Risk Of Several Cancer Types Research Articles

Association between prediagnostic leukocyte telomere length and breast cancer risk: the Singapore Chinese Health Study

BackgroundTelomeres and telomerase play key roles in the chromosomal maintenance and stability. Recent epidemiological studies have shown that longer telomeres are associated with increased risk of several cancer types. However, epidemiological data for telomere length and risk of breast cancer are sparse.MethodsWe prospectively studied the association between telomere length and risk of breast cancer in 14,305 middle-aged or older Chinese women of the Singapore Chinese Health Study including 442 incident breast cancer cases after 12.3 years of follow-up. Relative telomere length in peripheral blood leukocytes was quantified using a validated monochrome multiple quantitative polymerase chain reaction method. The Cox proportional hazard regression method was used to estimate hazard ratios (HRs) and the corresponding 95% confidence intervals (CIs) for breast cancer associated with longer telomeres after adjustment for potential confounders.ResultsLonger telomeres were significantly associated with higher risk of breast cancer in a dose-dependent manner (Ptrend = 0.006); the highest quartile of telomere length was associated with a statistically significant 47% higher risk of breast cancer compared with the lowest quartile of telomere length after the adjustment for age and other known risk factors for breast cancer (HRQ4 vs Q1 = 1.47, 95% CI = 1.11, 1.94).ConclusionsThe findings of the present study support the hypothesis that longer telomeres may be a risk factor for breast cancer. Telomere length in peripheral blood leukocytes may be developed as a biomarker for breast cancer risk prediction.

Cancer risk among young men with weight gain after smoking cessation: A population-based cohort study

BackgroundSmoking cessation may help the current smokers to reduce cancer risk. However, weight gain following smoking cessation may attenuate the protective association of cessation with cancer. Patients and methodsOur study included 1,278,794 men who were aged 20–39 years and underwent two consecutive health examinations by the National Health Insurance Service, without previous diagnosis of cancer. Participants were categorized into continual smokers, quitters with different degree of body weight change, and never smokers based on the biennial national health screening program (2002–2003 and 2004–2005) and were followed from January 1, 2006 to December 31, 2015. Cox proportional hazard models and restricted cubic spline model was used to evaluate the association of post-cessation weight change and cancer risk after adjustment for potential confounders. ResultsDuring the 10 years of follow-up, the analyses included 1,278,794 men with 21,494 cancer incidences. Compared to continual smokers, quitters without weight gain of 2.0 kg had significantly lower risk of obesity-related cancer (hazard ratio [HR], 0.88; 95% confidence interval [CI], 0.79-0.97), smoking-related cancer (HR, 0.90; 95% CI, 0.83 to 0.98), and gastrointestinal cancer (HR, 89; 95% CI, 0.80 to 0.98). Weight gain among quitters attenuated the risk reduction of cancer compared to continual smoking. Among quitters, weight gain up to 5.0 kg with smoking cessation showed protective association with cancer risk among quitters without weight gain. ConclusionExcessive weight gain with smoking cessation among quitters was not associated with reduced risk of several cancer types. This association should be taken into account when recommending smoking cessation to prevent cancer

Meta-analysis of the association between the inflammatory potential of diet and urologic cancer risk.

BackgroundThe inflammatory potential of diet has been shown to have an association with the risk of several cancer types, but the evidence is inconsistent regarding the related risk of urologic cancer (UC). Therefore, we conducted the present meta-analysis to investigate the association between the inflammatory potential of diet and UC.MethodsPubMed, Embase and Web of Science were searched up to July 31, 2018. Two reviewers independently selected the studies and extracted the data. The pooled risk ratio (RR) and its 95% confidence interval (CI) were calculated using the Stata12.0 software package.ResultsNine case-control studies and three cohort studies including 83,197 subjects met the inclusion criteria. The overall meta-analysis results showed that individuals with the highest category of DII (dietary inflammatory index) were associated with an increased risk of prostate cancer (RR = 1.62, 95% CI: 1.30–2.02); subgroup analysis showed consistent results. For kidney and bladder cancer, significant positive associations were found in individuals with the highest category of DII score; however, no significant association was found between DII and the risk of urothelial cell carcinoma (UCC).ConclusionAvailable data suggest that more pro-inflammatory diets are associated with an increased risk of prostate cancer, kidney cancer and bladder cancer. However, further well designed large-scaled cohort studies are warranted to provide more conclusive evidence.

