Background:

ABO blood group is associated with pancreatic cancer risk. Whether ABO blood group alone or when combined with inherited mutation status of index pancreatic cancer cases (probands) can enhance pancreatic cancer risk estimation in first-degree relatives (FDR) is unclear. We examined FDRs' risk for pancreatic cancer based on probands' ABO blood group and probands' cancer susceptibility gene mutation status.

Methods:

Data on 23,739 FDRs, identified through 3,268 pancreatic cancer probands, were analyzed. Probands' ABO blood groups were determined serologically or genetically, and 20 cancer susceptibility genes were used to classify probands as “mutation-positive” or “mutation-negative.” SIRs and 95% confidence intervals (CI) were calculated, comparing observed pancreatic cancer cases in the FDRs with the number expected in SEER-21 (reference population).

Results:

Overall, FDRs had 2-fold risk of pancreatic cancer (SIR = 2.00; 95% CI = 1.79–2.22). Pancreatic cancer risk was higher in FDRs of mutation-positive (SIR = 3.80; 95% CI = 2.81–5.02) than mutation-negative (SIR = 1.79; 95% CI = 1.57–2.04) probands (P < 0.001). The magnitude of risk did not differ by ABO blood group alone (SIRblood-group-O = 1.57; 95% CI = 1.20–2.03, SIRnon-O = 1.83; 95% CI = 1.53–2.17; P = 0.33). Among FDRs of probands with non-O blood group, pancreatic cancer risk was higher in FDRs of mutation-positive (SIR = 3.98; 95% CI = 2.62–5.80) than mutation-negative (SIR = 1.66; 95% CI = 1.35–2.03) probands (P < 0.001), but risk magnitudes were statistically similar when probands had blood group O (SIRmutation-positive = 2.65; 95% CI = 1.09–5.47, SIRmutation-negative = 1.48; 95% CI = 1.06–5.47; P = 0.16).

Conclusions:

There is a range of pancreatic cancer risk to FDRs according to probands' germline mutation status and ABO blood group, ranging from 1.48 for FDRs of probands with blood group O and mutation-negative to 3.98 for FDRs of probands with non-O blood group and mutation-positive.

Impact:

Combined ABO blood group and germline mutation status of probands can inform pancreatic cancer risk estimation in FDRs.

Pancreatic cancer, despite being the 10th most common cancer among men and 8th among women, is the 4th leading cause of cancer-related death in both men and women (1). The major risk factors for pancreatic cancer include older age, male sex, diabetes mellitus, chronic pancreatitis, cigarette smoking, excessive alcohol intake, and obesity (2–4). Inherited (germline) genetic factors also play essential roles in pancreatic cancer development and can influence host physiologic responses to modifiable risk factors, such as cigarette smoking and alcohol intake (2–5). Family history of pancreatic cancer and ABO blood group are also associated with pancreatic cancer risk, further demonstrating the importance of heritable factors in pancreatic cancer development (2, 6–11).

Our group previously reported a higher risk of pancreatic cancer among first-degree relatives (FDR) of index pancreatic cancer patients (probands), with substantially higher pancreatic cancer risk among FDRs of probands who carry one or more mutations in cancer susceptibility genes (7). ABO blood group is a genetically determined trait (12–14) and having a non-O ABO blood group has been consistently associated with higher risk for pancreatic cancer in both case–control and cohort studies (8–11, 15, 16). Given the consistent association between ABO blood group and pancreatic cancer risk, it is plausible that the familial aggregation of pancreatic cancer may in part be due to inheritance of ABO blood group alleles within families (12–14).

The precise mechanism by which ABO blood group predisposes to pancreatic cancer is unknown. The ABO gene encodes glycosyltransferase enzymes that catalyze the transfer of different sugar residues, N-acetyl-galactosamine or galactose, to a biosynthetic precursor (the H antigen) to form an A or B antigen, respectively, or AB antigen (13, 17). Individuals who lack the glycosyltransferase enzyme activity have the O blood group and express the H antigen (12–14). These antigenic expressions on erythrocytes generally serve as the basis for ABO blood typing (12, 13, 17). The glycans that catalyze the biosynthesis of the ABO histo-blood groups play important physiologic roles, including protein maturation and turnover, receptor binding and activation, and host immune responses (18). The ABO blood groups themselves have been implicated in modulation of systemic inflammation and membrane signaling (8, 19–22), all of which could influence pancreatic cancer development (23, 24). Specifically, ABO blood groups have been implicated in systemic inflammation measured by circulating levels of soluble intercellular adhesion molecule 1 (sICAM-1), tumor necrosis factor-alpha (TNFα), C-reactive protein (CRP), interleukin 6 (IL6), or E-selectin (20–22). Studies have also shown that Helicobacter pylori (H. pylori) colonization, a flagellated gram-negative bacillus infection, is associated with pancreatic cancer risk, but the association is modulated by ABO blood group, such that an association between CagA-negative H. pylori seropositivity and pancreatic cancer risk is seen only in individuals who have a non-O blood group (25). Experimental studies have also shown that the expressions of ABO blood group antigens on the surfaces of tumor cells are associated with variation in in vitro cell motility, cellular resistance to apoptosis, and immune escape by tumor cells (26).

Few studies have inferred FDRs' risk for pancreatic cancer based on probands' germline mutation status under assumptions of Mendelian laws of inheritance (7, 27–29). To our knowledge, no study has yet investigated the potential contribution of ABO blood groups to the familial aggregation of pancreatic cancer. Therefore, the aims of this study were to investigate FDRs' risk of pancreatic cancer based on probands' ABO blood group and investigate FDRs' pancreatic cancer risk by combining probands' ABO blood group and germline cancer susceptibility gene mutation status. We used standardized incidence ratios (SIRs) to estimate pancreatic cancer risk among FDRs of pancreatic cancer probands in comparison with data from the U.S. Surveillance, Epidemiology, and End Results (SEER) program (30). We assessed SIR by probands' ABO blood group alone, probands' cancer susceptibility gene mutation status alone, and a combination of probands' blood group and cancer susceptibility gene mutation status to more robustly estimate familial risk of pancreatic cancer to inform strategies for cancer risk assessment and generate evidence to guide genetic counseling in pancreatic cancer families.

Study population

Following approval by the Mayo Clinic Institutional Review Board, data were obtained from the Mayo Clinic Biospecimen Resource for Pancreas Research, a patient registry supported by the Mayo Clinic Specialized Program of Research Excellence (SPORE) in pancreatic cancer (4, 7, 31, 32). The registry utilizes an ultra-rapid case ascertainment process, which ensures that approximately 86% of pancreatic cancer cases diagnosed at Mayo Clinic are recruited within 30 days of diagnosis (4, 32). The pancreatic cancer probands included in this study were recruited between October 2000 and March 2020, with participation rate of approximately 70% (4, 7). The primary reasons for nonparticipation in the registry are the severe morbidity associated with pancreatic cancer and rapid death of patients following pancreatic cancer diagnosis. For this study, we analyzed data on 23,739 FDRs, identified through 3,268 consecutively enrolled probands with a primary diagnosis of ductal adenocarcinoma of the exocrine pancreas, determined pathologically (∼95%) or radiologically. The sample for this study overlaps partially with samples used in a previous study, which primarily included data from the years 2000 to 2016 (7). The current sample contains 963 (29%) newly added probands, 6,577 (28%) newly added FDRs, with an additional 271,406 (28%) person-years at risk.

Data collection

The probands completed structured questionnaires that included questions about probands' demographics and comprehensive family health history, including history of pancreatic cancer in an FDR (parents, siblings, and offspring). Therefore, analyses were based on probands' recall of cancer diagnosis in their FDRs. However, in our registry, we have found a 98% concordance between probands report of pancreatic cancer diagnosis in an FDR and the FDRs' own report (7). We compared the reported number of pancreatic cancer cases in the FDRs to the expected number of cases based on SEER data (SEER 21 registries, 2000–2017), covering approximately 28% of the general U.S. population (33). Because pancreatic cancer is rarely diagnosed before age 20 years, we restricted analyses to FDRs who were ≥20 years at the time of questionnaire completion, and constructed pedigrees based on family information provided by the probands.

