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1.  Flavonoid intake and risk of pancreatic cancer in the National Institutes of Health-AARP Diet and Health Study Cohort 
British Journal of Cancer  2013;108(5):1168-1172.
Limited epidemiological studies show inverse associations between dietary flavonoid intake and pancreatic cancer risk, but results are inconsistent and are based on few cases. We examined the association between intake of flavonoids and pancreatic cancer risk in the large, prospective National Institutes of Health-AARP Diet and Health Study Cohort.
During follow-up through 2006 (median follow-up 10.6 years), 2379 pancreatic cancer cases were identified. We used Cox proportional hazards modelling to estimate hazard ratios (HRs) and 95% confidence intervals (CIs).
We found no association between total flavonoid intake (Q5 vs Q1 HR=1.09, 95% CI: 0.96–1.24) or any flavonoid subtypes and pancreatic cancer risk. Significant interactions were not observed by age, sex, smoking status, BMI or diabetes.
Our results do not support the hypothesis that flavonoids have a protective role in pancreatic cancer carcinogenesis.
PMCID: PMC3619057  PMID: 23299536
pancreatic neoplasms; flavonoids; epidemiology; cohort studies
2.  Frequency of mutations in mismatch repair genes in a population-based study of women with ovarian cancer 
British Journal of Cancer  2012;107(10):1783-1790.
Mutations in genes for hereditary non-polyposis colorectal cancer (HNPCC) in ovarian cancer patients remains poorly defined. We sought to estimate the frequency and characteristics of HNPCC gene mutations in a population-based sample of women with epithelial ovarian cancer.
The analysis included 1893 women with epithelial ovarian cancer ascertained from three population-based studies. Full-germline DNA sequencing of the coding regions was performed on three HNPCC genes, MLH1, MSH2 and MSH6. Collection of demographic, clinical and family history information was attempted in all women.
Nine clearly pathogenic mutations were identified, including five in MSH6, two each in MLH1 and MSH2. In addition, 28 unique predicted pathogenic missense variants were identified in 55 patients. Pathogenic mutation carriers had an earlier mean age at diagnosis of ovarian cancer, overrepresentation of cancers with non-serous histologies and a higher number of relatives with HNPCC-related cancers.
Our findings suggest that fewer than 1% of women with ovarian cancer harbour a germline mutation in the HNPCC genes, with overrepresentation of MSH6 mutations. This represents a lower-range estimate due to the large number of predicted pathogenic variants in which pathogenicity could not definitively be determined. Identification of mismatch repair gene mutations has the potential to impact screening and treatment decisions in these women.
PMCID: PMC3493867  PMID: 23047549
epithelial ovarian cancer; mismatch repair genes; MLH1; MSH2; MSH6; hereditary non-polyposis colorectal cancer
3.  Pancreatitis and pancreatic cancer risk: a pooled analysis in the International Pancreatic Cancer Case-Control Consortium (PanC4) 
Annals of Oncology  2012;23(11):2964-2970.
Pancreatitis is a known risk factor for pancreatic cancer; however, an unknown fraction of the disease is thought to be a consequence of tumor-related duct obstruction.
Patients and methods
A pooled analysis of a history of pancreatitis and risk of pancreatic cancer was carried out considering the time interval between diagnoses and potential modification by covariates. Adjusted pooled odds ratios (ORs) and 95% confidence intervals (CIs) were estimated from 10 case–control studies (5048 cases of ductal pancreatic adenocarcinoma and 10 947 controls) taking part in the International Pancreatic Cancer Case-Control Consortium (PanC4).
The association between pancreatitis and pancreatic cancer was nearly three-fold at intervals of >2 years between diagnoses (OR: 2.71, 95% CI: 1.96–3.74) and much stronger at intervals of ≤2 years (OR: 13.56, 95% CI: 8.72–21.90) probably reflecting a combination of reverse causation and antecedent misdiagnosis of pancreas cancer as pancreatitis. The younger (<65 years) pancreatic cancer cases showed stronger associations with previous (>2 years) pancreatitis (OR: 3.91, 95% CI: 2.53–6.04) than the older (≥65 years) cases (OR: 1.68, 95% CI: 1.02–2.76; P value for interaction: 0.006).
Despite a moderately strong association between pancreatitis (diagnosed before >2 years) and pancreatic cancer, the population attributable fraction was estimated at 1.34% (95% CI: 0.612–2.07%), suggesting that a relatively small proportion of pancreatic cancer might be avoided if pancreatitis could be prevented.
