Dennis P. Robinson

Aspirin, Nonsteroidal Anti-inflammatory Drugs, Acetaminophen, and Pancreatic Cancer Risk: a Clinic-Based Case–Control Study

Aspirin and other nonsteroidal anti-inflammatory drugs (NSAID) show indisputable promise as cancer chemoprevention agents. However, studies have been inconsistent as to whether aspirin has a protective effect in development of pancreatic cancer. To further evaluate the association between aspirin, NSAID, and acetaminophen use with pancreatic cancer risk, we used a clinic-based case–control study of 904 rapidly ascertained histologically or clinically documented pancreatic ductal adenocarcinoma cases, and 1,224 age- and sex-matched healthy controls evaluated at Mayo Clinic from April 2004 to September 2010. Overall, there is no relationship between non-aspirin NSAID or acetaminophen use and risk of pancreatic cancer. Aspirin use for 1 d/mo or greater was associated with a significantly decreased risk of pancreatic cancer (OR = 0.74, 95% CI: 0.60–0.91, P = 0.005) compared with never or less than 1 d/mo. Analysis by frequency and frequency-dosage of use categories showed reduced risk (P = 0.007 and 0.022, respectively). This inverse association was also found for those who took low-dose aspirin for heart disease prevention (OR = 0.67, 95% CI: 0.49–0.92, P = 0.013). In subgroup analyses, the association between aspirin use and pancreatic cancer was not significantly affected by pancreatic cancer stage, smoking status, or body mass index. Our data suggest that aspirin use, but not non-aspirin NSAID use, is associated with lowered risk of developing pancreatic cancer. Cancer Prev Res; 4(11); 1835–41. ©2011 AACR.

Rationale and Design of the International Lymphoma Epidemiology Consortium (InterLymph) Non-Hodgkin Lymphoma Subtypes Project

BACKGROUND Non-Hodgkin lymphoma (NHL), the most common hematologic malignancy, consists of numerous subtypes. The etiology of NHL is incompletely understood, and increasing evidence suggests that risk factors may vary by NHL subtype. However, small numbers of cases have made investigation of subtype-specific risks challenging. The International Lymphoma Epidemiology Consortium therefore undertook the NHL Subtypes Project, an international collaborative effort to investigate the etiologies of NHL subtypes. This article describes in detail the project rationale and design. METHODS We pooled individual-level data from 20 case-control studies (17471 NHL cases, 23096 controls) from North America, Europe, and Australia. Centralized data harmonization and analysis ensured standardized definitions and approaches, with rigorous quality control. RESULTS The pooled study population included 11 specified NHL subtypes with more than 100 cases: diffuse large B-cell lymphoma (N = 4667), follicular lymphoma (N = 3530), chronic lymphocytic leukemia/small lymphocytic lymphoma (N = 2440), marginal zone lymphoma (N = 1052), peripheral T-cell lymphoma (N = 584), mantle cell lymphoma (N = 557), lymphoplasmacytic lymphoma/Waldenström macroglobulinemia (N = 374), mycosis fungoides/Sézary syndrome (N = 324), Burkitt/Burkitt-like lymphoma/leukemia (N = 295), hairy cell leukemia (N = 154), and acute lymphoblastic leukemia/lymphoma (N = 152). Associations with medical history, family history, lifestyle factors, and occupation for each of these 11 subtypes are presented in separate articles in this issue, with a final article quantitatively comparing risk factor patterns among subtypes. CONCLUSIONS The International Lymphoma Epidemiology Consortium NHL Subtypes Project provides the largest and most comprehensive investigation of potential risk factors for a broad range of common and rare NHL subtypes to date. The analyses contribute to our understanding of the multifactorial nature of NHL subtype etiologies, motivate hypothesis-driven prospective investigations, provide clues for prevention, and exemplify the benefits of international consortial collaboration in cancer epidemiology.

