we conducted a case-control study of 1,059 pathologically confirmed panNEN cases from the ANONYMISED HOSPITAL Biospecimen Resource for Pancreas Research and 33,018 cancer-free controls from the ANONYMISED HOSPITAL Biobank. Using germline genotype data, we inferred ABO blood group, FUT2-defined secretor status, and FUT3-defined Lewis antigen phenotypes, and calculated odds ratios (ORs) and 95% confidence intervals (CIs) using logistic regression adjusted for age, sex, and ancestry principal components. ABO blood group was not associated with panNEN risk: compared with blood group O, the OR for non-O was 0.98 (95%CI: 0.87-1.11), with similarly null findings for blood groups A, B, and AB individually. Secretor status (OR=0.98, 95%CI: 0.84-1.14) and Lewis-positive phenotypes (OR=0.91, 95%CI: 0.75-1.13) were also not associated with risk, and no interactions were observed between blood group and secretor status or Lewis antigen phenotypes. Given our high statistical power to detect previously reported PDAC effect sizes for non-O blood group, these null findings are informative, indicating that the ABO-linked glycosylation, inflammatory, and host-microbe interaction pathways implicated in PDAC are unlikely to be major determinants of panNEN susceptibility. This study therefore sharpens the etiologic distinction between pancreatic exocrine and neuroendocrine cancers, redirecting panNEN research beyond PDAC paradigms toward alternative mechanisms of endocrine tumorigenesis.