ABO blood groups

Data on ABO blood groups were available for 2,082 (64%) of the 3,268 pancreatic cancer probands. For the majority of the probands (n = 1,147), ABO blood groups were determined through serologic testing, retrieved from medical records. For the remaining 935 probands, ABO blood groups were genetically determined using two tagging single-nucleotide polymorphisms (SNPs rs505922/rs687289 and rs8176746) in the ABO gene locus (9q34.1-q34.2) that we (11) and others (8, 34) have shown to predict serologic ABO blood groups. The SNPs were genotyped as part of the Pancreatic Cancer Cohort Consortium's genome-wide association studies (GWAS; refs. 15, 35) or the Pancreatic Cancer Case Control Consortium's GWAS (36). We primarily used rs505922 and rs8176746 for imputation of the blood groups. Where rs505922 was not available for a particular proband, we used rs687289 instead, because rs505922 and rs687289 are in complete linkage disequilibrium (r2 = 1.0 in HapMap CEU subjects; ref. 37) and are perfect surrogates for each other (see online Supplementary Methods for additional details; ref. 8). Studies have shown that these SNPs predict serologic blood groups with ≥90% accuracy when blood groups are imputed genetically as A, B, AB, and O, and ≥99% accuracy when imputed as O versus non-O (8–10). However, we evaluated concordance between serologically determined and genotype determined ABO blood groups among probands who had data on both serotype- and genotype-derived ABO blood groups to assess the accuracy of our imputations (Supplementary Tables S1 and S2).

Cancer susceptibility genes

Genetic sequencing data were available for 2,799 (86%) of the probands. We selected previously established candidate cancer susceptibility genes for assessment of FDRs' risk of pancreatic cancer based on whether their respective proband carried a pathogenic or likely pathogenic variant (mutation) in one or more cancer susceptibility genes (38). The genes were sequenced in two genetic studies among the probands. The first sequencing project was performed with a custom capture multiplex polymerase chain reaction using a QIAseq assay (Qiagen Inc.), as described previously (38). The second sequencing project was performed by Color Genomics using a clinical-grade assay (39). A detailed description of the sequencing methods, bioinformatics pipeline, and quality control checks used by Color Genomics has been published (39, 40). For analyses, we selected 20 cancer susceptibility genes that overlapped the QIAseq and Color Genomics sequencing projects: APC, ATM, BARD1, BRCA1, BRCA2, BRIP1, CDH1, CDKN2A, CHEK2, EPCAM, MLH1, MSH2, MSH6, NBN, PALB2, PMS2, PTEN, RAD51C, RAD51D, and TP53. We classified probands as “mutation-positive” if they carried at least one pathogenic or likely pathogenic variant, as determined previously (38), in any of the 20 cancer genes. Probands who did not carry pathogenic or likely pathogenic variants in any of the 20 genes were classified as “mutation-negative.” FDRs' risk of pancreatic cancer was based on the mutation status of their respective proband.

Statistical analysis

SIRs and 95% confidence intervals (CI) were calculated to assess risk of pancreatic cancer among the FDRs by dividing the observed number of cases of pancreatic cancer by the expected number of cases calculated from age-specific (five-year intervals) and sex-specific incidence rates in the SEER-21 data (30) then multiplied by person-years at risk. The observed number of cases was based on probands' report of pancreatic cancer diagnosis in an FDR. SIRs were calculated for the overall sample, and by FDRs' smoking status and kinship to the proband based on age- and sex-specific incidence rates in SEER, and for male and female FDRs' separately based on age-specific rates. We also calculated age- and sex-standardized incidence ratios for pancreatic cancer risk among the FDRs based on: (i) their respective proband's ABO blood group (blood group A, B or AB, or O; and O vs. non-O); (ii) the proband's susceptibility gene mutation status (mutation-positive vs. mutation-negative), and (iii) a combination of proband's ABO blood group and mutation status (blood group O and mutation-positive, blood group O and mutation-negative, non-O blood group and mutation-positive, and non-O blood group and mutation-negative). We further calculated P values to test for statistical difference in SIRs between groups assuming binomial distribution (41). These analyses were repeated in subgroups defined by FDRs' sex, FDRs' smoking status, and kinship to the proband. In a subset of probands who had data on both serologic blood group and genetically determined blood group (n = 393), we assessed concordance between the serotype- and genotype-derived ABO blood groups. All statistical tests were two-sided, and a P value < 0.05 was considered statistically significant. Analyses were performed using SAS version 9.4 (SAS Institute, Cary, NC) and R version 3.6.2.

Descriptive characteristics of the 3,268 pancreatic cancer probands are reported in Table 1. The probands were predominantly white (98%), and a majority were male (55%). Mean age of pancreatic cancer diagnosis among the probands was 66 years. Data on ABO blood group were available for 2,082 (64%) probands, determined serologically (55%) or genetically. Most of the probands had blood group A (49%) or O (34%), fewer had B or AB (17%). Among probands with data on both serotype and genotype determined ABO blood groups, we found 99% (391/393) concordance between serotype- and genotype-derived blood groups when imputed as A, B or AB, and O, and remained 99% when compared as O versus non-O (Supplementary Table S2). Data on germline mutation status were available for 2,799 (86%) probands, among whom 266 (9.5%) tested positive for one or more mutations in the 20 cancer susceptibility genes tested (Table 1). The top five genes with the most pathogenic variants in the probands were ATM (n = 72, 2.6% of probands), BRCA2 (n = 66, 2.3%), CHECK2 (n = 29, 1.0%), CDKN2A (n = 23, 0.8%), and BRCA1 (n = 18, 0.6%).

Table 1.

Descriptive characteristics of the pancreatic cancer probands.

Patient characteristicsN = 3,268
Age, yearsa 
 Mean (SD) 65.7 (10.3) 
 Median 66.0 
 Range (20.0–92.0) 
Sex 
 Male 1,799 (55.0%) 
 Female 1,469 (45.0%) 
Race 
 White 3,188 (97.7%) 
 Black/African American 33 (1.0%) 
 Asian/Asian American 18 (0.6%) 
 American Indian/Alaska Native 10 (0.3%) 
 Native Hawaiian/Other Pacific Islander 2 (0.1%) 
 Multiracial 13 (0.4%) 
 Unknown 
ABO blood groupb 
 A 1,019 (48.9%) 
 B 289 (13.9%) 
 AB 58 (2.8%) 
 O 716 (34.4%) 
 Missing 1,186 
O vs. non-O ABO blood groupb,c 
 O 716 (34.4%) 
 Non-O 1,366 (65.6%) 
 Missing 1,186 
ABO data source 
 Serology 1,147 (55.1%) 
 Genotype-derived 935 (44.9%) 
 Missing 1,186 
Germline mutation statusd 
 Mutation positive 266 (9.5%) 
 Mutation negative 2,533 (90.5%) 
 Missing 469 
Patient characteristicsN = 3,268
Age, yearsa 
 Mean (SD) 65.7 (10.3) 
 Median 66.0 
 Range (20.0–92.0) 
Sex 
 Male 1,799 (55.0%) 
 Female 1,469 (45.0%) 
Race 
 White 3,188 (97.7%) 
 Black/African American 33 (1.0%) 
 Asian/Asian American 18 (0.6%) 
 American Indian/Alaska Native 10 (0.3%) 
 Native Hawaiian/Other Pacific Islander 2 (0.1%) 
 Multiracial 13 (0.4%) 
 Unknown 
ABO blood groupb 
 A 1,019 (48.9%) 
 B 289 (13.9%) 
 AB 58 (2.8%) 
 O 716 (34.4%) 
 Missing 1,186 
O vs. non-O ABO blood groupb,c 
 O 716 (34.4%) 
 Non-O 1,366 (65.6%) 
 Missing 1,186 
ABO data source 
 Serology 1,147 (55.1%) 
 Genotype-derived 935 (44.9%) 
 Missing 1,186 
Germline mutation statusd 
 Mutation positive 266 (9.5%) 
 Mutation negative 2,533 (90.5%) 
 Missing 469 

aAge at PDAC diagnosis.

bBlood group was determined serologically or genetically imputed based on the following polymorphisms in the ABO locus that predict ABO blood groups (rs505922/rs687289 and rs8176749). Those with missing information did not have serologic or genetic data available and were excluded from the ABO blood group analyses.

cNon-O blood group was categorized by combining blood groups A, B, and AB into one group.

dProbands were categorized as mutation-positive if they tested positive for one or more mutations in any of the following cancer susceptibility genes: APC, ATM, BARD1, BRCA1, BRCA2, BRIP1, CDH1, CDKN2A, CHEK2, EPCAM, MLH1, MSH2, MSH6, NBN, PALB2, PMS2, PTEN, RAD51C, RAD51D, and TP53. Probands were classified as mutation-negative if they had no mutation in all 20 genes tested.