Fatty acids found in dairy, protein and unsaturated fatty acids are associated with risk of pancreatic cancer in a case–control study

Although many studies have investigated meat and total fat in relation to pancreatic cancer risk, few have investigated dairy, fish and specific fatty acids (FAs). We evaluated the association between intake of meat, fish, dairy, specific FAs and related nutrients and pancreatic cancer. In our American‐based Mayo Clinic case–control study 384 cases and 983 controls frequency matched on recruitment age, race, sex and residence area (Minnesota, Wisconsin or Iowa, USA) between 2004 and 2009. All subjects provided demographic information and completed 144‐item food frequency questionnaire. Logistic regression‐calculated odds ratios (ORs) and 95% confidence intervals (95% CIs) were adjusted for age, sex, cigarette smoking, body mass index and diabetes mellitus. Significant inverse association (trend p‐value < 0.05) between pancreatic cancer and the groupings (highest vs. lowest consumption quintile OR [95% CI]) was as follows: meat replacement (0.67 [0.43–1.02]), total protein (0.58 [0.39–0.86]), vitamin B12 (0.67 [0.44, 1.01]), zinc (0.48 [0.32, 0.71]), phosphorus (0.62 [0.41, 0.93]), vitamin E (0.51 [0.33, 0.78]), polyunsaturated FAs (0.64 [0.42, 0.98]) and linoleic acid (FA 18:2) (0.62 [0.40–0.95]). Increased risk associations were observed for saturated FAs (1.48 [0.97–2.23]), butyric acid (FA 4:0) (1.77 [1.19–2.64]), caproic acid (FA 6:0) (2.15 [1.42–3.27]), caprylic acid (FA 8:0) (1.87 [1.27–2.76]) and capric acid (FA 10:0) (1.83 [1.23–2.74]). Our study suggests that eating a diet high in total protein and certain unsaturated FAs is associated with decreased risk of developing pancreatic cancer in a dose‐dependent manner, whereas fats found in dairy increase risk.

Meat-Related Mutagens and Pancreatic Cancer: Null Results from a Clinic-Based Case–Control Study

Background: Pancreatic cancer is a devastating disease for which the role of dietary factors remains inconclusive. The study objective was to evaluate risk of pancreatic cancer associated with meat preparation methods and meat-related mutagen consumption using a clinic-based case–control design. Methods: There were 384 cases and 983 controls; subjects provided demographic information and completed a 144-item food frequency questionnaire, which was used to estimate meat mutagen intake using the National Cancer Institutes CHARRED database (Bethesda, MD). Logistic regression was used to calculate ORs and 95% confidence intervals (CI), adjusted for factors including age, sex, cigarette smoking, body mass index, and diabetes mellitus. Results: Overall, the findings were null with respect to meat mutagen intake and pancreatic cancer. Conclusions: The results do not support an association between well-done meat or meat-related mutagen intake and pancreatic cancer and contrast with generally increased risks reported in previous studies. Impact: These data contribute to evidence about pancreatic cancer and potentially carcinogenic compounds in meat. Cancer Epidemiol Biomarkers Prev; 22(7); 1336–9. ©2013 AACR.

Polymorphisms in metabolism/antioxidant genes may mediate the effect of dietary intake on pancreatic cancer risk.

Objectives A source of variation for inconsistent dietary-pancreatic cancer associations may be individuals carrying constitutional metabolism/antioxidant gene variants that differentially benefit compared to homozygous individuals. Seventy-six tag single-nucleotide polymorphisms were genotyped in 13 candidate genes to test differential associations with pancreatic adenocarcinoma. Methods A clinic-based case-control design was used to rapidly ascertain 251 cases and 970 frequency matched controls who provided blood samples and completed a 144-item food frequency questionnaire. Single-nucleotide polymorphisms were evaluated using a dominant genetic model and dietary categories split on controls’ median intake. Logistic regression was used to calculate odds ratios and 95% confidence intervals, adjusted for potential confounders. Results Significant increased associations (Bonferroni corrected P ⩽ 0.0007) were observed for carriers of greater than or equal to 1 minor allele for rs3816257 (glucosidase, &agr;; acid [GAA]) and lower intake of deep-yellow vegetables (1.90 [1.28-2.83]); and carriers of no minor allele for rs12807961 (catalase [CAT]) and high total grains intake (2.48 [1.50–4.09]), whereas those with greater than or equal to 1 minor allele had a decreasing slope (across grains). The reference group was no minor alleles with low dietary intake. Conclusions Interindividual variation in metabolism/antioxidant genes could interact with dietary intake to influence pancreatic cancer risk.