Pre-diagnostic circulating insulin-like growth factor-I and bladder cancer risk in the European Prospective Investigation into Cancer and Nutrition.

Previous in vitro and case–control studies have found an association between the insulin‐like growth factor (IGF)‐axis and bladder cancer risk. Circulating concentrations of IGF‐I have also been found to be associated with an increased risk of several cancer types; however, the relationship between pre‐diagnostic circulating IGF‐I concentrations and bladder cancer has never been studied prospectively. We investigated the association of pre‐diagnostic plasma concentrations of IGF‐I with risk of overall bladder cancer and urothelial cell carcinoma (UCC) in a case–control study nested within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. A total of 843 men and women diagnosed with bladder cancer between 1992 and 2005 were matched with 843 controls by recruitment centre, sex, age at recruitment, date of blood collection, duration of follow‐up, time of day and fasting status at blood collection using an incidence density sampling protocol. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using conditional logistic regression with adjustment for smoking status. No association was found between pre‐diagnostic circulating IGF‐I concentration and overall bladder cancer risk (adjusted OR for highest versus lowest fourth: 0.91, 95% CI: 0.66–1.24, p trend = 0.40) or UCC (n of cases = 776; 0.91, 0.65–1.26, p trend = 0.40). There was no significant evidence of heterogeneity in the association of IGF‐I with bladder cancer risk by tumour aggressiveness, sex, smoking status, or by time between blood collection and diagnosis (p heterogeneity > 0.05 for all). This first prospective study indicates no evidence of an association between plasma IGF‐I concentrations and bladder cancer risk.

Association Between MALAT1 and THRIL Polymorphisms and Precancerous Cervical Lesions.

The occurrence of cervical cancer is a complex process, for which human papillomavirus (HPV) infection is a risk factor, although not all women infected with HPV will develop the disease. Knockout of mammalian lung metastasis associated transcript 1 (MALAT1) is associated with increased risk for several cancer types, whereas the long non-coding RNA (lncRNA) THRIL is essential for induction of tumor necrosis factor-α expression, which plays important roles in HPV infection. To investigate the effects of polymorphisms in the lncRNAs MALAT1 and THRIL on the susceptibility to precancerous cervical lesions, 12 single nucleotide polymorphisms (SNPs) were analyzed from 164 cervical precancerous lesion cases and 428 controls. Gene-gene and gene-environment interactions and haplotype associations were also evaluated. We found a significantly decreased risk of precancerous cervical lesions for the THRIL rs7133268 AG genotype (odds ratio adjusted = 0.63, 95% confidence interval: 0.42-0.94, p = 0.025). Multifactor dimensionality reduction analysis identified a significant two-locus interaction model involved in HPV infection and THRIL rs7133268 (training balanced accuracy = 0.6957, testing balanced accuracy = 0.6948, cross-validation consistency = 10/10, p = 0.0046). Other SNPs, including the two identified for MALAT1, were not significantly related to the risk of precancerous cervical lesions. Our results suggest that the rs7133268 polymorphism of the lncRNA THRIL gene can reduce the genetic susceptibility of precancerous cervical lesions and in turn reduce the risk of HPV infection.

Abstract 4986: Association of sirtuins and diet in cancer development: Studying the roles of SIRT2/3

