Shannon M. Lynch

Genome-wide association study identifies variants in the ABO locus associated with susceptibility to pancreatic cancer

We conducted a two-stage genome-wide association study of pancreatic cancer, a cancer with one of the lowest survival rates worldwide. We genotyped 558,542 SNPs in 1,896 individuals with pancreatic cancer and 1,939 controls drawn from 12 prospective cohorts plus one hospital-based case-control study. We conducted a combined analysis of these groups plus an additional 2,457 affected individuals and 2,654 controls from eight case-control studies, adjusting for study, sex, ancestry and five principal components. We identified an association between a locus on 9q34 and pancreatic cancer marked by the SNP rs505922 (combined P = 5.37 × 10−8; multiplicative per-allele odds ratio 1.20; 95% confidence interval 1.12–1.28). This SNP maps to the first intron of the ABO blood group gene. Our results are consistent with earlier epidemiologic evidence suggesting that people with blood group O may have a lower risk of pancreatic cancer than those with groups A or B.

Anthropometric Measures, Body Mass Index and Pancreatic Cancer: a Pooled Analysis from the Pancreatic Cancer Cohort Consortium (PanScan)

BACKGROUND Obesity has been proposed as a risk factor for pancreatic cancer. METHODS Pooled data were analyzed from the National Cancer Institute Pancreatic Cancer Cohort Consortium (PanScan) to study the association between prediagnostic anthropometric measures and risk of pancreatic cancer. PanScan applied a nested case-control study design and included 2170 cases and 2209 control subjects. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using unconditional logistic regression for cohort-specific quartiles of body mass index (BMI [calculated as weight in kilograms divided by height in meters squared]), weight, height, waist circumference, and waist to hip ratio as well as conventional BMI categories (underweight, <18.5; normal weight, 18.5-24.9; overweight, 25.0-29.9; obese, 30.0-34.9; and severely obese, > or = 35.0). Models were adjusted for potential confounders. RESULTS In all of the participants, a positive association between increasing BMI and risk of pancreatic cancer was observed (adjusted OR for the highest vs lowest BMI quartile, 1.33; 95% CI, 1.12-1.58; P(trend) < .001). In men, the adjusted OR for pancreatic cancer for the highest vs lowest quartile of BMI was 1.33 (95% CI, 1.04-1.69; P(trend) < .03), and in women it was 1.34 (95% CI, 1.05-1.70; P(trend) = .01). Increased waist to hip ratio was associated with increased risk of pancreatic cancer in women (adjusted OR for the highest vs lowest quartile, 1.87; 95% CI, 1.31-2.69; P(trend) = .003) but less so in men. CONCLUSIONS These findings provide strong support for a positive association between BMI and pancreatic cancer risk. In addition, centralized fat distribution may increase pancreatic cancer risk, especially in women.

Cigarette Smoking and Pancreatic Cancer: A Pooled Analysis From the Pancreatic Cancer Cohort Consortium

Smoking is an established risk factor for pancreatic cancer; however, detailed examination of the association of smoking intensity, smoking duration, and cumulative smoking dose with pancreatic cancer is limited. The authors analyzed pooled data from the international Pancreatic Cancer Cohort Consortium nested case-control study (1,481 cases, 1,539 controls). Odds ratios and 95% confidence intervals were calculated by using unconditional logistic regression. Smoking intensity effects were examined with an excess odds ratio model that was linear in pack-years and exponential in cigarettes smoked per day and its square. When compared with never smokers, current smokers had a significantly elevated risk (odds ratio (OR) = 1.77, 95% confidence interval (CI): 1.38, 2.26). Risk increased significantly with greater intensity (> or =30 cigarettes/day: OR = 1.75, 95% CI: 1.27, 2.42), duration (> or =50 years: OR = 2.13, 95% CI: 1.25, 3.62), and cumulative smoking dose (> or =40 pack-years: OR = 1.78, 95% CI: 1.35, 2.34). Risk more than 15 years after smoking cessation was similar to that for never smokers. Estimates of excess odds ratio per pack-year declined with increasing intensity, suggesting greater risk for total exposure delivered at lower intensity for longer duration than for higher intensity for shorter duration. This finding and the decline in risk after smoking cessation suggest that smoking has a late-stage effect on pancreatic carcinogenesis.