Comprehensive family histories were provided by the probands and were used to derive the analytic sample of 23,739 FDRs, with up to 956,491 person-years at risk. The FDRs comprised 6,536 parents, 9,619 siblings, and 7,584 offspring. The average age of the FDRs was 60 years, with nearly equal proportion of men and women (49.2% vs. 50.8%), and most FDRs were nonsmokers (Supplementary Table S3). Age- and sex-standardized incidence ratio showed a 2-fold higher-than-expected risk of pancreatic cancer among the FDRs (SIR = 2.00; 95% CI = 1.79–2.22), compared with the SEER population (Table 2). We also found a higher than expected age-standardized pancreatic cancer risk among male (SIR = 1.71; 95% CI = 1.45–1.99) and female (SIR = 2.30; 95% CI = 1.97–2.67) FDRs. Additional analysis showed that the magnitude of risk for female FDRs is significantly higher than the magnitude of risk for male FDRs (between-group comparison, P = 0.006). Furthermore, pancreatic cancer risk was substantially higher among FDRs who ever smoked (SIR = 2.45; 95% CI = 2.09–2.85) than FDRs who never smoked (SIR = 1.63; 95% CI = 1.36–1.92; between-group comparison, P < 0.001). SIRs (95% CIs) for pancreatic cancer risk among mothers, fathers, and siblings of the probands were 3.50 (2.86–4.23), 2.94 (2.40–3.56), and 1.61 (1.34–1.93), respectively. For mutation status only, we found a substantially higher pancreatic cancer risk among FDRs of mutation-positive probands (SIR = 3.80; 95% CI = 2.81–5.02) than among FDRs of mutation-negative probands (SIR = 1.79; 95% CI = 1.57–2.04; between-group comparison, P < 0.001).

Table 2.

Risk of pancreatic cancer among FDRs of pancreatic cancer probands.

Study sampleProbands (N)FDRs (N)Person-years at riskPC observed in FDR (N)PC expected in FDR (N)SIR (95% CI)aP valueb
Overall 3,268 23,739 956,491 336 168.3 2.00 (1.79–2.22)  
 Male FDRs 1,799 12,052 474,629 162 94.9 1.71 (1.45–1.99) 0.006 
 Female FDRs 1,469 11,687 481,862 174 75.7 2.30 (1.97–2.67)  
FDRs' smoking status 
 Never smokers 3,066 12,446 478,791 137 84.3 1.63 (1.36–1.92) <0.001 
 Ever smokers 2,887 9,167 387,355 167 68.2 2.45 (2.09–2.85)  
Kinship to proband 
 Mother 3,268 3,268 191,228 105 33.0 3.50 (2.86–4.23)  
 Father 3,268 3,268 175,391 103 35.1 2.94 (2.40–3.56)  
 Siblings 2,987 9,619 422,492 120 74.4 1.61 (1.34–1.93) <0.001 
 Parentsc 3,268 6,536 366,618 208 64.5 3.22 (2.80–3.69)  
Mutation positived 266 1,908 73,328 49 12.9 3.80 (2.81–5.02) <0.001 
Mutation negative 2,533 18,505 745,578 235 131.2 1.79 (1.57–2.04)  
Study sampleProbands (N)FDRs (N)Person-years at riskPC observed in FDR (N)PC expected in FDR (N)SIR (95% CI)aP valueb
Overall 3,268 23,739 956,491 336 168.3 2.00 (1.79–2.22)  
 Male FDRs 1,799 12,052 474,629 162 94.9 1.71 (1.45–1.99) 0.006 
 Female FDRs 1,469 11,687 481,862 174 75.7 2.30 (1.97–2.67)  
FDRs' smoking status 
 Never smokers 3,066 12,446 478,791 137 84.3 1.63 (1.36–1.92) <0.001 
 Ever smokers 2,887 9,167 387,355 167 68.2 2.45 (2.09–2.85)  
Kinship to proband 
 Mother 3,268 3,268 191,228 105 33.0 3.50 (2.86–4.23)  
 Father 3,268 3,268 175,391 103 35.1 2.94 (2.40–3.56)  
 Siblings 2,987 9,619 422,492 120 74.4 1.61 (1.34–1.93) <0.001 
 Parentsc 3,268 6,536 366,618 208 64.5 3.22 (2.80–3.69)  
Mutation positived 266 1,908 73,328 49 12.9 3.80 (2.81–5.02) <0.001 
Mutation negative 2,533 18,505 745,578 235 131.2 1.79 (1.57–2.04)  

Abbreviation: PC, pancreatic cancer.

aAge and sex standardized incidence ratio, except for sex-specific analyses, which were standardized by age alone.

bP values comparing male versus female FDRs, FDRs who ever smoked versus never smoked, siblings versus parents, FDRs of mutation-positive versus mutation-negative probands.

cMother and father combined into one group.

dProbands were categorized as mutation positive if they tested positive for one or more mutations in the following genes: APC, ATM, BARD1, BRCA1, BRCA2, BRIP1, CDH1, CDKN2A, CHEK2, EPCAM, MLH1, MSH2, MSH6, NBN, PALB2, PMS2, PTEN, RAD51C, RAD51D, and TP53; otherwise, the probands were categorized as mutation negative if they tested negative for all the genes.

Table 3 presents age- and sex-standardized incidence ratios for pancreatic cancer among FDRs based on probands' ABO blood group, and both the probands' blood group and probands' germline mutation status, compared with the SEER population. For ABO blood group only, we found a 1.75 (95% CI, 1.41–2.14) times higher than expected risk of pancreatic cancer for FDRs of probands with blood group A, a 2.06 (95% CI, 1.46–2.83) times higher than expected risk for FDRs of probands with blood group B or AB, and a 1.57 (95% CI, 1.20–2.03) times higher than expected risk for FDRs of probands with blood group O. Collectively, pancreatic cancer risk for FDRs of probands with a non-O blood group was 1.83 (95% CI = 1.53–2.17) times higher than expected, but this did not differ significantly from the risk among FDRs of probands with blood group O (P = 0.33).

Table 3.

Risk of pancreatic cancer among FDRs of pancreatic cancer probands by probands' ABO blood group and probands' germline susceptibility gene mutation status.

Proband characteristicsaProbands (N)FDRs (N)Person-years at riskPC observed in FDR (N)PC expected in FDR (N)SIR (95% CI)P valueb
ABO blood group A 1,019 7,501 298,962 92 52.6 1.75 (1.41–2.14)  
ABO blood group B/ABc 347 2,620 104,699 38 18.4 2.06 (1.46–2.83)  
ABO blood group non-Od 1,366 10,121 403,662 130 71.0 1.83 (1.53–2.17)  
ABO blood group O 716 5,300 213,410 59 37.6 1.57 (1.20–2.03) 0.33 
ABO blood group non-O 
 Mutation positivee 142 998 38,508 27 6.8 3.98 (2.62–5.80) <0.001 
 Mutation negative 1,123 8,404 334,684 98 58.9 1.66 (1.35–2.03)  
ABO blood group O 
 Mutation positivee 52 405 14,991 2.6 2.65 (1.06–5.47) 0.16 
 Mutation negative 608 4,472 180,546 47 31.8 1.48 (1.09–1.97)  
Proband characteristicsaProbands (N)FDRs (N)Person-years at riskPC observed in FDR (N)PC expected in FDR (N)SIR (95% CI)P valueb
ABO blood group A 1,019 7,501 298,962 92 52.6 1.75 (1.41–2.14)  
ABO blood group B/ABc 347 2,620 104,699 38 18.4 2.06 (1.46–2.83)  
ABO blood group non-Od 1,366 10,121 403,662 130 71.0 1.83 (1.53–2.17)  
ABO blood group O 716 5,300 213,410 59 37.6 1.57 (1.20–2.03) 0.33 
ABO blood group non-O 
 Mutation positivee 142 998 38,508 27 6.8 3.98 (2.62–5.80) <0.001 
 Mutation negative 1,123 8,404 334,684 98 58.9 1.66 (1.35–2.03)  
ABO blood group O 
 Mutation positivee 52 405 14,991 2.6 2.65 (1.06–5.47) 0.16 
 Mutation negative 608 4,472 180,546 47 31.8 1.48 (1.09–1.97)  