Abstract Lifestyle factors, especially diet, affects health and lifespan. Dietary restriction (DR) has been shown as a beneficial regimen to increase longevity and protect from cancer. On the other hand, high fat intake has been found to be associated with greater risk of several cancer types. In this regard, several studies suggest that the beneficial effect of calorie restriction (CR) is mediated by the increased activity of sirtuins, a family of NAD-dependent deacetylases that plays a role in aging and age-related diseases. However, the specific role of individual family members in the inhibitory role of CR in tumorigenesis has not been elucidated. With the exception of SIRT1, there is no evidence for the contribution of other sirtuins in the diet-induced effects on tumorigenesis. In this study, we investigated, for the first time, the role of SIRT2 and SIRT3, which are found predominantly in the cytoplasm and mitochondria respectively, in this context. To do this, Sirt2-/- and Sirt3-/- mice were crossed with p53-/- mice to generate: p53+/-, (Sirt2-/-; p53+/-), (Sirt3-/-; p53+/-), p53-/-, (Sirt2-/-; p53-/-), and (Sirt3-/-; p53-/-) mice. Subsequently, mice with the different genotypes were subjected to 3 dietary regimes; ad libitum control diet, 30% calorie restriction diet (CR), and high-fat diet (HFD). As expected, CR reduced tumor incidence and increased survival of mice wild type for both SIRT2 and SIRT3. In contrast, HFD significantly increased body weight, tumor incidence and decreased overall survival. Interestingly, the protective effect of CR was enhanced in (Sirt3-/-; p53-/-) compared to (Sirt3+/+; p53-/-) mice, as evidenced by delayed tumor incidence (median age 257 days vs 189 days) and increased survival. On the other hand, Sirt2 deletion in both p53+/- and p53-/- backgrounds abolished the protective effect of CR. In addition, loss of Sirt2 decreased tumor incidence age (111 days vs 184 days) and accelerated the death of p53 deficient mice on HFD. Our results highlight a new role of SIRT2 in mediating the diet-induced effect on tumorigenesis. Citation Format: Mohamed A. Ahmed, Carol O'Callaghan, Athanasios Vassilopulos. Association of sirtuins and diet in cancer development: Studying the roles of SIRT2/3 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4986.

Effects of Nonsteroidal Anti-Inflammatory Drugs at the Molecular Level.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are commonly used for their anti-inflammatory, analgesic, and antipyretic effects. NSAIDs generally work by blocking the production of prostaglandins (PGs) through the inhibition of two cyclooxygenase enzymes. PGs are key factors in many cellular processes, such as gastrointestinal cytoprotection, hemostasis and thrombosis, inflammation, renal hemodynamics, turnover of cartilage, and angiogenesis. Interest has grown in the various effects of NSAIDs during the last decade. Epidemiological studies have revealed the reduced risk of several cancer types and neurodegenerative diseases by prolonged use of NSAIDs. Recent advances in the understanding of the cellular and molecular mechanisms of NSAIDs will accelerate the processes of discovery and clinical implementation. This review summarizes the molecular mechanisms of NSAIDs on the body systems.

Transcriptional regulation by NR5A2 links differentiation and inflammation in the pancreas.

SummaryChronic inflammation increases the risk of several cancer types. The current notion is that the control of inflammatory responses relies on transcriptional networks distinct from those involved in cell differentiation 1–3. The orphan nuclear receptor NR5A2 participates in a wide variety of processes including cholesterol and glucose metabolism in the liver, resolution of ER stress, intestinal glucocorticoid production, pancreatic development, and acinar differentiation 4–8. Single nucleotide polymorphisms (SNPs) in the vicinity of NR5A2 have been associated with the risk of pancreatic adenocarcinoma (PDAC) through genome wide association studies 9,10. In mice, Nr5a2 heterozygosity sensitizes the pancreas to damage, impairs regeneration, and cooperates with mutant KRas in tumor progression 11. Through global transcriptomic analysis, we describe here an epithelial cell-autonomous basal pre-inflammatory state in the pancreas of Nr5a2+/− mice that is reminiscent of early stages of pancreatitis-induced inflammation and is conserved in histologically normal human pancreata with reduced NR5A2 mRNA expression. In Nr5a2+/− mice, Nr5a2 undergoes a dramatic transcriptional switch relocating from differentiation-specific to inflammatory genes thereby promoting AP-1-dependent gene transcription. Pancreatic deletion of c-Jun rescues the pre-inflammatory phenotype, Nr5a2 binding to inflammatory gene promoters, and the defective regenerative response to damage. These findings support the notion that, in the pancreas, the same transcriptional networks involved in differentiation-specific functions suppress inflammatory programmes. These networks can be subverted to foster inflammation upon genetic or environmental constraints.

Statin use and pancreatic cancer risk in two prospective cohort studies.

