Dominique S. Michaud

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.

Fluid Intake and the Risk of Bladder Cancer in Men

BACKGROUND Studies in animals have shown that the frequency of urination is inversely associated with the level of potential carcinogens in the urothelium. In humans, an increase in total fluid intake may reduce contact time between carcinogens and urothelium by diluting urinary metabolites and increasing the frequency of voiding. The data on fluid intake in relation to the risk of bladder cancer are inconclusive. METHODS We examined the relation between total fluid intake and the risk of bladder cancer over a period of 10 years among 47,909 participants in the prospective Health Professionals Follow-up Study. There were 252 newly diagnosed cases of bladder cancer during the follow-up period. Information on total fluid intake was derived from the reported frequency of consumption of the 22 types of beverages on the food-frequency questionnaire, which was completed by each of the 47,909 participants who were free of cancer in 1986. Logistic-regression analyses were performed to adjust for known and suspected risk factors for bladder cancer. RESULTS Total daily fluid intake was inversely associated with the risk of bladder cancer; the multivariate relative risk was 0.51 (95 percent confidence interval, 0.32 to 0.80) for the highest quintile of total daily fluid intake (>2531 ml per day) as compared with the lowest quintile (<1290 ml per day). The consumption of water contributed to a lower risk (relative risk, 0.49 [95 percent confidence interval, 0.28 to 0.86] for > or =1440 ml [6 cups] per day vs. <240 ml [1 cup] per day), as did the consumption of other fluids (relative risk, 0.63 [95 percent confidence interval, 0.39 to 0.99] for >1831 ml per day vs. <735 ml per day). CONCLUSIONS A high fluid intake is associated with a decreased risk of bladder cancer in men.

Epidemiology of Pancreatic Cancer

Worldwide, over 200000 people die annually of pancreatic cancer. The highest incidence and mortality rates of pancreatic cancer are found in developed countries. In the United States, pancreatic cancer is the 4(th) leading cause of cancer death, and in Europe it is the 6th. Because of high fatality rates, pancreatic cancer incidence rates are almost equal to mortality rates. Pancreatic cancer is diagnosed late in the natural history of the disease, given the few early indicators of illness, and the lack of screening tests for this disease. Treatment has not improved substantially over the past few decades and has little effect on prolonging survival time. Therefore, prevention could play an important role in reducing pancreatic cancer mortality. International variations in rates and time trends suggest that environmental factors are likely to play a role in the etiology of pancreatic cancer. Variations in rates are substantial and occur even within industrialized nations. While rates have been stabilizing over the past 2 decades in many countries where they are already high, they continue to increase in countries where rates were relatively low 4 decades ago, such as Japan. In the US, the highest rates of pancreatic cancer incidence and mortality are observed among blacks, who have some of the highest rates in the world. A known cause of pancreatic cancer is tobacco smoking. This risk factor is likely to explain some of the international variations and gender differences. A number of studies observed a reduction in pancreatic cancer risk within a decade after smoking cessation, when compared to current smokers. With tobacco smoking as an exception, risk factors for pancreatic cancer are not well-established. Over the past 2 decades, epidemiological studies on pancreatic cancer have been plagued with methodological issues associated with studying a highly fatal disease, and inconsistent findings have hindered our understanding of the etiology of pancreatic cancer. Although familial pancreatic cancer is well-documented, the genes responsible for this condition have not been identified and are unlikely to explain more than 5-10% of all pancreatic cancer cases. Chronic pancreatitis and diabetes mellitus are medical conditions that have been consistently related to pancreatic cancer. Data from numerous studies suggest that these conditions are likely to be causally related to pancreatic cancer, rather than being consequences of the cancer. Recent cohort studies, which are less prone to biases than case-control studies, suggest that obesity increases the risk of pancreatic cancer. Other studies support the hypothesis that glucose intolerance and hyperinsulinemia are important in the development of pancreatic cancer. Other potential risk factors include physical inactivity, aspirin use, occupational exposure to certain pesticides, and dietary factors such as carbohydrate or sugar intake.

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.

A prospective study on intake of animal products and risk of prostate cancer.

