Genetic variability in energy balance and pancreatic cancer risk in a population-based case-control study in Minnesota

OBJECTIVES: Accumulating evidence suggests that energy imbalance plays a role in pancreatic carcinogenesis. However, it remains unclear whether single-nucleotide polymorphisms (SNPs) in genes regulating energy homeostasis influence pancreatic cancer risk. We investigated this question in a case-control study conducted from 1994 to 1998. METHODS: Patients (n = 173) were ascertained from hospitals in the Twin Cities and Mayo Clinic, Minnesota. Control subjects (n = 476) were identified from the general population and frequency matched to patients by age and sex. Seven SNPs were evaluated in relation to pancreatic cancer using unconditional logistic regression. RESULTS: After adjustment for confounders, the leucine/proline or proline/proline genotype of the neuropeptide Y (NPY) gene rs16139 was associated with a lower risk than the leucine/leucine genotype (odds ratio, 0.40 [95% confidence interval, 0.15-0.91]). Conversely, an increased risk was observed for the glycine/arginine or arginine/arginine genotype of the adrenoceptor β2, surface (ADRB2) gene rs1042713 as compared with the glycine/glycine genotype (odds ratio, 1.52 [95% confidence interval, 1.01-2.31]). CONCLUSIONS: This study first reveals that SNPs in genes modulating energy intake (NPY) and energy expenditure (ADRB2) altered pancreatic cancer risk. If confirmed by other studies, our findings may shed new light on the etiology and prevention of pancreatic cancer

Body mass index at early adulthood, subsequent weight change and cancer incidence and mortality: Body mass index, weight change and cancer risk

Obesity later in adulthood is associated with increased risks of many cancers. However, the effect of body fatness in early adulthood, and change in weight from early to later adulthood on cancer risk later in life is less clear. We used data from 13,901 people aged 45-64 in the Atherosclerosis Risk in Communities cohort who at baseline (1987-1989) self-reported their weight at the age of 25 and had weight and height measured. Incident cancers were identified through 2006 and cancer deaths were ascertained through 2009. Multivariable Cox proportional hazard models were used to relate body mass index (BMI) at age 25 and percent weight change from age 25 to baseline to cancer incidence and mortality. After adjusting for weight change from age 25 until baseline, a 5 kg/m2 increment in BMI at age 25 was associated with a greater risk of incidence of all cancers in women [hazard ratio (95% confidence interval): 1.10 (1.02-1.20)], but not in men. Associations with incident endometrial cancer were strong [1.83 (1.47-2.26)]. After adjusting for BMI at age 25, a 5% increment in weight from age 25 to baseline was associated with a greater risk of incident post-menopausal breast cancer [1.05 (1.02-1.07)] and endometrial cancer [1.09 (1.04-1.14)] in women and incident colorectal cancer [1.05 (1.00-1.10)] in men. Excess weight during young adulthood and weight gain from young to older adulthood may be independently associated with subsequent cancer risk. Excess weight and weight gain in early adulthood should be avoided

Associations between Intake of Calcium, Magnesium, and Phosphorus and Risk of Pancreatic Cancer: A Population-Based, Case-Control Study in Minnesota

Experimental studies suggest that abnormal levels of calcium, magnesium, and phosphorus are implicated in pancreatic carcinogenesis. We investigated the associations between intakes of these minerals and the risk of pancreatic cancer in a case-control study conducted in 1994-1998. Cases of pancreatic cancer (n150) were recruited from all hospitals in the metropolitan area of the Twin Cities and Mayo Clinic, Minnesota. Controls (n459) were randomly selected from the general population and frequency matched to cases by age, sex, and race. All dietary variables were adjusted for energy intake using the residual method prior to data analysis. Logistic regression was performed to evaluate the associations between intake of three nutrients examined and the risk of pancreatic cancer. Total intake of calcium (936 vs. 1026 mg/day) and dietary intake of magnesium (315 vs. 331 mg/day) and phosphorus (1350 vs. 1402 mg/day) were significantly lower in cases than in controls. After adjustment for confounders, there were not significant associations of total and dietary intakes of calcium, magnesium, and phosphorus with the risk of pancreatic cancer. In addition, no significant interactions exist between intakes of these minerals and total fat on pancreatic cancer risk. In conclusion, the present study does not suggest that intakes of calcium, magnesium, and phosphorus were significantly associated with the risk of pancreatic cancer

Inflammatory processes and risk of cancer: epidemiological research.