Statins, 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors, are common lipid-lowering agents and may reduce the risk of several cancer types including pancreatic cancer. However, the association between statin use and pancreatic cancer risk has not been fully evaluated in prospective studies. We studied the association between statin use and incident pancreatic cancer in 113,059 participants from the prospective Nurses' Health Study and Health Professionals Follow-up Study. Statin use was self-reported via study questionnaires and updated biennially. Hazard ratios (HRs) and 95% confidence intervals (CIs) for incidence of pancreatic cancer were estimated using multivariable Cox proportional hazards models with adjustment for potential confounders. In total, 583 participants developed incident pancreatic cancer during 1.4 million person-years of follow-up. No difference was identified in pancreatic cancer risk for regular versus non-regular statin users (multivariable-adjusted HR 0.98; 95% CI 0.82-1.16). There was no significant heterogeneity in the association of statin use with pancreatic cancer risk between the cohorts. Similarly, longer duration of regular statin use was not associated with decreased risk of pancreatic cancer (Ptrend=0.65). The results remained similar when we examined statin use status at baseline or accounting for 4-year latency period. We observed no statistically significant effect modification for the association of statin use with pancreatic cancer risk by body mass index, smoking status, or diabetes mellitus status (all Pinteraction>0.21). Regular statin use was not associated with pancreatic cancer risk in two large prospective cohort studies in the U.S.

Adherence to Mediterranean Diet and Risk of Cancer: An Updated Systematic Review and Meta-Analysis.

The aim of the present systematic review and meta-analysis was to gain further insight into the effects of adherence to Mediterranean Diet (MedD) on risk of overall cancer mortality, risk of different types of cancer, and cancer mortality and recurrence risk in cancer survivors. Literature search was performed using the electronic databases PubMed, and Scopus until 25 August 2017. We included randomized trials (RCTs), cohort (for specific tumors only incidence cases were used) studies, and case-control studies. Study-specific risk ratios, hazard ratios, and odds ratios (RR/HR/OR) were pooled using a random effects model. Observational studies (cohort and case-control studies), and intervention trials were meta-analyzed separately. The updated review process showed 27 studies that were not included in the previous meta-analysis (total number of studies evaluated: 83 studies). An overall population of 2,130,753 subjects was included in the present update. The highest adherence score to a MedD was inversely associated with a lower risk of cancer mortality (RRcohort: 0.86, 95% CI 0.81 to 0.91, I2 = 82%; n = 14 studies), colorectal cancer (RRobservational: 0.82, 95% CI 0.75 to 0.88, I2 = 73%; n = 11 studies), breast cancer (RRRCT: 0.43, 95% CI 0.21 to 0.88, n = 1 study) (RRobservational: 0.92, 95% CI 0.87 to 0.96, I2 = 22%, n = 16 studies), gastric cancer (RRobservational: 0.72, 95% CI 0.60 to 0.86, I2 = 55%; n = 4 studies), liver cancer (RRobservational: 0.58, 95% CI 0.46 to 0.73, I2 = 0%; n = 2 studies), head and neck cancer (RRobservational: 0.49, 95% CI 0.37 to 0.66, I2 = 87%; n = 7 studies), and prostate cancer (RRobservational: 0.96, 95% CI 0.92 to 1.00, I2 = 0%; n = 6 studies). Among cancer survivors, the association between the adherence to the highest MedD category and risk of cancer mortality, and cancer recurrence was not statistically significant. Pooled analyses of individual components of the MedD revealed that the protective effects appear to be most attributable to fruits, vegetables, and whole grains. The updated meta-analysis confirms an important inverse association between adherence to a MedD and cancer mortality and risk of several cancer types, especially colorectal cancer. These observed beneficial effects are mainly driven by higher intakes of fruits, vegetables, and whole grains. Moreover, we were able to report for the first time a small decrease in breast cancer risk (6%) by pooling seven cohort studies.

Abstract 5302: Projections of cancer incidence and burden among the HIV-positive population in the United States through 2030