Pancreatic Cancer Risk and ABO Blood Group Alleles: Results from the Pancreatic Cancer Cohort Consortium

A recent genome-wide association study (PanScan) identified significant associations at the ABO gene locus with risk of pancreatic cancer, but the influence of specific ABO genotypes remains unknown. We determined ABO genotypes (OO, AO, AA, AB, BO, and BB) in 1,534 cases and 1,583 controls from 12 prospective cohorts in PanScan, grouping participants by genotype-derived serologic blood type (O, A, AB, and B). Adjusted odds ratios (ORs) for pancreatic cancer by ABO alleles were calculated using logistic regression. Compared with blood type O, the ORs for pancreatic cancer in subjects with types A, AB, and B were 1.38 [95% confidence interval (95% CI), 1.18-1.62], 1.47 (95% CI, 1.07-2.02), and 1.53 (95% CI, 1.21-1.92), respectively. The incidence rates for blood types O, A, AB, and B were 28.9, 39.9, 41.8, and 44.5 cases per 100,000 subjects per year. An increase in risk was noted with the addition of each non-O allele. Compared with OO genotype, subjects with AO and AA genotype had ORs of 1.33 (95% CI, 1.13-1.58) and 1.61 (95% CI, 1.22-2.18), whereas subjects with BO and BB genotypes had ORs of 1.45 (95% CI, 1.14-1.85) and 2.42 (1.28-4.57). The population attributable fraction for non-O blood type was 19.5%. In a joint model with smoking, current smokers with non-O blood type had an adjusted OR of 2.68 (95% CI, 2.03-3.54) compared with nonsmokers of blood type O. We concluded that ABO genotypes were significantly associated with pancreatic cancer risk.A recent genome-wide association study (PanScan) identified significant associations at the ABO gene locus with pancreatic cancer risk; however, the mechanisms underlying these associations and the influence of specific ABO genotypes remain unknown. We determined ABO genotypes (OO, AO, AA, AB, BO, BB) in 1534 cases and 1583 controls from 12 prospective cohort studies participating in PanScan. We also grouped participants by genotype-derived serologic blood type (O, A, AB, B). Adjusted odds ratios (ORs) for pancreatic cancer by ABO alleles were calculated using logistic regression. Compared to blood type O, the ORs for pancreatic cancer in subjects with types A, AB, and B were 1.38 (95% confidence interval [CI], 1.18-1.62), 1.47 (95% CI, 1.07-2.02), and 1.53 (95% CI, 1.21-1.92), respectively. The incidence rates (cases per 100,000 subjects per year) for blood types O, A, AB, and B were 28.9, 39.9, 41.8, and 44.5. An increase in risk was noted with the addition of each non-O allele. Compared to OO, subjects with AO and AA had ORs of 1.33 (95% CI, 1.13-1.58) and 1.61 (95% CI, 1.22-2.18), while subjects with BO and BB had ORs of 1.45 (95% CI, 1.14-1.85) and 2.42 (1.28-4.57). The population attributable fraction for non-O blood type was 19.5%. In a joint model with smoking, current smokers with non-O blood type had an adjusted OR of 2.68 (95% CI, 2.03-3.54), compared with non-smokers with blood type O. Among participants in a large prospective cohort consortium, ABO genotypes were significantly associated with pancreatic cancer risk.

Solution structure of the mature HIV-1 protease monomer: Insight into the tertiary fold and stability of a precursor

We present the first solution structure of the HIV-1 protease monomer spanning the region Phe1–Ala95 (PR1–95). Except for the terminal regions (residues 1–10 and 91–95) that are disordered, the tertiary fold of the remainder of the protease is essentially identical to that of the individual subunit of the dimer. In the monomer, the side chains of buried residues stabilizing the active site interface in the dimer, such as Asp25, Asp29, and Arg87, are now exposed to solvent. The flap dynamics in the monomer are similar to that of the free protease dimer. We also show that the protease domain of an optimized precursor flanked by 56 amino acids of the N-terminal transframe region is predominantly monomeric, exhibiting a tertiary fold that is quite similar to that of PR1–95 structure. This explains the very low catalytic activity observed for the protease prior to its maturation at its N terminus as compared with the mature protease, which is an active stable dimer under identical conditions. Adding as few as 2 amino acids to the N terminus of the mature protease significantly increases its dissociation into monomers. Knowledge of the protease monomer structure and critical features of its dimerization may aid in the screening and design of compounds that target the protease prior to its maturation from the Gag-Pol precursor.