Abbreviation: PC, pancreatic cancer.

aABO blood group was determined by combining serologic data with data on polymorphisms in the ABO locus that are known to encode ABO blood group.

bP value comparing FDRs of probands with O versus non-O blood groups, FDRs of probands who are mutation-positive versus mutation negative, FDRs of probands with blood group O and mutation positive versus those with blood group O and mutation negative, or FDRs of probands with non-O blood group and mutation positive versus those with non-O blood group and mutation negative.

cBlood group B and AB were combined into one group because the polymorphisms used to infer blood group were able to detect the presence of blood group B, but could distinguish blood group AB from blood group B.

dNon-O blood group categorized by combining A, B, and AB into one group.

eProbands were categorized as mutation positive if they tested positive for one or more mutations in the following genes: APC, ATM, BARD1, BRCA1, BRCA2, BRIP1, CDH1, CDKN2A, CHEK2, EPCAM, MLH1, MSH2, MSH6, NBN, PALB2, PMS2, PTEN, RAD51C, RAD51D, and TP53; otherwise, the probands were categorized as mutation negative if they tested negative for all of the genes.

In the combined analysis of probands' ABO blood group and mutation status, we found that among FDRs of probands with blood group O, those FDRs of mutation-positive probands had a higher risk for pancreatic cancer (SIR = 2.65; 95% CI = 1.06–5.47), as did FDRs of mutation-negative probands (SIR = 1.48; 95% CI = 1.09–1.97; Table 3). However, the risk estimates did not differ significantly by probands' mutation status among FDRs of probands with ABO blood group O (P = 0.16). In contrast, among FDRs of probands with non-O blood group, the FDRs of mutation-positive probands had a 3.98 times higher pancreatic cancer risk (SIR = 3.98; 95% CI = 2.62–5.80), while FDRs of mutation-negative probands had a 1.66 times higher risk (SIR = 1.66; 95% CI = 1.35–2.03), and the risk estimates differed significantly by probands' mutation status (P < 0.001). These differences are shown graphically in Fig. 1.

Figure 1.

SIRs and 95% CIs for associations of probands' ABO blood group and mutation status on FDRs' risk for pancreatic cancer. P values were computed for comparisons within the same blood group, but different mutation status. Abbreviations: ABO-O, ABO blood group O; ABO-non-O, ABO blood group non-O; mut-pos, mutation-positive; mut-neg, mutation-negative.

Figure 1.

SIRs and 95% CIs for associations of probands' ABO blood group and mutation status on FDRs' risk for pancreatic cancer. P values were computed for comparisons within the same blood group, but different mutation status. Abbreviations: ABO-O, ABO blood group O; ABO-non-O, ABO blood group non-O; mut-pos, mutation-positive; mut-neg, mutation-negative.

Close modal

We also performed subgroup analyses sex and smoking status of the FDRs according to the respective proband's blood group and mutation status (Table 4). The major findings include a higher pancreatic cancer risk among females FDRs of probands with blood group O (SIR = 2.13; 95% CI = 1.49–2.95), whereas no association was found among male FDRs of probands with blood group O (SIR = 1.09; 95% CI = 0.69–1.63). Both male and female FDRs of probands with non-O blood group and mutation-positive had higher pancreatic cancer risk (male, SIR = 3.99; 95% CI = 2.23–6.58; female, SIR = 3.88; 95% CI = 2.00–6.77). However, while no association was found among male FDRs of probands with blood group O and mutation-negative (SIR = 1.06; 95% CI = 0.64–1.65), a significant association was found for female FDRs of probands with blood group O and mutation-negative (SIR = 1.97; 95% CI = 1.31–2.84). FDRs who ever smoked generally had higher pancreatic cancer risk than FDRs who never smoked irrespective of probands' ABO blood group and mutation status. For example, a significant association was observed among FDRs who were smokers and are related to probands with blood group O (SIR = 1.93; 95% CI = 1.29–2.77), but no association was found among FDRs who never smoked and are related to probands with blood group O (SIR = 1.43; 95% CI = 0.97–2.08). FDRs who ever smoked and are related to mutation-positive probands with non-O blood group also had higher pancreatic cancer risk (SIR = 4.92; 95% CI = 2.69–8.26) than FDRs who never smoked and are related to mutation-positive probands with non-O blood group (SIR = 2.69; 95% CI = 1.23–5.11; Table 4).

Table 4.

SIRs for pancreatic cancer risk among FDRs of pancreatic cancer probands according to probands' ABO blood group and probands' germline susceptibility gene mutation status, stratified by FDRs' sex and FDRs' smoking status.