Abstract Background: People living with HIV (PLWH) are at an elevated risk of several cancer types. With widespread use of highly active antiretroviral therapy (HAART) to treat HIV, survival has improved among PLWH, resulting in an aging U.S. HIV population. Though HAART use has reduced the risk of certain cancers, in the near future, a larger fraction of PLWH will reach age groups where cancer risks are further elevated, potentially shifting the distribution of cancers in the population. Here, we projected cancer incidence rates and burden among U.S. PLWH through 2030 for Kaposi sarcoma, non-Hodgkin lymphoma (NHL) and cervical cancer (3 AIDS-defining cancers [ADCs]), and anal, breast, colon, lung, liver, prostate and oral cancers, Hodgkin lymphoma and all other cancers combined (all non-AIDS-defining cancers [NADCs]). Methods: We used cancer incidence data (2000-12) collected from the HIV/AIDS Cancer Match Study, a record linkage study of HIV and cancer registries. Using Poisson regression, we estimated cancer incidence rates in PLWH stratified by age group and, for some cancers, risk group (e.g., men who have sex with men, people who inject drugs) during 2013-30. The number of PLWH in the U.S. by age, risk group and calendar year (2006-30) was estimated using a dynamic compartmental model. To estimate cancer burden, observed and projected incidence rates and HIV population counts were multiplied. Results: The proportion of the total U.S. HIV population that is aged ≥65 years is projected to increase from 4.1% (of 1.06 million) in 2006 to 21.4% (of 1.09 million) in 2030. Based on significant declines during 2000-12, age-specific rates are projected to decrease across age groups for NHL, cervical cancer, lung cancer and all other cancers, and for some age groups for KS, Hodgkin lymphoma and colon cancer. All other age-specific rates did not change significantly, with the exception of prostate cancer rates, which are projected to continue to increase. We estimated that the total cancer burden in PLWH will decrease from 7908 cases in 2010 (2719 ADC and 5190 NADC) to 6495 cases in 2030 (701 ADC and 5794 NADC), indicating a strong decrease in ADCs and a slight increase in NADCs. In 2030, the most common cancers among PLWH will include: prostate (n=1624), lung (n=786), liver (n=498) and anal cancers (n=447) and NHL (n=429). Conclusions: Though cancer rates are generally decreasing, cancer will remain an important co-morbidity as the U.S. HIV population ages. If recent trends in cancer incidence continue into the future, the burden of NADCs, particularly prostate, lung, liver and anal cancers, will far exceed the burden of ADCs in 2030. Targeted cancer prevention, early detection and control efforts are needed for PLWH in the U.S., including smoking cessation, treatment of hepatitis C and B viruses, cancer screening and continued widespread treatment with HAART. Citation Format: Jessica Y. Islam, Philip S. Rosenberg, H Irene Hall, Evin U. Jacobson, Eric A. Engels, Meredith S. Shiels. Projections of cancer incidence and burden among the HIV-positive population in the United States through 2030 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5302. doi:10.1158/1538-7445.AM2017-5302

Childhood cancer risk in those with chromosomal and non-chromosomal congenital anomalies in Washington State: 1984-2013.

BackgroundThe presence of a congenital anomaly is associated with increased childhood cancer risk, likely due to large effects of Down syndrome and chromosomal anomalies for leukemia. Less is known about associations with presence of non-chromosomal anomalies.MethodsRecords of children diagnosed with cancer at <20 years of age during 1984–2013 in Washington State cancer registries were linked to their birth certificates (N = 4,105). A comparison group of children born in the same years was identified. Congenital anomalies were assessed from birth records and diagnosis codes in linked hospital discharge data. Logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI) for cancer, and for specific cancer types in relation to the presence of any anomaly and specific anomalies.ResultsHaving any congenital anomaly was associated with an increased risk of childhood cancer (OR: 1.46, 95% CI 1.28–1.65). Non-chromosomal anomalies were also associated with increased childhood cancer risk overall (OR: 1.35; 95% CI: 1.18–1.54), and with increased risk of several cancer types, including neuroblastoma, renal, hepatoblastoma, soft-tissue sarcoma, and germ cell tumors. Increasing number of non-chromosomal anomalies was associated with a stronger risk of childhood cancer (OR for 3+ anomalies: 3.11, 95% CI: 1.54–6.11). Although central nervous system (CNS) anomalies were associated with CNS tumors (OR: 6.05, 95% CI 2.75–13.27), there was no strong evidence of other non-chromosomal anomalies being specifically associated with cancer occurring in the same organ system or anatomic location.ConclusionsNon-chromosomal anomalies increased risk of several cancer types. Additionally, we found that increasing number of non-chromosomal anomalies was associated with a stronger risk of cancer. Pooling similar data from many regions would increase power to identify specific associations in order to inform molecular studies examining possible common developmental pathways in the etiologies of birth defects and cancer.

Tooth loss and liver cancer incidence in a Finnish cohort.