Family history of cancer and risk of pancreatic cancer: a pooled analysis from the Pancreatic Cancer Cohort Consortium (PanScan).

A family history of pancreatic cancer has consistently been associated with increased risk of pancreatic cancer. However, uncertainty remains about the strength of this association. Results from previous studies suggest a family history of select cancers (i.e., ovarian, breast and colorectal) could also be associated, although not as strongly, with increased risk of pancreatic cancer. We examined the association between a family history of 5 types of cancer (pancreas, prostate, ovarian, breast and colorectal) and risk of pancreatic cancer using data from a collaborative nested case‐control study conducted by the Pancreatic Cancer Cohort Consortium. Cases and controls were from cohort studies from the United States, Europe and China, and a case‐control study from the Mayo Clinic. Analyses of family history of pancreatic cancer included 1,183 cases and 1,205 controls. A family history of pancreatic cancer in a parent, sibling or child was associated with increased risk of pancreatic cancer [multivariate‐adjusted odds ratios (ORs) = 1.76, 95% confidence interval (CI) = 1.19–2.61]. A family history of prostate cancer was also associated with increased risk (OR = 1.45, 95% CI = 1.12–1.89). There were no statistically significant associations with a family history of ovarian cancer (OR = 0.82, 95% CI = 0.52–1.31), breast cancer (OR = 1.21, 95% CI = 0.97–1.51) or colorectal cancer (OR = 1.17, 95% CI = 0.93–1.47). Our results confirm a moderate sized association between a family history of pancreatic cancer and risk of pancreatic cancer and also provide evidence for an association with a family history of prostate cancer worth further study.

Family history of cancer and risk of pancreatic cancer: a pooled analysis from the Pancreatic Cancer Cohort Consortium (PanScan)

A family history of pancreatic cancer has consistently been associated with increased risk of pancreatic cancer. However, uncertainty remains about the strength of this association. Results from previous studies suggest a family history of select cancers (i.e., ovarian, breast and colorectal) could also be associated, although not as strongly, with increased risk of pancreatic cancer. We examined the association between a family history of 5 types of cancer (pancreas, prostate, ovarian, breast and colorectal) and risk of pancreatic cancer using data from a collaborative nested case‐control study conducted by the Pancreatic Cancer Cohort Consortium. Cases and controls were from cohort studies from the United States, Europe and China, and a case‐control study from the Mayo Clinic. Analyses of family history of pancreatic cancer included 1,183 cases and 1,205 controls. A family history of pancreatic cancer in a parent, sibling or child was associated with increased risk of pancreatic cancer [multivariate‐adjusted odds ratios (ORs) = 1.76, 95% confidence interval (CI) = 1.19–2.61]. A family history of prostate cancer was also associated with increased risk (OR = 1.45, 95% CI = 1.12–1.89). There were no statistically significant associations with a family history of ovarian cancer (OR = 0.82, 95% CI = 0.52–1.31), breast cancer (OR = 1.21, 95% CI = 0.97–1.51) or colorectal cancer (OR = 1.17, 95% CI = 0.93–1.47). Our results confirm a moderate sized association between a family history of pancreatic cancer and risk of pancreatic cancer and also provide evidence for an association with a family history of prostate cancer worth further study.

Mitochondrial DNA Copy Number and Pancreatic Cancer in the Alpha-Tocopherol Beta-Carotene Cancer Prevention Study

Diabetes, obesity, and cigarette smoke, consistent risk factors for pancreatic cancer, are sources of oxidative stress in humans that could cause mitochondrial DNA (mtDNA) damage and increase mtDNA copy number. To test whether higher mtDNA copy number is associated with increased incident pancreatic cancer, we conducted a nested case–control study in the Alpha-Tocopherol Beta Carotene Cancer Prevention (ATBC) Study cohort of male smokers, aged 50 to 69 years at baseline. Between 1992 and 2004, 203 incident cases of pancreatic adenocarcinoma occurred (follow-up: 12 years) among participants, with whole blood samples used for mtDNA extraction. For these cases and 656 controls, we calculated ORs and 95% CIs using unconditional logistic regression, adjusting for age, smoking, and diabetes history. All statistical tests were two sided. Higher mtDNA copy number was significantly associated with increased pancreatic cancer risk (highest vs. lowest mtDNA copy number quintile, OR = 1.64, 95% CI = 1.01–2.67, continuous OR = 1.14, 95% CI 1.06–1.23), particularly for cases diagnosed during the first 7 years of follow-up (OR = 2.14, 95% CI = 1.16–3.96, Ptrend = 0.01, continuous OR = 1.21, 95% CI = 1.10–1.33), but not for cases occurring during follow-up of 7 years or greater (OR = 1.14, 95% CI = 0.53–2.45, continuous OR = 1.05, 95% CI = 0.93–1.18). Our results support the hypothesis that mtDNA copy number is associated with pancreatic cancer and could possibly serve as a biomarker for pancreatic cancer development. Cancer Prev Res; 4(11); 1912–9. ©2011 AACR.