Association of polygenic risk score with the risk of chronic lymphocytic leukemia and monoclonal B-cell lymphocytosis

Inherited loci have been found to be associated with risk of chronic lymphocytic leukemia (CLL). A combined polygenic risk score (PRS) of representative single nucleotide polymorphisms (SNPs) from these loci may improve risk prediction over individual SNPs. Herein, we evaluated the association of a PRS with CLL risk and its precursor, monoclonal B-cell lymphocytosis (MBL). We assessed its validity and discriminative ability in an independent sample and evaluated effect modification and confounding by family history (FH) of hematological cancers. For discovery, we pooled genotype data on 41 representative SNPs from 1499 CLL and 2459 controls from the InterLymph Consortium. For validation, we used data from 1267 controls from Mayo Clinic and 201 CLL, 95 MBL, and 144 controls with a FH of CLL from the Genetic Epidemiology of CLL Consortium. We used odds ratios (ORs) to estimate disease associations with PRS and c-statistics to assess discriminatory accuracy. In InterLymph, the continuous PRS was strongly associated with CLL risk (OR, 2.49; P = 4.4 × 10-94). We replicated these findings in the Genetic Epidemiology of CLL Consortium and Mayo controls (OR, 3.02; P = 7.8 × 10-30) and observed high discrimination (c-statistic = 0.78). When jointly modeled with FH, PRS retained its significance, along with FH status. Finally, we found a highly significant association of the continuous PRS with MBL risk (OR, 2.81; P = 9.8 × 10-16). In conclusion, our validated PRS was strongly associated with CLL risk, adding information beyond FH. The PRS provides a means of identifying those individuals at greater risk for CLL as well as those at increased risk of MBL, a condition that has potential clinical impact beyond CLL.

Abstract PR03: Association of environmental risk factors, family history, and polygenic risk scores with chronic lymphocytic leukemia