Periodontal disease, a major cause of tooth loss in adults, may have systemic effects and has been associated with higher risk of several cancer types. However, the associations of periodontal disease or tooth loss with liver cancer have only been examined prospectively in two studies, neither of which had sufficient statistical power. In addition, no studies assessed the potential confounding by viral hepatitis or Helicobacter pylori infection status. In this study, we examined the association between tooth loss and primary liver cancer incidence in a prospective cohort of Finnish male smokers (n=29,096). We used Cox proportional hazards models to calculate multivariable-adjusted hazard ratios (HRs) and 95% CIs. As a sensitivity analysis, we conducted a nested case-control study within the original cohort to assess confounding by hepatitis B or C virus infection and seropositivity of H. pylori. A total of 213 incident primary liver cancers occurred during a mean follow-up of 17years. Among these cases, having 11-31 permanent teeth lost (HR 1.42, 95% CI 1.01-1.98) or all 32 teeth lost (HR 1.45, 95% CI 1.00-2.10) was each associated with higher risk of liver cancer, compared to those having 0-10 teeth lost. Adjusting for H. pylori seropositivity yielded a small attenuation of the effect estimate. Greater number of teeth lost was associated with higher risk of primary liver cancer in our study. The role of periodontal infection in the development of liver cancer warrants further investigation.

Superoxide-hydrogen peroxide genetic imbalance modulates differentially the oxidative metabolism on human peripheral blood mononuclear cells exposed to seleno-L-methionine

Superoxide-hydrogen peroxide (S-HP) imbalance genetically caused by a gene polymorphism in the human manganese superoxide dismutase enzyme (Val16Ala-MnSOD) is associated with several diseases. Into mitochondria, MnSOD catalyses superoxide radical producing HP and oxygen. Ala-MnSOD genotype presents a high MnSOD efficiency and generates the highest HP concentrations that has been associated with the risk of several cancer types. Cellular selenoenzymes glutathione peroxidase and thioredoxin reductase (TrxR) and catalase (CAT) are essential to HP removal produced in excess in cells. Since, synthesis and activities of selenoenzymes are selenium dependent, we hypothesized that AA-MnSOD cells could have an improvement on antioxidant status undergoing Seleno-L-methionine (SeMet) treatment. This study performed an in vitro protocol to evaluate the response of peripheral blood mononuclear cells (PBMC) carriers of different Val16Ala-MnSOD genotypes exposed to SeMet. SeMet effects on cell viability, apoptosis induction and modulation of oxidative variables were determined using spectrophotometric, flow cytometry, fluorimetric and immunoassays. Gene modulation of antioxidant enzymes was also performed by qRT-PCR. From an initial protocol using heterozygous (AV) cells was determined that 1nM SeMet presented a cytoprotective effect. However, whereas this concentration did not change AA viability, in VV cells it was cytotoxic by increasing necrosis events. SeMet induced higher selenoenzymes levels in AA and VV cells and decreased oxidative markers levels including DNA damage. The results suggest a pharmacogenetic positive response of SeMet effect on AA-cells. Future studies in vivo could be essential to evaluate the potential clinical impact of S-HP imbalance after use of foods or supplements containing SeMet.

The Definition and Prevalence of Obesity and Metabolic Syndrome.

Increase in prevalence of obesity has become a worldwide major health problem in adults, as well as among children and adolescents. Furthermore, total adiposity and truncal subcutaneous fat accumulation during adolescence are positively and independently associated with atherosclerosis at adult ages. Centrally accumulation of body fat is associated with insulin resistance, whereas distribution of body fat in a peripheral pattern is metabolically less important. Obesity is associated with a large decrease in life expectancy. The effect of extreme obesity on mortality is greater among younger than older adults. In this respect, obesity is also associated with increased risk of several cancer types. However, up to 30% of obese patients are metabolically healthy with insulin sensitivity similar to healthy normal weight individuals, lower visceral fat content, and lower intima media thickness of the carotid artery than the majority of metabolically "unhealthy" obese patients.Abdominal obesity is the most frequently observed component of metabolic syndrome. The metabolic syndrome; clustering of abdominal obesity, dyslipidemia, hyperglycemia and hypertension, is a major public health challenge. The average prevalence of metabolic syndrome is 31%, and is associated with a two-fold increase in the risk of coronary heart disease, cerebrovascular disease, and a 1.5-fold increase in the risk of all-cause mortality.