Cancer incidence among pesticide applicators exposed to butylate in the Agricultural Health Study (AHS).

Although limited, epidemiologic studies suggest possible associations between butylate use and cancer risk, specifically prostate cancer and non-Hodgkin lymphoma (NHL). We examined butylate use and cancer risk more broadly in the AHS, a cohort of licensed pesticide applicators in Iowa and North Carolina. Pesticide use information was collected using self-administered questionnaires. Poisson regression was used to calculate rate ratios (RR) and 95% confidence intervals (CI). Two exposure metrics were used: lifetime exposure days (LD) and intensity-weighted lifetime exposure days (IWLD). We used two referent groups: unexposed to butylate and the lowest butylate usage category. This analysis included 19,655 applicators with complete butylate use information; 5297 applicators were exposed to butylate, making this the largest study of butylate to date. The mean follow-up time since enrollment was 9 years. Prostate cancer risk was significantly elevated among applicators in the highest LD category in both referent groups (low-exposed referent: RR(LD)=2.09, 95% CI=1.27-3.44). We observed a significantly elevated joint effect of prostate cancer family history and high butylate usage across both exposure metrics and both referent groups (low-exposed referent: RR(LD)=2.00, 95% CI=1.07-3.74), and a non-significant, elevated interaction between butylate use and prostate cancer family history, similar to a previous AHS finding. Statistically significant increased risks and exposure-response trends were seen for all lymphohematopoietic cancers (AL) and NHL for both exposure metrics and referent groups (low-exposed referent: AL:RR(LD)=2.27, 95% CI=1.18-4.37; NHL: RR(LD)=3.44, 95% CI=1.29-9.21). Our analysis did not find meaningful associations for other cancers analyzed. Further study is warranted for AL, NHL and prostate cancers.

Cancer incidence among pesticide applicators exposed to cyanazine in the agricultural health study

Background Cyanazine is a common pesticide used frequently in the United States during the 1980s and 1990s. Animal and human studies have suggested that triazines may be carcinogenic, but results have been mixed. We evaluated cancer incidence in cyanazine-exposed pesticide applicators among the 57,311 licensed pesticide applicators in the Agricultural Health Study (AHS). Methods We obtained detailed pesticide exposure information from a self-administered questionnaire completed at enrollment (1993–1997). Cancer incidence was followed through January 2002. Over half of cyanazine-exposed applicators had ≥ 6 years of exposure at enrollment, and approximately 85% had begun using cyanazine before the 1990s. We used adjusted Poisson regression to calculate rate ratios (RRs) and 95% confidence intervals (CIs) of multiple cancer sites among cyanazine-exposed applicators. We calculated ptrend values, and all statistical tests were two-sided. Two exposure metrics were used: tertiles of lifetime days of exposure (LD) and intensity-weighted LD. Results A total of 20,824 cancer-free AHS applicators reported ever using cyanazine at enrollment. Cancer incidence comparisons between applicators with the lowest cyanazine exposure and those with the highest exposure yielded the following for the LD metric: all cancers, RR = 0.99 (95% CI, 0.80–1.24); prostate cancer, RR = 1.23 (95% CI, 0.87–1.70); all lymphohematopoietic cancers, RR = 0.92 (95% CI, 0.50–1.72); non-Hodgkin lymphoma, RR = 1.25 (95% CI, 0.47–3.35); lung cancer, RR = 0.52 (95% CI, 0.22–1.25). Conclusions We did not find any clear, consistent associations between cyanazine exposure and any cancer analyzed. The number of sites was small for certain cancers, limiting any conclusion with regard to ovarian, breast, and some other cancers.