Background: Chronic lymphocytic leukemia (CLL) is a lymphoid malignancy with a strong genetic component. There are over 30 common single nucleotide polymorphisms (SNPs) associated with the risk of CLL. Moreover, in the InterLymph Subtypes Project a number of non-genetic exposures have been found to be associated with CLL, including family history (FH), height, history of atopic conditions, UV radiation, and farming exposures. However there has not been a study evaluating the joint effects among these genetic and non-genetic factors with CLL risk. Methods: Using the Mayo Clinic CLL case-control study of 587 newly diagnosed CLL cases and 790 controls, we performed analyses evaluating joint effects of genetic and non-genetic factors. For genetic effects, we computed a polygenetic risk score (PRS), a weighted averaged of the number of risk alleles across 34 SNPs, with the weights being the log of the odds ratio for each SNP. Exposure data was available for 65% of the cases and 79% of the controls. We evaluated individual and joint associations of FH of any hematological malignancy, total sun exposure categorized by quartiles based on the controls, ever living or working on a farm, any atopy, any allergies, asthma, height, and PRSs categorized by quintiles based on the controls. Multivariate logistic regression analyses were used to estimate odds ratios (ORs) and 95% confidence intervals (CIs). Results: In our preliminary results, the frequency of CLL cases in the upper PRS quintile was 49% while in the lowest quintile only 5%. The PRS has a strong evidence of association with CLL (OR= 3.04, CI =2.20-4.20 for highest versus the middle quintile). When adjusting for PRS, we still found a positive association with FH for any hematological malignancy (OR = 1.90, CI = 1.25-2.88), FH of non-Hodgkin lymphoma (OR = 2.02, CI = 1.08-3.79), and FH of leukemia (OR = 1.73, CI = 0.98-3.07). When stratifying by FH, the upper quintile of the PRS had a 5.85-fold (CI = 1.69-20.3) increased risk of CLL relative to those in the middle quintile in the FH strata, and a 2.65-fold (CI = 1.75-4.01) increased risk in the non-FH strata. After adjusting for PRS, FH and age, there remained an inverse association with sun exposure in the highest quartile (hours per week) (OR = 0.49, CI = 0.31-0.79) and a positive association with height (per 10 cm change) (OR = 1.37, CI = 1.17-1.62), but there were no associations with atopy, any allergies, history of asthma, or farming. No statistical evidence of an interaction among the variables was observed. Conclusions: We found evidence of independent effects among the genetic and non-genetic factors with risk of CLL. Among these factors, the PRS had the largest effect size. Although we did not observe any statistical interactions, larger sample sizes are warranted to fully evaluate these effects on risk of CLL. We are currently increasing our sample size through collaboration with other research groups. Final results will be presented in the meeting. This abstract is also being presented as Poster A06. Citation Format: Geffen Kleinstern, Dennis Robinson, Tim G. Call, Mark Liebow, Silvia de Sanjose, Yolanda Benavente, James R. Cerhan, Susan L. Slager. Association of environmental risk factors, family history, and polygenic risk scores with chronic lymphocytic leukemia. [abstract]. In: Proceedings of the AACR Special Conference: Improving Cancer Risk Prediction for Prevention and Early Detection; Nov 16-19, 2016; Orlando, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2017;26(5 Suppl):Abstract nr PR03.

Abstract 3749: Polymorphisms in metabolism genes may mediate the effect of dietary intake on pancreatic cancer risk

Proceedings: AACR 102nd Annual Meeting 2011‐‐ Apr 2‐6, 2011; Orlando, FL Background: The role of dietary fruit, vegetable, fiber, and whole grain intake is implicated as a potential protective factor against pancreatic cancer, but studies are inconsistent. A possible explanation for the variability is that individuals who carry constitutional metabolism gene variants (minor alleles) may differentially benefit compared to those who are homozygous for the major allele, which over a life-time could lead to altered pancreatic cancer risk. Methods: We genotyped 70 SNPs that tag ten candidate metabolism genes (CAT, GAA, GCK, MT1E, UGT1A6, UGT1A7, UGT1A8, UGT1A9, UGT2B4, and UGT2B7) involved in the metabolism of components of fruits, vegetables, fibers, and whole grains to test if differential associations exist with pancreatic adenocarcinoma. We used a clinic-based case-control design, excluding participants who reported changing their diet within 5 years prior to entering the study. Three hundred eighty-four rapidly ascertained cases and nine hundred eighty-three non-cases from a primary care clinic (frequency matched on age at recruitment (+ 5 years), race, sex, and region of residence) provided blood samples for DNA and completed epidemiologic surveys plus a 144-item food frequency questionnaire developed by the National Cancer Institute. We used a dominant model to code SNPs and split dietary intake categories based on the sex-specific median intake level among non-cases. Logistic regression was used to calculate odds ratios (OR) and 95% confidence intervals, adjusted for age, sex, family-history of pancreatic cancer, smoking (never/ former/ current), body mass index, energy intake, and alcohol consumption. The reference group was defined as carriers of no minor alleles in the lowest intake category. Results: The greatest benefit was observed for carriers of no minor alleles, for rs11032702 (CAT) with higher insoluble dietary fiber intake (OR [95%CI]: 0.515 [0.37, 0.71]); for [rs735670][1] (GCK) with higher soluble dietary intake (0.473 [0.34, 0.67]); for rs2070971 (GCK) and rs2268569 (GCK) with higher fruit intake not from citrus, melon, and berries (0.513 [0.36, 0.73] and 0.554 [0.40, 0.78]); and for rs17832252 (GCK) with higher whole grain intake (0.530 [0.37, 0.76]); all comparisons had a reference group of no minor alleles with low dietary intake and a p-value for interaction <0.001. Conclusions: Inter-individual variation in metabolism of fruits, vegetables, fiber, and whole grain via metabolism gene variants may influence pancreatic cancer risk. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3749. doi:10.1158/1538-7445.AM2011-3749 [1]: /lookup/external-ref?link_type=GEN&access_num=rs735670&atom=%2Fcanres%2F71%2F8_Supplement%2F3749.atom