Common germline variants within the CDKN2A/2B region affect risk of pancreatic neuroendocrine tumors.

Pancreatic neuroendocrine tumors (PNETs) are heterogeneous neoplasms which represent only 2% of all pancreatic neoplasms by incidence, but 10% by prevalence. Genetic risk factors could have an important role in the disease aetiology, however only a small number of case control studies have been performed yet. To further our knowledge, we genotyped 13 SNPs belonging to the pleiotropic CDKN2A/B gene region in 320 PNET cases and 4436 controls, the largest study on the disease so far. We observed a statistically significant association between the homozygotes for the minor allele of the rs2518719 SNP and an increased risk of developing PNET (ORhom = 2.08, 95% CI 1.05–4.11, p = 0.035). This SNP is in linkage disequilibrium with another polymorphic variant associated with increased risk of several cancer types. In silico analysis suggested that the SNP could alter the sequence recognized by the Neuron-Restrictive Silencer Factor (NRSF), whose deregulation has been associated with the development of several tumors. The mechanistic link between the allele and the disease has not been completely clarified yet but the epidemiologic evidences that link the DNA region to increased cancer risk are convincing. In conclusion, our results suggest rs2518719 as a pleiotropic CDKN2A variant associated with the risk of developing PNETs.

From obesity to cancer: a review on proposed mechanisms.

Nowadays, obesity is considered as a serious and growing global health problem. It is documented that the overweight and obesity are major risk factors for a series of noncommunicable diseases, and in recent years, the obesity-cancer link has received much attention. Numerous epidemiological studies have shown that obesity is associated with increased risk of several cancer types, including colon, breast, endometrium, liver, kidney, esophagus, gastric, pancreatic, gallbladder, and leukemia, and can also lead to poorer treatment. We review here the epidemiological and experimental evidences for the association between obesity and cancer. Specifically, we discuss potential mechanisms focusing how dysfunctional angiogenesis, chronic inflammation, interaction of proinflammatory cytokines, endocrine hormones, and adipokines including leptin, adiponectin insulin, growth factors, estrogen, and progesterone and strikingly, cell metabolism alteration in obesity participate in tumor development and progression, resistance to chemotherapy, and targeted therapies such as antiangiogenic and immune therapies.

Risk of cancer in Asian Americans: a Kaiser Permanente cohort study.

To supplement published cohort data about incident cancer in Asian Americans (Asians) including risk of specific Asian ethnic groups. A cohort study in 124,193 persons (13,344 Asians) with baseline examination data in 1978-1985 used Cox proportional hazards models with seven covariates to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). Through 2012 cancer was diagnosed in 18,687 persons including 1,522 Asians. Compared to Whites, the HR (CIs) for any cancer in Asians was 0.8 (0.7-0.9, p<0.001). Lower Asian risk was stronger for men (HR=0.7, p<0.001) than for women (HR=0.9, p=0.003). Lower Asian vs. White risks with p<0.05 were found for cancers of the upper airway digestive area, hematologic malignancies, melanoma, and cancers of the prostate, bladder, and brain. Melanoma contributed substantially to lower Asian risk, especially in women. HRs for specific Asian groups versus Whites follow: Chinese=0.9 (p<0.001), Japanese=0.9 (p=0.01), Filipinos=0.8 (p<0.001), South Asians=0.5 (p<0.001), and Other Asians=0.7 (p=0.006). Both South Asian men and women had lower risk than Whites, and South Asians had lower risk than any other racial/ethnic group. Asians had lower cancer risk than Whites, due to lower risk of several cancer types. Each Asian ethnic group had lower risk than Whites with South Asians at the lowest risk.