University of Minnesota Ph.D. dissertation. May 2010. Major: Epidemiology. Advisor: Kristin E Anderson. 1 computer file (PDF); xi, 147 pages, appendix leaf 147.Chronic inflammation has been implicated in cancer etiology but it is unclear whether inflammation causes cancer or results from tumor growth. To address these questions, we examined three hypotheses about the role of inflammation in incident cancers in large prospective cohorts. In the first manuscript, we hypothesized that increased levels of circulating acute-phase reactants, which are markers of inflammation, such as white blood cells, fibrinogen, factor VIII, von Willebrand factor, and C-reactive protein (CRP) (positive reactants) and decreased levels of albumin (a negative reactant) are associated with increased risk of subsequent colorectal cancer (CRC) in a prospective cohort - ARIC. After multivariate adjustment, there were statistically significant associations of CRC risk with two individual markers and a summary inflammation Z- score. For the highest versus lowest quartile, hazard ratios HR (95% confidence interval) were 1.50 (95%CI, 1.05; 2.15) for fibrinogen (p-trend across quartiles was 0.03); 1.97 (95%CI, 1.13; 3.43) for CRP (p-trend=0.02); and 1.65 (95%CI, 1.15; 2.35) for Z-score (p-trend=0.01). To our knowledge, no previous studies have examined a summary inflammation score in relation to incident cancers. The second manuscript hypothesized that the frequency of NSAIDs use was inversely associated with incident ovarian and endometrial cancers in the IWHS cohort of elderly women. We found that compared to women who reported no use of aspirin, the multivariate-adjusted HRs of ovarian cancer for those who used aspirin less than 2, 2-5 times, and 6 or more times per week were 0.83, 0.77 and 0.61, respectively (p-trend=0.04). We did not observe associations between non-aspirin NSAIDs use and ovarian cancer risk or between any NSAIDs use and endometrial cancer risk. The third manuscript examined whether elderly women (65+) suffering from an inflammatory autoimmune disease - psoriasis - have an increased risk of total, breast, lung, or colon cancers in the IWHS cohort linked to Medicare. We observed an association between psoriasis and colon cancer risk: multivariate-adjusted HR=1.57 (95%CI, 1.02; 2.42) for those with versus without psoriasis. This association was stronger for severe psoriasis. Findings from these studies give further support to the hypothesis that chronic inflammation may play a role in colorectal and ovarian carcinogenesis

Adherence to the World Cancer Research Fund/American Institute for Cancer Research recommendations for cancer prevention is associated with better health-related quality of life among elderly female cancer survivors

PURPOSE: The 2007 World Cancer Research Fund/American Institute for Cancer Research (WCRF/AICR) diet and physical activity guidelines encourage cancer survivors to follow its cancer prevention recommendations. We evaluated whether adherence to the WCRF/AICR recommendations was associated with health-related quality of life (HRQOL) among elderly female cancer survivors. PATIENTS AND METHODS: A total of 2,193 women with a confirmed cancer diagnosis (1986 through 2002) in the Iowa Women's Health Study were identified. We calculated a WCRF/AICR recommendation adherence score (range, 0 to 7), assigning one point each for seven recommendations. Physical and mental component summary scores (PCS, MCS) from the Medical Outcomes Study Short Form–36 Health Survey were compared by recommendation adherence scores. RESULTS: Mean adherence score was 4.0 ± 1.2. Overall, higher adherence to the WCRF/AICR guidelines was significantly associated with better PCS and MCS after adjustment for age, education, marital status, number of comorbidities, smoking, cancer stage, and current cancer treatment (P(trend) < .001 for both). PCS was 43.5 versus 37.0 and MCS was 54.2 versus 52.0 among women with adherence scores ≥ 5 compared with women scoring ≤ 3. Adherence to the physical activity recommendation was associated with higher PCS and MCS after adjusting for demographic and medical confounders, body mass index, and dietary recommendation adherence. For the body weight recommendation, adherence was associated with higher PCS but lower MCS, whereas adherence to the dietary recommendations was associated with higher MCS only. CONCLUSION: Following the lifestyle guidelines for cancer prevention may improve HRQOL among elderly female cancer survivors. Physical activity may be a key lifestyle factor to improve HRQOL