Abstract 1902: Aspirin, nonsteroidal antiinflammatory drugs (NSAIDs) acetaminophen and risk of pancreatic cancer

Proceedings: AACR 102nd Annual Meeting 2011‐‐ Apr 2‐6, 2011; Orlando, FL Background: Aspirin and nonsteroidal antiinflammatory drugs (NSAIDs) show indisputable promise as cancer chemoprevention agents. While aspirin and NSAID use have been suggested to lower risk of developing pancreatic cancer, the results of several epidemiological studies are not in consensus. Methods: Using a case-control design, we examined the association between aspirin, NSAID and acetaminophen use and the risk of pancreatic cancer. We enrolled 904 histological or clinically documented pancreatic ductal adenocarcinoma cases, and 1,223 age and gender matched healthy clinic-based controls evaluated at Mayo Clinic from April 2004 and September 2010. All subjects were ≥ 55 years old and self-reported by questionnaire their use of aspirin, NSAIDs, and acetaminophen at ages 41-60, along with extensive epidemiologic and demographic information. Multivariate logistic regression analysis was used to estimate risk of pancreatic cancer after adjusting for potential confounders. Results: The use of aspirin was associated with a decreased risk of pancreatic cancer. The unadjusted odds ratio (OR) associated with aspirin use ≥ 1 day/month, compared with never or < 1 day/month, was 0.79 [95% confidence interval (CI) 0.65. 0.96, p = 0.015]. This effect remained significant [OR 0.71, 95% CI 0.58,0.87, p = 0.0008], after adjusting for the potential confounders of body mass index and smoking status (never, former, current). The inverse relationship was stronger among former smokers (OR 0.61, 95% CI 0.46, 0.82, p =0.0008) than never and current smokers, although there was not a statistically significant interaction (Pintereaction = 0.333). NSAID and acetaminophen use was not associated with the risk of pancreatic cancer. Conclusions: Results from this large case-control study suggest that aspirin use, but not non-aspirin NSAID use, was associated with lower risk of developing pancreatic cancer and was more pronounced among former smokers than never and current smokers. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1902. doi:10.1158/1538-7445.AM2011-1902

Abstract A85: Fruit and vegetable consumption reduces the risk of pancreatic cancer

Pancreatic cancer is a devastating disease for which the role of dietary risk factors remains inconclusive. We evaluated fruit, vegetable, fiber, and grain consumption with pancreatic cancer risk using a clinic-based case-control design, excluding participants who reported changing their diet within 5 years prior to entering the study. Our study included 384 rapidly ascertained cases and 983 non-cases (frequency matched on age at time of recruitment (± 5 years), race, sex, and region of residence) who completed epidemiologic surveys and a 144-item food frequency questionnaire developed by the National Cancer Institute. Logistic regression was used to calculate odds ratios (OR) and 95% CIs, adjusted for age, sex, smoking, body mass index, energy intake, and alcohol consumption. Comparing highest to lowest quintiles, we observed significant (OR Citation Information: Cancer Prev Res 2010;3(12 Suppl):A85.