Associations by FDRs' sex
Male FDRs (n = 12,052)Female FDRs (n = 11,687)
Proband characteristicsaPC observed in FDR (N)PC expected in FDR (N)Person-years at riskSIR (95% CI)PC observed in FDR (N)PC expected in FDR (N)Person-years at riskSIR (95% CI)
ABO blood group A 45 29.3 146,674 1.53 (1.12–2.05) 47 23.9 152,288 1.97 (1.44–2.61) 
ABO blood group B/ABb 21 10.3 51,446 2.04 (1.26–3.12) 17 8.4 53,253 2.03 (1.18–3.26) 
ABO blood group non-Oc 66 39.6 198,121 1.67 (1.29–2.12) 64 32.3 205,541 1.98 (1.53–2.53) 
ABO blood group O 23 21.2 105,812 1.09 (0.69–1.63) 36 16.9 107,599 2.13 (1.49–2.95) 
ABO blood group non-O 
 Mutation positived 15 3.8 18,798 3.99 (2.23–6.58) 12 3.1 19,710 3.88 (2.00–6.77) 
 Mutation negative 50 32.9 164,700 1.52 (1.13–2.00) 48 26.7 169,984 1.80 (1.33–2.38) 
ABO blood group O 
 Mutation positived 1.4 7,200 2.08 (0.42–6.09) 1.2 7,791 3.27 (0.88–8.37) 
 Mutation negative 19 18.0 89,921 1.06 (0.64–1.65) 28 14.2 90,625 1.97 (1.31–2.84) 
Associations by FDRs' sex
Male FDRs (n = 12,052)Female FDRs (n = 11,687)
Proband characteristicsaPC observed in FDR (N)PC expected in FDR (N)Person-years at riskSIR (95% CI)PC observed in FDR (N)PC expected in FDR (N)Person-years at riskSIR (95% CI)
ABO blood group A 45 29.3 146,674 1.53 (1.12–2.05) 47 23.9 152,288 1.97 (1.44–2.61) 
ABO blood group B/ABb 21 10.3 51,446 2.04 (1.26–3.12) 17 8.4 53,253 2.03 (1.18–3.26) 
ABO blood group non-Oc 66 39.6 198,121 1.67 (1.29–2.12) 64 32.3 205,541 1.98 (1.53–2.53) 
ABO blood group O 23 21.2 105,812 1.09 (0.69–1.63) 36 16.9 107,599 2.13 (1.49–2.95) 
ABO blood group non-O 
 Mutation positived 15 3.8 18,798 3.99 (2.23–6.58) 12 3.1 19,710 3.88 (2.00–6.77) 
 Mutation negative 50 32.9 164,700 1.52 (1.13–2.00) 48 26.7 169,984 1.80 (1.33–2.38) 
ABO blood group O 
 Mutation positived 1.4 7,200 2.08 (0.42–6.09) 1.2 7,791 3.27 (0.88–8.37) 
 Mutation negative 19 18.0 89,921 1.06 (0.64–1.65) 28 14.2 90,625 1.97 (1.31–2.84) 
Associations by FDRs' smoking status
Ever smokers (n = 9,167)Never smokers (n = 12,446)
Proband characteristicsaPC observed in FDR (N)PC expected in FDR (N)Person-years at riskSIR (95% CI)PC observed in FDR (N)PC expected in FDR (N)Person-years at riskSIR (95% CI)
ABO blood group A 41 20.9 118,857 1.96 (1.41–2.66) 41 26.6 151,205 1.54 (1.11–2.09) 
ABO blood group B/ABb 20 7.3 41,601 2.73 (1.67–4.22) 12 9.2 52,313 1.30 (0.67–2.28) 
ABO blood group non-Oc 61 28.2 160,458 2.16 (1.65–2.77) 53 35.8 203,518 1.48 (1.11–1.94) 
ABO blood group O 29 15.0 85,400 1.93 (1.29–2.77) 27 18.9 107,244 1.43 (0.94–2.08) 
ABO blood group non-O 
 Mutation positived 14 2.8 16,168 4.92 (2.69–8.26) 3.3 19,010 2.69 (1.23–5.11) 
 Mutation negative 46 23.3 132,612 1.97 (1.44–2.63) 40 29.5 167,739 1.35 (0.97–1.85) 
ABO blood group O 
 Mutation positived 1.0 5,949 3.82 (1.03–9.78) 1.3 7,352 2.32 (0.47–6.77) 
 Mutation negative 25 13.0 73,975 1.92 (1.24–2.83) 20 15.9 90,607 1.25 (0.77–1.94) 
Associations by FDRs' smoking status
Ever smokers (n = 9,167)Never smokers (n = 12,446)
Proband characteristicsaPC observed in FDR (N)PC expected in FDR (N)Person-years at riskSIR (95% CI)PC observed in FDR (N)PC expected in FDR (N)Person-years at riskSIR (95% CI)
ABO blood group A 41 20.9 118,857 1.96 (1.41–2.66) 41 26.6 151,205 1.54 (1.11–2.09) 
ABO blood group B/ABb 20 7.3 41,601 2.73 (1.67–4.22) 12 9.2 52,313 1.30 (0.67–2.28) 
ABO blood group non-Oc 61 28.2 160,458 2.16 (1.65–2.77) 53 35.8 203,518 1.48 (1.11–1.94) 
ABO blood group O 29 15.0 85,400 1.93 (1.29–2.77) 27 18.9 107,244 1.43 (0.94–2.08) 
ABO blood group non-O 
 Mutation positived 14 2.8 16,168 4.92 (2.69–8.26) 3.3 19,010 2.69 (1.23–5.11) 
 Mutation negative 46 23.3 132,612 1.97 (1.44–2.63) 40 29.5 167,739 1.35 (0.97–1.85) 
ABO blood group O 
 Mutation positived 1.0 5,949 3.82 (1.03–9.78) 1.3 7,352 2.32 (0.47–6.77) 
 Mutation negative 25 13.0 73,975 1.92 (1.24–2.83) 20 15.9 90,607 1.25 (0.77–1.94) 

Abbreviation: PC, pancreatic cancer.

aABO blood group was determined by combining serologic data with data on polymorphisms in the ABO locus known to encode ABO blood groups.

bBlood group B and AB were combined into one group because the polymorphisms used to infer blood group were able to detect the presence of blood group B, but could distinguish blood group AB from blood group B.

cNon-O blood group categorized by combining A, B, and AB into one group.

dProbands were categorized as mutation positive if they tested positive for one or more mutations in the following genes: APC, ATM, BARD1, BRCA1, BRCA2, BRIP1, CDH1, CDKN2A, CHEK2, EPCAM, MLH1, MSH2, MSH6, NBN, PALB2, PMS2, PTEN, RAD51C, RAD51D, and TP53; otherwise, the probands were categorized as mutation negative if they tested negative for all of the genes.

Additional analyses were performed by probands' blood group and combination of probands' ABO blood group and mutation status according to FDRs' kinship to the proband (Table 5). The results generally show higher pancreatic cancer risk among mothers of the FDRs, except that in probands with non-O blood group and were mutation-positive, fathers of the proband had substantially higher risk (SIR = 8.05; 95% CI = 4.15–14.06) than mothers (SIR = 4.09; 95% CI = 1.32–9.55) and siblings (SIR = 2.90; 95% CI = 1.32–5.50). Among FDRs of probands with blood group O and mutation-negative, a significant association was found among mothers of the proband (SIR = 23; 95% CI = 1.91–5.11) but no association was found among fathers or siblings (Table 5).

Table 5.

Risk for pancreatic cancer among FDRs of pancreatic cancer probands according to probands' ABO blood group and probands' germline susceptibility gene mutation status, stratified by kinship to the proband.

Mother (n = 3,268, from 3,268 pedigrees)Father (n = 3,268, from 3,268 pedigrees)Siblings (n = 9,619, from 2,987 pedigrees)
Proband characteristicsaPC observed in FDR (N)PC expected in FDR (N)Person-years at riskSIR (95% CI)PC observed in FDR (N)PC expected in FDR (N)Person-years at riskSIR (95% CI)PC observed in FDR (N)PC expected in FDR (N)Person-years at riskSIR (95% CI)
ABO blood group A 28 9.4 59,928 2.98 (1.98–4.30) 30 10.9 54,255 2.76 (1.86–3.95) 29 23.2 131,949 1.25 (0.84–1.79) 
ABO blood group B/ABb 10 3.1 19,865 3.21 (1.54–5.90) 16 3.6 18,240 4.39 (2.51–7.12) 11 8.2 46,629 1.34 (0.67–2.40) 
ABO blood group non-Oc 38 12.5 79,793 3.03 (2.15–4.16) 46 14.5 72,495 3.17 (2.32–4.23) 40 31.4 178,578 1.27 (0.91–1.73) 
ABO blood group O 20 6.5 41,619 3.06 (1.87–4.73) 12 7.7 38,573 1.56 (0.80–2.72) 25 16.6 94,520 1.50 (0.97–2.22) 
ABO blood group non-O 
 Mutation positived 1.2 7,784 4.09 (1.32–9.55) 12 1.5 7,455 8.05 (4.15–14.06) 3.1 17,653 2.90 (1.32–5.50) 
 Mutation negative 31 10.4 66,019 2.99 (2.03–4.25) 33 11.9 59,589 2.77 (1.91–3.89) 29 26.0 147,482 1.12 (0.75–1.60) 
ABO blood group O 
 Mutation positived 0.4 2,793 2.28 (0.03–12.69) 0.5 2,736 NE 1.1 6,515 4.36 (1.41–10.18) 
 Mutation negative 18 5.6 35,482 3.23 (1.91–5.11) 12 6.6 32,956 1.82 (0.94–3.18) 17 14 79,670 1.21 (0.71–1.94) 
Mother (n = 3,268, from 3,268 pedigrees)Father (n = 3,268, from 3,268 pedigrees)Siblings (n = 9,619, from 2,987 pedigrees)
Proband characteristicsaPC observed in FDR (N)PC expected in FDR (N)Person-years at riskSIR (95% CI)PC observed in FDR (N)PC expected in FDR (N)Person-years at riskSIR (95% CI)PC observed in FDR (N)PC expected in FDR (N)Person-years at riskSIR (95% CI)
ABO blood group A 28 9.4 59,928 2.98 (1.98–4.30) 30 10.9 54,255 2.76 (1.86–3.95) 29 23.2 131,949 1.25 (0.84–1.79) 
ABO blood group B/ABb 10 3.1 19,865 3.21 (1.54–5.90) 16 3.6 18,240 4.39 (2.51–7.12) 11 8.2 46,629 1.34 (0.67–2.40) 
ABO blood group non-Oc 38 12.5 79,793 3.03 (2.15–4.16) 46 14.5 72,495 3.17 (2.32–4.23) 40 31.4 178,578 1.27 (0.91–1.73) 
ABO blood group O 20 6.5 41,619 3.06 (1.87–4.73) 12 7.7 38,573 1.56 (0.80–2.72) 25 16.6 94,520 1.50 (0.97–2.22) 
ABO blood group non-O 
 Mutation positived 1.2 7,784 4.09 (1.32–9.55) 12 1.5 7,455 8.05 (4.15–14.06) 3.1 17,653 2.90 (1.32–5.50) 
 Mutation negative 31 10.4 66,019 2.99 (2.03–4.25) 33 11.9 59,589 2.77 (1.91–3.89) 29 26.0 147,482 1.12 (0.75–1.60) 
ABO blood group O 
 Mutation positived 0.4 2,793 2.28 (0.03–12.69) 0.5 2,736 NE 1.1 6,515 4.36 (1.41–10.18) 
 Mutation negative 18 5.6 35,482 3.23 (1.91–5.11) 12 6.6 32,956 1.82 (0.94–3.18) 17 14 79,670 1.21 (0.71–1.94) 

