Marcia Irene Canto

Background: Pancreatic surveillance commonly detects pancreatic cysts, most of which are presumed intraductal papillary mucinous neoplasms (IPMN). FUT2, the gene responsible for secretor status, has been implicated in IPMN development, although not with pancreatic cancer risk. Methods: We evaluated the association between inactivating variants in FUT2, FUT3, and ABO and pancreatic cysts in 1,865 patients in the multicenter Cancer of the Pancreas Screening (CAPS) cohort. Multivariable logistic regression was performed to estimate adjusted odds for presumed IPMN prevalence. A Johns Hopkins surgical cohort of 1,582 patients with IPMN, pancreatic ductal adenocarcinoma (PDAC), or carcinoma arising from IPMN was analyzed to examine trend in variant proportion by malignant progression. Results: In the CAPS cohort, older age [OR per year, 1.06 (1.05–1.07); P < 0.001], being FUT2 null [nonsecretors; OR, 1.66 (1.30–2.12); P < 0.001], non-O blood group [OR, 1.31 (1.06–1.62); P = 0.012], having familial-only versus genetic/familial risk [OR, 1.49 (1.20–1.85); P < 0.001], and participating site [OR, 2.20 (1.78–2.73); P < 0.001] were associated with having pancreatic cysts. There were no significant FUT2/ABO-presumed IPMN prevalence interactions. In the combined cohort, the proportion of FUT2-null patients with IPMN without carcinoma (by imaging or pathology) was 319 (27.4%) of 1,162, 57 (24.3% of 234) with IPMN and carcinoma, and 225 (22.5%) of 998 with PDAC alone (P = 0.009 for trend). Conclusions: IPMN is more prevalent in FUT2-null patients under pancreas surveillance, but the increased FUT2-null prevalence is not observed in patients with IPMN with carcinoma. Impact: Pancreatic cancer risk conferred by having IPMN may be lower in FUT2-null compared with FUT2-intact individuals.

Supplementary Table S4: Minor allele frequencies by racial group in controls

Supplementary Table S2: Clinicopathological features and CA125 levels in controls and patients with PDAC

Supplementary Table S6: Clinical features of PDAC cases with true positive vs false negative CA125 levels (variant-based classification)

Supplementary Figure S2: CA125 levels by variant in 807 control subjects

Background:Cancer antigen 125 (CA125) is widely recognized as a useful biomarker for the surveillance of patients with ovarian and other cancers. Prior genome-wide association studies have identified variants that influence CA125 levels. We evaluated the utility of stratifying CA125 levels by such variants and evaluated diagnostic performance in control subjects and patients with pancreatic ductal adenocarcinoma (PDAC).Methods:We measured CA125 levels in 807 control subjects and 450 patients with PDAC and genotyped 10 variants involving four genes (GAL3ST2, MSLN, D2HGDH, and MUC16). We compared CA125 levels in controls by variant and generated variant-defined CA125 cutoffs and then classified cases and controls into functional groups based on their variant profile. We used this variant classification to evaluate the diagnostic performance of CA125 in patients with PDAC.Results:Six variants associated with CA125 levels were used to group controls into one of four groups. Mean CA125 levels in the highest variant group were approximately fourfold higher than in the lowest group. African Americans were more likely to have a variant group associated with low CA125 levels. After setting diagnostic cutoffs by variant group, the diagnostic sensitivity of CA125 for PDAC was 20.2% at 98% specificity (areas under the ROC curve, 0.702), not significantly different from a uniform CA125 diagnostic cutoff (areas under the ROC curve, 0.700).Conclusions:Gene variants can be used to generate personalized CA125 reference ranges. This approach did not significantly improve CA125’s diagnostic performance for pancreatic cancer, but it merits evaluation in other diagnostic settings, such as detecting ovarian cancer.Impact:Gene variants can be used to personalize CA125 levels.

Supplementary Figure S4: CA125 levels by variant group

Supplementary Table S3: Clinical features by gene variant-group in controls and patients with PDAC

Supplementary Figure S1: Relationship between CA125 levels and rs12469459 in controls