PMCID: PMC3477881  PMID: 22767586
case–control studies; pancreatitis; pancreatic cancer; pooled analysis; risk factors
4.  Cigarette smoking and pancreatic cancer: an analysis from the International Pancreatic Cancer Case-Control Consortium (Panc4) 
Annals of Oncology  2011;23(7):1880-1888.
To evaluate the dose–response relationship between cigarette smoking and pancreatic cancer and to examine the effects of temporal variables.
We analyzed data from 12 case–control studies within the International Pancreatic Cancer Case–Control Consortium (PanC4), including 6507 pancreatic cases and 12 890 controls. We estimated summary odds ratios (ORs) by pooling study-specific ORs using random-effects models.
Compared with never smokers, the OR was 1.2 (95% confidence interval [CI] 1.0–1.3) for former smokers and 2.2 (95% CI 1.7–2.8) for current cigarette smokers, with a significant increasing trend in risk with increasing number of cigarettes among current smokers (OR = 3.4 for ≥35 cigarettes per day, P for trend <0.0001). Risk increased in relation to duration of cigarette smoking up to 40 years of smoking (OR = 2.4). No trend in risk was observed for age at starting cigarette smoking, whereas risk decreased with increasing time since cigarette cessation, the OR being 0.98 after 20 years.
This uniquely large pooled analysis confirms that current cigarette smoking is associated with a twofold increased risk of pancreatic cancer and that the risk increases with the number of cigarettes smoked and duration of smoking. Risk of pancreatic cancer reaches the level of never smokers ∼20 years after quitting.
PMCID: PMC3387822  PMID: 22104574
case–control study; cigarette smoking; pancreatic cancer; pooled analysis
5.  Cigar and pipe smoking, smokeless tobacco use and pancreatic cancer: an analysis from the International Pancreatic Cancer Case-Control Consortium (PanC4) 
Annals of Oncology  2011;22(6):1420-1426.
Background: Cigarette smoking is the best-characterized risk factor for pancreatic cancer. However, data are limited for other tobacco smoking products and smokeless tobacco.
Materials and methods: We conducted a pooled analysis of cigar and pipe smoking and smokeless tobacco use and risk of pancreatic cancer using data from 11 case–control studies (6056 cases and 11 338 controls) within the International Pancreatic Cancer Case-Control Consortium (PanC4). Pooled odds ratios (OR) and the corresponding 95% confidence intervals (CI) were estimated by unconditional multiple logistic regression models adjusted for study center and selected covariates.
Results: Compared with never tobacco users, the OR for cigar-only smokers was 1.6 (95% CI: 1.2–2.3), i.e. comparable to that of cigarette-only smokers (OR 1.5; 95% CI 1.4–1.6). The OR was 1.1 (95% CI 0.69–1.6) for pipe-only smokers. There was some evidence of increasing risk with increasing amount of cigar smoked per day (OR 1.82 for ≥ 10 grams of tobacco), although not with duration. The OR for ever smokeless tobacco users as compared with never tobacco users was 0.98 (95% CI 0.75–1.3).
Conclusion: This collaborative analysis provides evidence that cigar smoking is associated with an excess risk of pancreatic cancer, while no significant association emerged for pipe smoking and smokeless tobacco use.
PMCID: PMC3139985  PMID: 21245160
cigar; pancreatic cancer; pooled analysis; smokeless tobacco; tobacco; pipe
7.  The BOADICEA model of genetic susceptibility to breast and ovarian cancers: updates and extensions 
British Journal of Cancer  2008;98(8):1457-1466.