Abbreviation: PC, pancreatic cancer.

aABO blood group was determined by combining serologic data with data on polymorphisms in the ABO locus that are known to encode ABO blood group.

bBlood group B and AB were combined into one group because the polymorphisms used to infer blood group were able to detect the presence of blood group B, but could distinguish blood group AB from blood group B.

cNon-O blood group categorized by combining A, B, and AB into one group.

dProbands were categorized as mutation positive if they tested positive for one or more mutations in the following genes: APC, ATM, BARD1, BRCA1, BRCA2, BRIP1, CDH1, CDKN2A, CHEK2, EPCAM, MLH1, MSH2, MSH6, NBN, PALB2, PMS2, PTEN, RAD51C, RAD51D, and TP53; otherwise, the probands were categorized as mutation negative if they tested negative for all of the genes.

We investigated pancreatic cancer risk among 23,739 FDRs with 956,491 person-years at risk, identified through 3,268 pancreatic cancer probands who were recruited at Mayo Clinic. The results show a 2-fold higher than expected risk of pancreatic cancer among FDRs. By estimating FDRs' risk according to probands' ABO blood group, we found that the FDRs had higher than expected risk of pancreatic cancer regardless of the probands' blood group, and the magnitude of risk did not differ significantly among FDRs of probands with blood group O versus non-O. In separate analyses based on probands' cancer susceptibility gene mutation status, we found higher pancreatic cancer risk in both FDRs of mutation-positive probands and FDRs of mutation-negative probands, but the risk magnitude was significantly higher in FDRs of mutation-positive probands. We also found that FDRs' risk for pancreatic cancer was substantially and significantly higher when the related proband had a non-O blood group in addition to carrying at least one mutation in a cancer susceptibility gene than when the proband had a non-O blood group but did not carry a mutation in any of the genes tested. Further, we examined associations of two characteristics (sex and smoking status) of the FDRs in the context of the probands' genetic status and found that pancreatic cancer risks were higher in both male and female FDRs, although female FDRs had significantly higher magnitude of risk than male FDRs. FDRs who smoked also had significantly higher pancreatic cancer risk compared with FDRs who never smoked. FDRs who ever smoked and are related to mutation-positive probands with non-O blood group had highest pancreatic cancer risk (SIR = 4.92) compared with all subgroups of non-smokers. Collectively, the combination of a non-O blood group and presence of a cancer susceptibility gene mutation in a proband appears to contribute to pancreatic cancer risk among FDRs of the pancreatic cancer probands.

In a previous study involving fewer FDRs (n = 17,162) and an earlier version of SEER data (SEER 9, 1973–2013), we estimated a 2-fold higher risk of pancreatic cancer among FDRs of pancreatic cancer probands (7), which is consistent with the findings of the current study that is based on a much larger sample size and more recent SEER data with expanded number of cancer registries. Other studies have reported similarly higher risks of pancreatic cancer among FDRs of pancreatic cancer probands (42, 43). In this study, we found that female FDRs had significantly higher pancreatic cancer risk than male FDRs, as was observed previously (7), but the reasons are not clear and could be due to potential differences in the reporting of pancreatic cancer diagnosis by the probands for male versus female FDRs. We also previously estimated a 4.32 times higher pancreatic cancer risk among FDRs of probands who carry one or more mutations in cancer susceptibility genes (7), slightly higher than the present SIR estimate of 3.80 among FDRs of mutation-positive probands.

This is the first study to evaluate FDRs' risk of pancreatic cancer based on probands' ABO blood group and a combination of probands' ABO blood group and probands' cancer gene mutation status. While we did not find a significant difference in the magnitude of risk between FDRs of probands with O versus non-O blood group, both groups of FDRs had higher than expected risk when compared with the SEER population. Importantly, we found that FDRs of probands who had a non-O blood group and tested positive for cancer susceptibility gene mutation had a statistically significantly higher magnitude of pancreatic cancer risk (SIR = 3.98) than FDRs of probands with non-O blood group and tested negative for cancer gene mutation (SIR = 1.66). Among FDRs of probands with blood group O, risk estimates were generally lower and did not vary significantly by probands' mutation status. This supports the hypothesis that pancreatic cancer risk is often less in families with predominance of blood group O, over other ABO blood groups.

Although it is not entirely clear whether ABO blood group alone can be used as an independent indicator for predicting familial pancreatic cancer risk, we posit that a combination of familial aggregation of non-O blood groups with presence of germline mutation(s) in cancer susceptibility genes among family members could robustly predict familial pancreatic cancer risk. We previously demonstrated the role of germline mutations in pancreatic cancer susceptibility (38) and the utility of a proband's susceptibility gene mutation status to infer FDRs' risk for pancreatic cancer (7). Here, we add evidence that the presence of a non-O blood group in a proband in addition to germline mutation(s) in cancer susceptibility gene in the proband is strongly associated with pancreatic cancer risk among FDRs of the proband. This study demonstrates the importance of two discrete heritable factors in the familial aggregation of pancreatic cancer, which if confirmed by others, could guide genetic counseling considerations.

We also emphasize that in addition to heritability factors, shared environmental risk factors could contribute to the familial aggregation of pancreatic cancer. While heritable genetic factors are estimated to account for up to 10% of pancreatic cancer cases, cigarette smoking alone currently accounts for about 12% of pancreatic cancer cases (2, 44). We found that FDRs who smoked had substantially higher pancreatic cancer risk, particularly if they are related to a mutation-positive proband. Rulyak and colleagues have shown that smoking in an independent risk factor for pancreatic cancer in familial pancreatic cancer kindreds (45). In that study, smokers had a 3.7-fold higher risk of pancreatic cancer and were diagnosed with pancreatic cancer a decade earlier than nonsmoking family members (45). Otten and colleagues (46) and Gilman and colleagues (47) have both shown that parental smoking strongly influences smoking initiation by their offspring, which may partly explain the aggregation of smoking-related cancers, such as pancreatic cancer, in families. To a lesser extent, similar patterns could exist for other shared lifestyle factors, such as poor dietary habits or physical inactivity, both of which are associated with a higher risk of pancreatic cancer (2). This suggests a potential research direction that when combined with the risk factors we have examined here, nongenetic exposures of the FDRs may further enhance risk assessment.

Our study has several strengths and limitations. It is limited to a predominantly white population, which hinders ability to generalize broadly to minority populations. Diagnosis of pancreatic cancer among probands was determined histologically or radiologically, but such level of detail was not possible for the FDRs, and we relied on probands' report of pancreatic cancer diagnosis in an FDR. In our pancreas registry, we have found a 98% concordance between probands' report and FDRs' self-report of pancreatic cancer diagnosis (7), indicating that the probands' reports are highly reliable. We also did not have ABO blood group information for the FDRs. Furthermore, we genetically imputed ABO blood groups for some of the probands (45%) using tag SNPs in the ABO gene locus that have been shown to predict serologic ABO blood groups. The use of SNPs to determine blood groups is generally less granular than serotype-derived blood groups because of the possibility of measurement error. While the SNPs were able to identify the presence of the B ABO allele, they could not distinguish the B blood group from the AB blood group; therefore, we combined the B with the AB blood group for analyses to assess risk of pancreatic cancer in families of probands who carry the B allele. In addition, only 20 cancer susceptibility genes were assessed; hence, mutations in other cancer genes in the probands could have a modest effect due to misclassification. Some cells in the stratified analyses are small and those results need to be interpreted with caution. Strengths of the study include its uniquely large sample size and the use of a structured and comprehensive risk factor questionnaire that ensured uniform collection of family history data. Availability of data on probands' susceptibility gene mutation status and probands' ABO blood groups also add to the study strengths. Furthermore, this is the first study to estimate FDRs' risk of pancreatic cancer based on probands' ABO blood group (9, 13), providing suggestive evidence of pancreatic cancer risk based on familial aggregation of ABO blood group alleles.