AbstractObjective: Association between animal products and prostate cancer have been observed in numerous observational studies, but it is not clear whether the high fat content of these foods or some other component accounts for these associations. We examine these associations among 51,529 men who contributed detailed dietary data. Methods: Participants of the Health Professionals Follow-Up Study completed a semiquantitative food-frequency questionnaire in 1986, and subsequently in 1990 and 1994. Other data on potential risk factors were collected at baseline and in subsequent questionnaires during follow-up. Between 1986 and 1996, 1897 total cases of prostate cancer (excluding stage A1) and 249 metastatic cancers were identified. We used pooled logistic regression for analyses of diet and prostate cancer. Results: Intakes of total meat, red meat, and dairy products were not associated with risk of total or advanced prostate cancer. An elevated risk for metastatic prostate cancer was observed with intake of red meat (relative risk (RR) = 1.6 for top vs. bottom quintile comparison, 95% confidence interval (CI) = 1.0–2.5); this association was slightly attenuated after controlling for saturated and α-linolenic fatty acids (RR = 1.5, 95% CI = 0.88–2.5). Processed meats, bacon and beef, pork or lamb as a main dish each contributed to an elevated risk of metastatic prostate cancer. Dairy product intake increased risk of metastatic prostate cancer (RR = 1.4, 95% CI = 0.91–2.2 for top vs. bottom quintile comparison), but no association remained after controlling for calcium and other fatty acids. A high intake in both red meat and dairy product was associated with a statistically significant two-fold elevation in risk of metastatic prostate cancer, compared to low intake of both products; however, most of the excess risk could be explained by known nutritional components of these foods. Conclusions: Intakes of red meat and dairy products appear to be related to increased risk of metastatic prostate cancer. While known nutrients, such as calcium and fatty acids, may explain most of the dairy association observed, it appears that a portion of the risk of metastatic prostate cancer associated with red meat intake remains unexplained.

Periodontal disease, tooth loss, and cancer risk in male health professionals: a prospective cohort study.

BACKGROUND Studies suggest that tooth loss and periodontal disease might increase the risk of developing various cancers; however, smoking might have confounded the reported associations. We aimed to assess whether periodontal disease or tooth loss is associated with cancer risk. METHODS The analysis was done in a prospective study (the Health Professionals Follow-Up Study [HPFS]), which was initiated in 1986 when US male health professionals aged 40-75 years responded to questionnaires posted by the Department of Nutrition, Harvard University School of Public Health, Boston, MA, USA. In addition to the baseline questionnaires, follow-up questionnaires were posted to all living participants every 2 years and dietary questionnaires every 4 years. At baseline, participants were asked whether they had a history of periodontal disease with bone loss. Participants also reported number of natural teeth at baseline and any tooth loss during the previous 2 years was reported on the follow-up questionnaires. Smoking status and history of smoking were obtained at baseline and in all subsequent questionnaires. Additionally at baseline, participants reported their mean frequency of food intake over the previous year on a 131-item semiquantitative food-frequency questionnaire. Participants reported any new cancer diagnosis on the follow-up questionnaires. Endpoints for this study were risk of total cancer and individual cancers with more than 100 cases. Multivariate hazard ratios (HRs) and 95% CIs were calculated by use of Cox proportional hazard models according to periodontal disease status and number of teeth at baseline. FINDINGS In the main analyses, 48 375 men with median follow-up of 17.7 years (1986 to Jan 31, 2004) were eligible after excluding participants diagnosed with cancer before 1986 (other than non-melanoma skin cancer, n=2076) and those with missing data on periodontal disease (n=1078). 5720 incident cancer cases were documented (excluding non-melanoma skin cancer and non-aggressive prostate cancer). The five most common cancers were colorectal (n=1043), melanoma of the skin (n=698), lung (n=678), bladder (n=543), and advanced prostate (n=541). After adjusting for known risk factors, including detailed smoking history and dietary factors, participants with a history of periodontal disease had an increased risk of total cancer (HR 1.14 [95% CI 1.07-1.22]) compared with those with no history of periodontal disease. By cancer site, significant associations for those with a history of periodontal disease were noted for lung (1.36 [1.15-1.60]), kidney (1.49 [1.12-1.97]), pancreas (1.54 [1.16-2.04]; findings previously published), and haematological cancers (1.30 [1.11-1.53]). Fewer teeth at baseline (0-16) was associated with an increase in risk of lung cancer (1.70 [1.37-2.11]) for those with 0-16 teeth versus those with 25-32 teeth. In never-smokers, periodontal disease was associated with significant increases in total (1.21 [1.06-1.39]) and haematological cancers (1.35 [1.01-1.81]). By contrast, no association was noted for lung cancer (0.96 [0.46-1.98]). INTERPRETATION Periodontal disease was associated with a small, but significant, increase in overall cancer risk, which persisted in never-smokers. The associations recorded for lung cancer are probably because of residual confounding by smoking. The increased risks noted for haematological, kidney, and pancreatic cancers need confirmation, but suggest that periodontal disease might be a marker of a susceptible immune system or might directly affect cancer risk.