Multiple genetic loci confer susceptibility to breast and ovarian cancers. We have previously developed a model (BOADICEA) under which susceptibility to breast cancer is explained by mutations in BRCA1 and BRCA2, as well as by the joint multiplicative effects of many genes (polygenic component). We have now updated BOADICEA using additional family data from two UK population-based studies of breast cancer and family data from BRCA1 and BRCA2 carriers identified by 22 population-based studies of breast or ovarian cancer. The combined data set includes 2785 families (301 BRCA1 positive and 236 BRCA2 positive). Incidences were smoothed using locally weighted regression techniques to avoid large variations between adjacent intervals. A birth cohort effect on the cancer risks was implemented, whereby each individual was assumed to develop cancer according to calendar period-specific incidences. The fitted model predicts that the average breast cancer risks in carriers increase in more recent birth cohorts. For example, the average cumulative breast cancer risk to age 70 years among BRCA1 carriers is 50% for women born in 1920–1929 and 58% among women born after 1950. The model was further extended to take into account the risks of male breast, prostate and pancreatic cancer, and to allow for the risk of multiple cancers. BOADICEA can be used to predict carrier probabilities and cancer risks to individuals with any family history, and has been implemented in a user-friendly Web-based program (
PMCID: PMC2361716  PMID: 18349832
BRCA1; BRCA2; cancer risk model; genetic testing
8.  Progesterone receptor variation and risk of ovarian cancer is limited to the invasive endometrioid subtype: results from the ovarian cancer association consortium pooled analysis 
British Journal of Cancer  2008;98(2):282-288.
There is evidence that progesterone plays a role in the aetiology of invasive epithelial ovarian cancer. Therefore, genes involved in pathways that regulate progesterone may be candidates for susceptibility to this disease. Previous studies have suggested that genetic variants in the progesterone receptor gene (PGR) may be associated with ovarian cancer risk, although results have been inconsistent. We have established an international consortium to pool resources and data from many ovarian cancer case–control studies in an effort to identify variants that influence risk. In this study, three PGR single nucleotide polymorphisms (SNPs), for which previous data have suggested they affect ovarian cancer risk, were examined. These were +331 C/T (rs10895068), PROGINS (rs1042838), and a 3′ variant (rs608995). A total of 4788 ovarian cancer cases and 7614 controls from 12 case–control studies were included in this analysis. Unconditional logistic regression was used to model the association between each SNP and ovarian cancer risk and two-sided P-values are reported. Overall, risk of ovarian cancer was not associated with any of the three variants studied. However, in histopathological subtype analyses, we found a statistically significant association between risk of endometrioid ovarian cancer and the PROGINS allele (n=651, OR=1.17, 95% CI=1.01–1.36, P=0.036). We also observed borderline evidence of an association between risk of endometrioid ovarian cancer and the +331C/T variant (n=725 cases; OR=0.80, 95% CI 0.62–1.04, P=0.100). These data suggest that while these three variants in the PGR are not associated with ovarian cancer overall, the PROGINS variant may play a modest role in risk of endometrioid ovarian cancer.
PMCID: PMC2361465  PMID: 18219286
ovarian cancer; progesterone receptor; SNPs; PROGINS; pooled analyses; endometrioid ovarian cancer
9.  Breast and ovarian cancer risks to carriers of the BRCA1 5382insC and 185delAG and BRCA2 6174delT mutations: a combined analysis of 22 population based studies 
Journal of Medical Genetics  2005;42(7):602-603.
A recent report estimated the breast cancer risks in carriers of the three Ashkenazi founder mutations to be higher than previously published estimates derived from population based studies. In an attempt to confirm this, the breast and ovarian cancer risks associated with the three Ashkenazi founder mutations were estimated using families included in a previous meta-analysis of populatrion based studies. The estimated breast cancer risks for each of the founder BRCA1 and BRCA2 mutations were similar to the corresponding estimates based on all BRCA1 or BRCA2 mutations in the meta-analysis. These estimates appear to be consistent with the observed prevalence of the mutations in the Ashkenazi Jewish population.
PMCID: PMC1736090  PMID: 15994883
10.  Intron variants of the p53 gene are associated with increased risk for ovarian cancer but not in carriers of BRCA1 or BRCA2 germline mutations 
British Journal of Cancer  1999;81(1):179-183.