In conclusion, we report a 2-fold higher risk of pancreatic among FDRs of pancreatic cancer probands compared with the SEER population. We also found that FDRs risk for pancreatic cancer is enhanced by the combined presence of non-O blood group and germline mutation(s) in cancer susceptibility genes in their respective proband, which could be useful for familial risk estimation and genetic counseling among relatives of pancreatic cancer probands. SIR for pancreatic cancer risk in FDRs ranged from as low as 1.48 for FDRs of probands with blood group O and mutation-negative to 3.98 for FDRs of probands with non-O blood group and mutation-positive.

S.O. Antwi reports grants from the National Cancer Institute during the conduct of the study. R.R. McWilliams reports grants from GSK, personal fees from NewLink Genetics and Zentalis Pharmaceuticals, and grants from Merck outside the submitted work. A.L. Oberg reports grants from NCI during the conduct of the study. No disclosures were reported by the other authors.

The data may be made available to researchers upon request to Dr. Gloria Petersen ([email protected]). Ethical and legal restrictions apply to these data.

S.O. Antwi: Funding acquisition, writing–original draft, project administration, writing–review and editing. K.G. Rabe: Resources, data curation, software, formal analysis, methodology, project administration, writing–review and editing. W.R. Bamlet: Resources, data curation, writing–review and editing. M. Meyer: Resources, data curation, writing–review and editing. S. Chandra: Writing–review and editing. S.E. Fagan: Resources, data curation, writing–review and editing. C. Hu: Resources, data curation, writing–review and editing. F.J. Couch: Resources, data curation, writing–review and editing. R.R. McWilliams: Writing–review and editing. A.L. Oberg: Resources, data curation, writing–review and editing. G.M. Petersen: Conceptualization, supervision, funding acquisition, methodology, writing–review and editing.

We thank the patients with pancreatic cancer and their families for their contributions that made this study possible. We also thank Christen Archer, Cassandra Bell, Bridget Rathbun, and Erin Carlson for their invaluable contributions to the study.

The study is supported by funding from the National Cancer Institute (P50 CA102701, U01 CA210138, R01 CA208517, R01 CA97075), Pancreatic Cancer Action Network, a Stand Up To Cancer-Lustgarten Foundation Pancreatic Cancer Interception Translational Cancer Research Grant (grant number: SU2C-AACR-DT25–17), and Centene Charitable Foundation to G.M. Petersen, and National Cancer Institute (K01 CA237875) to S.O. Antwi. Stand Up To Cancer is a division of the Entertainment Industry Foundation. The indicated SU2C research grant is administered by the American Association for Cancer Research, the scientific partner of SU2C.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