A review of the relationship between tooth loss, periodontal disease, and cancer

Recent studies have investigated the association between periodontal disease, tooth loss, and several systemic diseases including cancer, cardiovascular disease, and preterm birth. Periodontal disease, a chronic inflammatory condition, is highly prevalent in adult populations around the world, and may be preventable. Estimates of prevalence vary between races and geographic regions, with a marked increase in the occurrence of periodontal disease with advancing age. Worldwide estimates for the prevalence of severe periodontal disease generally range from 10 to 15%. The relationship between oral health and cancer has been examined for a number of specific cancer sites. Several studies have reported associations between periodontal disease or tooth loss and risk of oral, upper gastrointestinal, lung, and pancreatic cancer in different populations. In a number of studies, these associations persisted after adjustment for major risk factors, including cigarette smoking and socioeconomic status. This review provides a summary of these findings, discusses possible biological mechanisms involved, and raises methodological issues related to studying these relationships.

Cloning a balanced translocation associated with DiGeorge syndrome and identification of a disrupted candidate gene

DiGeorge syndrome (DGS), a developmental defect, is characterized by cardiac defects and aplasia or hypoplasia of the thymus and parathyroid glands. DGS has been associated with visible chromosomal abnormalities and microdeletions of 22q11, but only one balanced translocation — ADU/VDU t(2;22)(q14;q11.21). We now report the cloning of this translocation, the identification of a gene disrupted by the rearrangement and the analysis of other transcripts in its vicinity. Transcripts were identified by direct screening of cDNA libraries, exon amplification, cDNA selection and genomic sequence analysis using GRAIL. Disruption of a gene in 22q11.2 by the breakpoint and haploinsufficiency of this locus in deleted DGS patients make it a strong candidate for the major features associated with this disorder.

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.

Intakes of fruits and vegetables, carotenoids and vitamins A, E, C in relation to the risk of bladder cancer in the ATBC cohort study

We examined the relation between dietary fruit and vegetables, carotenoids and vitamin intakes and the risk of bladder cancer among male smokers in a prospective cohort study. Over a median of 11 years, we followed 27 111 male smokers aged 50–69 years who were initially enrolled in the Alpha-Tocopherol Beta-Carotene Cancer Prevention Study. During this period, 344 men developed bladder cancer. All of these men had completed a 276-food item dietary questionnaire at baseline. Cox proportional hazards models were used to estimate the relative risks and 95% confidence intervals and to simultaneously adjust for age, smoking history, energy intake and intervention group. Consumption of fruits and vegetables was not associated with the risk of bladder cancer (relative risk=1.28; 95% confidence intervals CI: 0.89–1.84, for highest vs lowest quintile). Similarly, no associations were observed for groups of fruits or vegetables (berries and cruciferous vegetables), or for specific fruits and vegetables. Dietary intakes of alpha-carotene, beta-carotene, lycopene, lutein/zeaxanthin, beta-cryptoxanthin, vitamins A, E, and C, and folate were not related to the risk of bladder cancer. These findings suggest that fruit and vegetable intakes are not likely to be associated with bladder cancer risk. However, these results may not be generalisable to non-smokers.