Lower Expression of <i>CFTR</i> Is Associated with Higher Mortality in a Meta-Analysis of Individuals with Colorectal Cancer

Individuals with cystic fibrosis (CF), caused by biallelic germline mutations in the cystic fibrosis transmembrane conductance regulator (CFTR), have higher risk and earlier onset of colorectal cancer (CRC). A subset of CRC patients in the non-CF population expresses low levels of tumoral CFTR mRNA which may also cause decreased CFTR activity. To determine the consequences of reduced CFTR expression in this population, we investigated association of tumoral CFTR expression with overall and disease-specific mortality in CRC patients. CFTR mRNA expression, clinical factors and survival data from 1177 CRC patients reported in the Cancer Genome Atlas (TCGA) and Gene Expression Omnibus studies GSE39582 and GSE17538 were included. Log-transformed and z-normalized [mean = 0, standard deviation (SD) = 1] CFTR expression values were modeled as quartiles or dichotomized at the median. Univariate and multivariable Cox proportional hazards regression models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI) for overall and disease-specific mortality in individual studies and meta-analyses. Analyses of each of the three individual datasets showed a robust association of decreased CFTR expression with increased mortality. In meta-analyses adjusted for stage at diagnosis, age and sex, CFTR expression was inversely associated with risk of overall death [pooled HR (95% CI): 0.70 (0.57–0.86)] and disease-specific death [pooled HR (95% CI): 0.68 (0.47–0.99)]. Associations did not differ by stage at diagnosis, age, or sex. Meta-analysis of overall death stratified by microsatellite instable (MSI) versus microsatellite stable (MSS) status indicated potential interaction between MSI/MSS status and CFTR expression, (p-interaction: 0.06). The findings from these three datasets support the hypothesis that low CFTR expression is associated with increased CRC mortality

Lower Expression of CFTR Is Associated with Higher Mortality in a Meta-Analysis of Individuals with Colorectal Cancer

Individuals with cystic fibrosis (CF), caused by biallelic germline mutations in the cystic fibrosis transmembrane conductance regulator (CFTR), have higher risk and earlier onset of colorectal cancer (CRC). A subset of CRC patients in the non-CF population expresses low levels of tumoral CFTR mRNA which may also cause decreased CFTR activity. To determine the consequences of reduced CFTR expression in this population, we investigated association of tumoral CFTR expression with overall and disease-specific mortality in CRC patients. CFTR mRNA expression, clinical factors and survival data from 1177 CRC patients reported in the Cancer Genome Atlas (TCGA) and Gene Expression Omnibus studies GSE39582 and GSE17538 were included. Log-transformed and z-normalized [mean = 0, standard deviation (SD) = 1] CFTR expression values were modeled as quartiles or dichotomized at the median. Univariate and multivariable Cox proportional hazards regression models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI) for overall and disease-specific mortality in individual studies and meta-analyses. Analyses of each of the three individual datasets showed a robust association of decreased CFTR expression with increased mortality. In meta-analyses adjusted for stage at diagnosis, age and sex, CFTR expression was inversely associated with risk of overall death [pooled HR (95% CI): 0.70 (0.57&ndash;0.86)] and disease-specific death [pooled HR (95% CI): 0.68 (0.47&ndash;0.99)]. Associations did not differ by stage at diagnosis, age, or sex. Meta-analysis of overall death stratified by microsatellite instable (MSI) versus microsatellite stable (MSS) status indicated potential interaction between MSI/MSS status and CFTR expression, (p-interaction: 0.06). The findings from these three datasets support the hypothesis that low CFTR expression is associated with increased CRC mortality