Abstract
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.
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).
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).
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.
Combined ABO blood group and germline mutation status of probands can inform pancreatic cancer risk estimation in FDRs.
Introduction
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.
Materials and Methods
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.
Results
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%).
Patient characteristics . | N = 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 | 4 |
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 characteristics . | N = 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 | 4 |
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).
Study sample . | Probands (N) . | FDRs (N) . | Person-years at risk . | PC observed in FDR (N) . | PC expected in FDR (N) . | SIR (95% CI)a . | P 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 sample . | Probands (N) . | FDRs (N) . | Person-years at risk . | PC observed in FDR (N) . | PC expected in FDR (N) . | SIR (95% CI)a . | P 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).
Proband characteristicsa . | Probands (N) . | FDRs (N) . | Person-years at risk . | PC 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 | 7 | 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 characteristicsa . | Probands (N) . | FDRs (N) . | Person-years at risk . | PC 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 | 7 | 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.
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).
Associations by FDRs' sex . | ||||||||
---|---|---|---|---|---|---|---|---|
. | Male FDRs (n = 12,052) . | Female FDRs (n = 11,687) . | ||||||
Proband characteristicsa . | PC observed in FDR (N) . | PC expected in FDR (N) . | Person-years at risk . | SIR (95% CI) . | PC observed in FDR (N) . | PC expected in FDR (N) . | Person-years at risk . | SIR (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 | 3 | 1.4 | 7,200 | 2.08 (0.42–6.09) | 4 | 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 characteristicsa . | PC observed in FDR (N) . | PC expected in FDR (N) . | Person-years at risk . | SIR (95% CI) . | PC observed in FDR (N) . | PC expected in FDR (N) . | Person-years at risk . | SIR (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 | 3 | 1.4 | 7,200 | 2.08 (0.42–6.09) | 4 | 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 characteristicsa . | PC observed in FDR (N) . | PC expected in FDR (N) . | Person-years at risk . | SIR (95% CI) . | PC observed in FDR (N) . | PC expected in FDR (N) . | Person-years at risk . | SIR (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) | 9 | 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 | 4 | 1.0 | 5,949 | 3.82 (1.03–9.78) | 3 | 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 characteristicsa . | PC observed in FDR (N) . | PC expected in FDR (N) . | Person-years at risk . | SIR (95% CI) . | PC observed in FDR (N) . | PC expected in FDR (N) . | Person-years at risk . | SIR (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) | 9 | 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 | 4 | 1.0 | 5,949 | 3.82 (1.03–9.78) | 3 | 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).
. | 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 characteristicsa . | PC observed in FDR (N) . | PC expected in FDR (N) . | Person-years at risk . | SIR (95% CI) . | PC observed in FDR (N) . | PC expected in FDR (N) . | Person-years at risk . | SIR (95% CI) . | PC observed in FDR (N) . | PC expected in FDR (N) . | Person-years at risk . | SIR (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 | 5 | 1.2 | 7,784 | 4.09 (1.32–9.55) | 12 | 1.5 | 7,455 | 8.05 (4.15–14.06) | 9 | 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 | 1 | 0.4 | 2,793 | 2.28 (0.03–12.69) | 0 | 0.5 | 2,736 | NE | 5 | 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 characteristicsa . | PC observed in FDR (N) . | PC expected in FDR (N) . | Person-years at risk . | SIR (95% CI) . | PC observed in FDR (N) . | PC expected in FDR (N) . | Person-years at risk . | SIR (95% CI) . | PC observed in FDR (N) . | PC expected in FDR (N) . | Person-years at risk . | SIR (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 | 5 | 1.2 | 7,784 | 4.09 (1.32–9.55) | 12 | 1.5 | 7,455 | 8.05 (4.15–14.06) | 9 | 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 | 1 | 0.4 | 2,793 | 2.28 (0.03–12.69) | 0 | 0.5 | 2,736 | NE | 5 | 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.
Discussion
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.
Authors' Disclosures
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.
Data Availability Statement
The data may be made available to researchers upon request to Dr. Gloria Petersen ([email protected]). Ethical and legal restrictions apply to these data.
Authors' Contributions
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.
Acknowledgments
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.