Abstract 5044: CtBP1 regulates olfactory and adhesion pathways in prostate cancer and metabolic syndrome

Abstract Metabolic syndrome (MeS) is a cluster of pathophysiological disorders that comprise at least three of the following factors: abdominal obesity, elevated triglycerides, dyslipidemia, high blood pressure and impaired glucose tolerance. Several studies associated MeS with increased risk for several cancer types, including prostate cancer (PCa). C-terminal binding protein 1 (CtBP1) is a potent transcriptional co-repressor of tumor suppressor genes. This protein is activated by low NAD+/NADH ratio produced by highly energetic environment such as high fat diet (HFD) intake. Previously, we identified CtBP1 as a novel molecular link between MeS and prostate tumor growth. The aim of this work was to assess the CtBP1 related pathways in PCa and MeS. We developed a MeS in vivo model by chronically feeding male nude mice with HFD. Control diet (CD) fed animals were maintained at the same conditions. These mice were inoculated with PC3 stable CtBP1 depleted or control cells. RNA obtained from xenografts was used for Genome-wide expression profiles (Affymetrix) and Gene Set Enrichment Analysis (GSEA). These analyses yielded several important pathways regulated by CtBP1, such as “Cell Adhesion” (COL17A1, PRRS2, CDH3, ITGB4, LCN2, CDH1, GJB5, TGM2 and SPARC) and “Olfactory” (OR4C45, OR5P2, GUCA1C and CLCA2). CtBP1 significantly diminished the capability of PCa cell lines to adhere to a collagen matrix, repressing the epithelial marker CDH1 and inducing the mesenchymal marker VIM expressions. Interestingly, CtBP1 associated to ITGB4 promoter gene, strongly repressing its expression. CtBP1 depletion increased the plasma membrane of the cell attached to the substrate and the number of filopodia. From olfactory pathway, we particularly focus on Chloride Channel Accessory 2 (CLCA2), a reported breast cancer tumor suppressor gene that function inhibiting epithelial to mesenchymal transition (EMT) and invasion processes. We found that CtBP1 regulates the transcription of CLCA2 in xenografts generated on HFD-fed mice. Using a panel of luciferase reporter plasmids with variable length of the CLCA2 promoter region, we determined that CtBP1 represses CLCA2 promoter activity in PC3 cells. Moreover, we established that CtBP1 associates to the CLCA2 proximal promoter region by chromatin immunoprecipitation (ChIP). Finally, several proteins regulate CLCA2 promoter activity independently (p53, ET2 and BRCA1) or dependently of CtBP1 (p300 and HDAC2). Altogether, these results demonstrated a new role for CtBP1 in the regulation of cellular adhesion, EMT and invasion reinforcing a potential function for this protein in cancer progression. Hence, CtBP1 pathway might help to identify new molecular candidates for better prediction of PCa progression in a subset of patients with MeS Citation Format: Guillermo N. Dalton, Juliana Porretti, Cintia Massillo, Georgina Scalise, Paula Lucía Farré, Cristian P. Moiola, Alejandra Paez, Geraldine Gueron, Paola De Luca, Adriana De Siervi. CtBP1 regulates olfactory and adhesion pathways in prostate cancer and metabolic syndrome. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 5044.

Pre-diagnostic Sleep Duration and Sleep Quality in Relation to Subsequent Cancer Survival.

Poor sleep quality and short sleep duration have been associated with elevated risk for several cancer types; however, the relationship between sleep and cancer outcomes has not been well characterized. We assessed the association between pre-diagnostic sleep attributes and subsequent cancer survival within the Women's Health Initiative (WHI). We identified WHI participants in whom a first primary invasive cancer had been diagnosed during follow-up (n = 21,230). Participants provided information on sleep characteristics at enrollment. Cox regression was used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) for associations between these pre-diagnostic sleep characteristics and cancer-specific survival for all cancers combined and separately for common cancers. Analyses were adjusted for age, study arm, cancer site, marital status, income, smoking, physical activity, and time to diagnosis. No individual pre-diagnostic sleep characteristics were found to be significantly associated with cancer survival in analyses of all cancer sites combined; however, women who reported short sleep duration (≤ 6 h sleep/night) combined with frequent snoring (≥ 5 nights/w experienced significantly poorer cancer-specific survival than those who reported 7-8 h of sleep/night and no snoring (HR = 1.32, 95% CI: 1.14-1.54). Short sleep duration (HR = 1.46, 95% CI: 1.07-1.99) and frequent snoring (HR = 1.34, 95% CI: 0.98-1.85) were each associated with poorer breast cancer survival; those reporting short sleep combined with frequent snoring combined had substantially poorer breast cancer survival than those reporting neither (HR = 2.14, 95% CI: 1.47-3.13). Short sleep duration combined with frequent snoring reported prior to cancer diagnosis may influence subsequent cancer survival, particularly breast cancer survival.