1.
American Cancer Society
.
Cancer facts & figures 2021
.
Atlanta, GA
:
American Cancer Society
; 
2021
.
2.
Antwi
SO
,
Jansen
RJ
,
Petersen
GM
. 
Cancer of the pancreas
.
Schottenfeld and Fraumeni Cancer Epidemiology and Prevention, Fourth Edition
:
Oxford University Press
; 
2017
.
p.
611
34
.
3.
Li
D
,
Xie
K
,
Wolff
R
,
Abbruzzese
JL
. 
Pancreatic cancer
.
Lancet
2004
;
363
:
1049
57
.
4.
Antwi
SO
,
Oberg
AL
,
Shivappa
N
,
Bamlet
WR
,
Chaffee
KG
,
Steck
SE
, et al
Pancreatic cancer: associations of inflammatory potential of diet, cigarette smoking and long-standing diabetes
.
Carcinogenesis
2016
;
37
:
481
90
.
5.
Malats
N
. 
Gene-environment interactions in pancreatic cancer
.
Pancreatology
2001
;
1
:
472
6
.
6.
McWilliams
RR
,
Maisonneuve
P
,
Bamlet
WR
,
Petersen
GM
,
Li
D
,
Risch
H
, et al
Risk factors for early-onset and very-early-onset pancreatic adenocarcinoma: a pancreatic cancer case-control consortium (PanC4) analysis
.
Pancreas
2016
;
45
:
311
.
7.
Antwi
SO
,
Fagan
SE
,
Chaffee
KG
,
Bamlet
WR
,
Hu
C
,
Polley
EC
, et al
Risk of different cancers among first-degree relatives of pancreatic cancer patients: influence of probands' susceptibility gene mutation status
.
J Natl Cancer Inst
2019
;
111
:
264
71
.
8.
Wolpin
BM
,
Kraft
P
,
Gross
M
,
Helzlsouer
K
,
Bueno-de-Mesquita
HB
,
Steplowski
E
, et al
Pancreatic cancer risk and ABO blood group alleles: results from the pancreatic cancer cohort consortium
.
Cancer Res
2010
;
70
:
1015
23
.
9.
Wolpin
BM
,
Chan
AT
,
Hartge
P
,
Chanock
SJ
,
Kraft
P
,
Hunter
DJ
, et al
ABO blood group and the risk of pancreatic cancer
.
J Natl Cancer Inst
2009
;
101
:
424
31
.
10.
Risch
HA
,
Lu
L
,
Wang
J
,
Zhang
W
,
Ni
Q
,
Gao
YT
, et al
ABO blood group and risk of pancreatic cancer: a study in Shanghai and meta-analysis
.
Am J Epidemiol
2013
;
177
:
1326
37
.
11.
Antwi
SO
,
Bamlet
WR
,
Pedersen
KS
,
Chaffee
KG
,
Risch
HA
,
Shivappa
N
, et al
Pancreatic cancer risk is modulated by inflammatory potential of diet and ABO genotype: a consortia-based evaluation and replication study
.
Carcinogenesis
2018
;
39
:
1056
67
.
12.
Storry
JR
,
Olsson
ML
. 
The ABO blood group system revisited: a review and update
.
Immunohematology
2009
;
25
:
48
59
.
13.
Yip
SP
. 
Sequence variation at the human ABO locus
.
Ann Hum Genet
2002
;
66
:
1
27
.
14.
Yamamoto
F
,
Clausen
H
,
White
T
,
Marken
J
,
Hakomori
S
. 
Molecular genetic basis of the histo-blood group ABO system
.
Nature
1990
;
345
:
229
33
.
15.
Petersen
GM
,
Amundadottir
L
,
Fuchs
CS
,
Kraft
P
,
Stolzenberg-Solomon
RZ
,
Jacobs
KB
, et al
A genome-wide association study identifies pancreatic cancer susceptibility loci on chromosomes 13q22.1, 1q32.1 and 5p15.33
.
Nat Genet
2010
;
42
:
224
8
.
16.
Nakao
M
,
Matsuo
K
,
Hosono
S
,
Ogata
S
,
Ito
H
,
Watanabe
M
, et al
ABO blood group alleles and the risk of pancreatic cancer in a Japanese population
.
Cancer Sci
2011
;
102
:
1076
80
.
17.
Cooling
L
. 
Blood groups in infection and host susceptibility
.
Clin Microbiol Rev
2015
;
28
:
801
70
.
18.
Moran
AP
,
Gupta
A
,
Joshi
L
. 
Sweet-talk: role of host glycosylation in bacterial pathogenesis of the gastrointestinal tract
.
Gut
2011
;
60
:
1412
25
.
19.
Hakomori
S
. 
Antigen structure and genetic basis of histo-blood groups A, B and O: their changes associated with human cancer
.
Biochim Biophys Acta
1999
;
1473
:
247
66
.
20.
Paré
G
,
Chasman
DI
,
Kellogg
M
,
Zee
RY
,
Rifai
N
,
Badola
S
, et al
Novel association of ABO histo-blood group antigen with soluble ICAM-1: results of a genome-wide association study of 6,578 women
.
PLoS Genet
2008
;
4
:
e1000118
.
21.
Melzer
D
,
Perry
JR
,
Hernandez
D
,
Corsi
AM
,
Stevens
K
,
Rafferty
I
, et al
A genome-wide association study identifies protein quantitative trait loci (pQTLs)
.
PLoS Genet
2008
;
4
:
e1000072
.
22.
Paterson
AD
,
Lopes-Virella
MF
,
Waggott
D
,
Boright
AP
,
Hosseini
SM
,
Carter
RE
, et al
Genome-wide association identifies the ABO blood group as a major locus associated with serum levels of soluble E-selectin
.
Arterioscler Thromb Vasc Biol
2009
;
29
:
1958
67
.
23.
Greer
JB
,
Whitcomb
DC
. 
Inflammation and pancreatic cancer: an evidence-based review
.
Curr Opin Pharmacol
2009
;
9
:
411
8
.
24.
Tempia-Caliera
AA
,
Horvath
LZ
,
Zimmermann
A
,
Tihanyi
TT
,
Korc
M
,
Friess
H
, et al
Adhesion molecules in human pancreatic cancer
.
J Surg Oncol
2002
;
79
:
93
100
.
25.
Risch
HA
,
Yu
H
,
Lu
L
,
Kidd
MS
. 
ABO blood group, Helicobacter pylori seropositivity, and risk of pancreatic cancer: a case-control study
.
J Natl Cancer Inst
2010
;
102
:
502
5
.
26.
Le Pendu
J
,
Marionneau
S
,
Cailleau-Thomas
A
,
Rocher
J
,
Le Moullac-Vaidye
B
,
Clément
M
. 
ABH and Lewis histo-blood group antigens in cancer
.
APMIS
2001
;
109
:
9
31
.
27.
Gronwald
J
,
Cybulski
C
,
Piesiak
W
,
Suchy
J
,
Huzarski
T
,
Byrski
T
, et al
Cancer risks in first-degree relatives of CHEK2 mutation carriers: effects of mutation type and cancer site in proband
.
Br J Cancer
2009
;
100
:
1508
12
.
28.
Mukherjee
B
,
Delancey
JO
,
Raskin
L
,
Everett
J
,
Jeter
J
,
Begg
CB
, et al
Risk of non-melanoma cancers in first-degree relatives of CDKN2A mutation carriers
.
J Natl Cancer Inst
2012
;
104
:
953
6
.
29.
Jenkins
MA
,
Baglietto
L
,
Dowty
JG
,
Van Vliet
CM
,
Smith
L
,
Mead
LJ
, et al
Cancer risks for mismatch repair gene mutation carriers: a population-based early onset case-family study
.
Clin Gastroenterol Hepatol
2006
;
4
:
489
98
.
30.
National Cancer Institute Database SRP
,
Cancer Statistics Branch
. 
Surveillance, Epidemiology, and End Results (SEER) Program SEER*Stat Database: Incidence -SEER 9 Regs Public-Use
.
Available from
: www.seer.cancer.gov. 
2021
.
31.
Antwi
SO
,
Bamlet
WR
,
Rabe
KG
,
Cawthon
RM
,
Umudi
I
,
Druliner
BR
, et al
Leukocyte telomere length and its interaction with germline variation in telomere-related genes in relation to pancreatic adenocarcinoma risk
.
Cancer Epidemiol Biomarkers Prev
2020
;
29
:
1492
500
.
32.
Antwi
SO
,
Bamlet
WR
,
Cawthon
RM
,
Rabe
KG
,
Druliner
BR
,
Sicotte
H
, et al
Shorter treatment-naïve leukocyte telomere length is associated with poorer overall survival of patients with pancreatic ductal adenocarcinoma
.
Cancer Epidemiol Biomarkers Prev
2021
;
30
:
210
6
.
33.
Doll
KM
,
Rademaker
A
,
Sosa
JA
. 
Practical guide to surgical data sets: Surveillance, Epidemiology, and End Results (SEER) Database
.
JAMA Surg
2018
;
153
:
588
9
.
34.
Zhao
SX
,
Xue
LQ
,
Liu
W
,
Gu
ZH
,
Pan
CM
,
Yang
SY
, et al
Robust evidence for five new Graves' disease risk loci from a staged genome-wide association analysis
.
Hum Mol Genet
2013
;
22
:
3347
62
.
35.
Amundadottir
L
,
Kraft
P
,
Stolzenberg-Solomon
RZ
,
Fuchs
CS
,
Petersen
GM
,
Arslan
AA
, et al
Genome-wide association study identifies variants in the ABO locus associated with susceptibility to pancreatic cancer
.
Nat Genet
2009
;
41
:
986
90
.
36.
Childs
EJ
,
Mocci
E
,
Campa
D
,
Bracci
PM
,
Gallinger
S
,
Goggins
M
, et al
Common variation at 2p13.3, 3q29, 7p13 and 17q25.1 associated with susceptibility to pancreatic cancer
.
Nat Genet
2015
;
47
:
911
6
.
37.
Xu
Z
,
Taylor
JA
. 
SNPinfo: integrating GWAS and candidate gene information into functional SNP selection for genetic association studies
.
Nucleic Acids Res
2009
;
37
:
W600
5
.
38.
Hu
C
,
Hart
SN
,
Polley
EC
,
Gnanaolivu
R
,
Shimelis
H
,
Lee
KY
, et al
Association between inherited germline mutations in cancer predisposition genes and risk of pancreatic cancer
.
JAMA
2018
;
319
:
2401
9
.
39.
Fahed
AC
,
Wang
M
,
Homburger
JR
,
Patel
AP
,
Bick
AG
,
Neben
CL
, et al
Polygenic background modifies penetrance of monogenic variants for tier 1 genomic conditions
.
Nat Commun
2020
;
11
:
3635
.
40.
Barrett
R
,
Neben
CL
,
Zimmer
AD
,
Mishne
G
,
McKennon
W
,
Zhou
AY
, et al
A scalable, aggregated genotypic-phenotypic database for human disease variation
.
Database
2019
;
2019
:
baz013
.
41.
Altman
D
,
Machin
D
,
Bryant
T
,
Gardner
M
.
Statistics with confidence: confidence intervals and statistical guidelines
.
John Wiley & Sons
; 
2013
.
42.
Permuth-Wey
J
,
Egan
KM
. 
Family history is a significant risk factor for pancreatic cancer: results from a systematic review and meta-analysis
.
Fam Cancer
2009
;
8
:
109
17
.
43.
Lynch
HT
,
Smyrk
T
,
Kern
SE
,
Hruban
RH
,
Lightdale
CJ
,
Lemon
SJ
, et al
Familial pancreatic cancer: a review
.
Semin Oncol
1996
;
23
:
251
75
.
44.
Siegel
RL
,
Jacobs
EJ
,
Newton
CC
,
Feskanich
D
,
Freedman
ND
,
Prentice
RL
, et al
Deaths due to cigarette smoking for 12 smoking-related cancers in the United States
.
JAMA Intern Med
2015
;
175
:
1574
6
.
45.
Rulyak
SJ
,
Lowenfels
AB
,
Maisonneuve
P
,
Brentnall
TA
. 
Risk factors for the development of pancreatic cancer in familial pancreatic cancer kindreds
.
Gastroenterology
2003
;
124
:
1292
9
.
46.
Otten
R
,
Engels
RC
,
van de Ven
MO
,
Bricker
JB
. 
Parental smoking and adolescent smoking stages: the role of parents' current and former smoking, and family structure
.
J Behav Med
2007
;
30
:
143
54
.
47.
Gilman
SE
,
Rende
R
,
Boergers
J
,
Abrams
DB
,
Buka
SL
,
Clark
MA
, et al
Parental smoking and adolescent smoking initiation: an intergenerational perspective on tobacco control
.
Pediatrics
2009
;
123
:
e274
81
.