Two biallelic polymorphisms in introns 3 and 6 of the p53 gene were analysed for a possible risk-modifying effect for ovarian cancer. Germline DNA was genotyped from 310 German Caucasian ovarian cancer patients and 364 healthy controls. We also typed 124 affected and 276 unaffected female carriers with known deleterious BRCA1 or BRCA2 germline mutation from high-risk breast-ovarian cancer families. Genotyping was based on PCR and high-resolution gel electrophoresis. German ovarian cancer patients who carried the rare allele of the MspI restriction fragment length polymorphism (RELP) in intron 6 were found to have an overall 1.93-fold increased risk (95% confidence internal (CI) 1.27–2.91) which further increased with the age at diagnosis of 41–60 years (odds ratio (OR) 2.71, 95% CI 1.10–6.71 for 41–50 and OR 2.44, 95% CI 1.12–5.28 for 51–60). The 16 bp duplication polymorphism in intron 3 was in a strong linkage to the MspI RFLP. In BRCA1 or BRCA2 mutation carriers, no difference in allele frequency was observed for carriers affected or unaffected with ovarian cancer. Our data suggest that intronic polymorphisms of the p53 gene modify the risk for ovarian cancer patients but not in carriers with BRCA1 or BRCA2 mutations. © 1999 Cancer Research Campaign
PMCID: PMC2374363  PMID: 10487631
ovarian cancer; p53; polymorphism; BRCA1; BRCA2; genetic susceptibility
11.  Accumulation of p53 protein is frequent in ovarian cancers associated with BRCA1 and BRCA2 germline mutations. 
Journal of Clinical Pathology  1999;52(5):372-375.
BACKGROUND: Mutations in the BRCA1 or BRCA2 genes are responsible for up to 95% of hereditary ovarian cancer cases. Both genes function as tumour suppressor genes, and development of a cancer is thought to require an accumulation of somatic genetic events in addition to the inherited germline predisposition. It is unknown whether these somatic events in BRCA associated ovarian cancer are similar to or distinct from those in sporadic cases. The most frequent somatic genetic event in ovarian cancer is a mutation of the p53 gene. AIM: To study the role of p53 in hereditary ovarian cancer, by analysing accumulation of the p53 protein in ovarian cancers which occurred in BRCA1 or BRCA2 germline mutation carriers and comparing the results with a panel of ovarian cancers from patients who tested negative for both BRCA1 and BRCA2. METHODS: The study group consisted of 39 ovarian cancer patients in whom a BRCA mutation had been confirmed previously. p53 Immunohistochemistry was performed on archival tissue using a standard microwave antigen retrieval technique. The rate of p53 accumulation was compared with 40 ovarian cancer cases who tested negative for BRCA1 and BRCA2 germline mutations. RESULTS: P53 Accumulation was similar in BRCA related ovarian cancers and BRCA negative controls. Overall 27 of 39 BRCA1 or BRCA2 positive cases (69%) had evidence of p53 accumulation, compared with 24 of 40 invasive ovarian cancer cases (60%) which tested negative for BRCA1 and BRCA2 germline mutations. BRCA1 related ovarian cancers showed p53 accumulation in 22 of 30 cases (73%); p53 accumulation was present in five of nine BRCA2 related ovarian cancers. CONCLUSIONS: In addition to germline BRCA1 and BRCA2 mutations, somatic p53 alterations leading to p53 accumulation are an important event in hereditary ovarian cancer and are as frequent as in non-BRCA-related ovarian cancer.
PMCID: PMC1023075  PMID: 10560359
12.  Occupational factors and the incidence of cancer of the bladder in Canada. 
During 1979-82, a case-control study of occupational factors and urinary bladder cancer was conducted in Edmonton, Calgary, Toronto, and Kingston, Canada. A total of 826 histologically verified cases of cancer were individually matched by sex, age, and area of residence to 792 randomly selected population controls. Subjects were specifically asked about employment in several industries thought relevant to risk of bladder cancer. Information was also obtained on lifelong occupational history, with special attention given regarding exposures to fumes, dusts, smoke, and chemicals. In addition, subjects provided data on past medical and residential history, on intake of certain dietary items, and on exposure to tobacco and other lifestyle factors. Conditional logistic regression methods were used for the analysis. Under adjustment for cumulative lifetime cigarette consumption, it appeared that for both men and women, most of the occupational factors examined were not associated with significant alteration in risk of bladder cancer. For exposures during the period eight to 28 years before diagnosis, however, raised risk was suggested for men employed at least six months in the chemicals industry (odds ratio = 2.37, p = 0.004), in dye manufacturing or the dyeing of cloth (OR = 3.62 and 4.63, p = 0.041 and 0.035, respectively), as tailors (OR = 3.85, p = 0.015), or in jobs in which contact with diesel or traffic fumes occurred (OR = 1.69, p = 0.0008). Increased risk was also seen for men occupationally exposed to tars or asphalt (OR = 3.11, p = 0.019). This study then, at least for men, supports perhaps a few of the suspect industries as related to risk of bladder cancer.
PMCID: PMC1009613  PMID: 3395572

Results 1-12 (12)