[Show abstract][Hide abstract] ABSTRACT: Marginal zone lymphoma (MZL) is the third most common subtype of B-cell non-Hodgkin lymphoma. Here we perform a two-stage GWAS of 1,281 MZL cases and 7,127 controls of European ancestry and identify two independent loci near BTNL2 (rs9461741, P=3.95 × 10(-15)) and HLA-B (rs2922994, P=2.43 × 10(-9)) in the HLA region significantly associated with MZL risk. This is the first evidence that genetic variation in the major histocompatibility complex influences MZL susceptibility.
[Show abstract][Hide abstract] ABSTRACT: Background
Following wider acceptance of “the thrifty phenotype” hypothesis and the convincing evidence that early life exposures can influence adult health even decades after the exposure, much interest has been placed on the mechanisms through which early life exposures become biologically embedded.Methods
In this review, we summarize the current literature regarding biological embedding of early life experiences. To this end we conducted a literature search to identify studies investigating early life exposures in relation to DNA methylation changes. In addition, we summarize the challenges faced in investigations of epigenetic effects, stemming from the peculiarities of this emergent and complex field. A proper systematic review and meta-analyses were not feasible given the nature of the evidence.ResultsWe identified 7 studies on early life socioeconomic circumstances, 10 studies on childhood obesity, and 6 studies on early life nutrition all relating to DNA methylation changes that met the stipulated inclusion criteria. The pool of evidence gathered, albeit small, favours a role of epigenetics and DNA methylation in biological embedding, but replication of findings, multiple comparison corrections, publication bias, and causality are concerns remaining to be addressed in future investigations.Conclusions
Based on these results, we hypothesize that epigenetics, in particular DNA methylation, is a plausible mechanism through which early life exposures are biologically embedded. This review describes the current status of the field and acts as a stepping stone for future, better designed investigations on how early life exposures might become biologically embedded through epigenetic effects.This article is protected by copyright. All rights reserved.
European Journal of Clinical Investigation 01/2015; · 3.37 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The etiology of renal cell carcinoma (RCC) is only partially understood, but a metabolic component appears likely. We investigated biomarkers of one-carbon metabolism and RCC onset and survival.
Journal of the National Cancer Institute. 12/2014; 106(12).
[Show abstract][Hide abstract] ABSTRACT: It has recently been demonstrated that memory B cells can reenter and reengage germinal center (GC) reactions, opening the possibility that multi-hit lymphomagenesis gradually occurs throughout life during successive immunological challenges. Here, we investigated this scenario in follicular lymphoma (FL), an indolent GC-derived malignancy. We developed a mouse model that recapitulates the FL hallmark t(14;18) translocation, which results in constitutive activation of antiapoptotic protein B cell lymphoma 2 (BCL2) in a subset of B cells, and applied a combination of molecular and immunofluorescence approaches to track normal and t(14;18)+ memory B cells in human and BCL2-overexpressing B cells in murine lymphoid tissues. BCL2-overexpressing B cells required multiple GC transits before acquiring FL-associated developmental arrest and presenting as GC B cells with constitutive activation-induced cytidine deaminase (AID) mutator activity. Moreover, multiple reentries into the GC were necessary for the progression to advanced precursor stages of FL. Together, our results demonstrate that protracted subversion of immune dynamics contributes to early dissemination and progression of t(14;18)+ precursors and shapes the systemic presentation of FL patients.
The Journal of clinical investigation. 11/2014; 124(12):5337.
[Show abstract][Hide abstract] ABSTRACT: Fish is a source of important nutrients and may play a role in preventing heart diseases and other health
outcomes. However, studies of overall mortality and causespecific mortality related to fish consumption are inconclusive. We examined the rate of overall mortality, as well as mortality from ischaemic heart disease and cancer in relation to the intake of total fish, lean fish, and fatty fish in a large prospective cohort including ten European countries. More than 500,000 men and women completed a dietary questionnaire in 1992–1999 and were followed up for mortality until the end of 2010. 32,587 persons were reported dead since enrolment. Hazard ratios and their 99 % confidence interval were estimated using Cox proportional hazard regression models. Fish consumption was examined using quintiles based on reported consumption, using moderate fish consumption (third quintile) as reference, and as continuous variables, using ncrements of 10 g/day. All analyses were adjusted for possible confounders. No association was seen for fish consumption and overall or cause-specific mortality for both the categorical and the continuous analyses, but there seemed to be a U-shaped trend (p\0.000) with fatty fish consumption and total mortality and with total fish consumption and cancer mortality (p = 0.046).
European Journal of Epidemiology 11/2014; · 5.15 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: A carbohydrate-rich diet, resulting in high blood glucose and insulin, has been hypothesized as involved in colorectal cancer etiology. We investigated dietary glycemic index (GI) and glycemic load (GL), in relation to colorectal cancer, in the prospectively recruited EPIC-Italy cohort. After a median 11.7 years, 421 colorectal cancers were diagnosed among 47,749 recruited adults. GI and GL were estimated from validated food frequency questionnaires. Multivariable Cox modeling estimated hazard ratios (HRs) for associations between colorectal cancer and intakes of total, high GI and low GI carbohydrate, and GI and GL. The adjusted HR of colorectal cancer for highest vs. lowest GI quartile was 1.35; 95% CI 1.03-1.78; p trend 0.031. Increasing high GI carbohydrate intake was also significantly associated with increasing colorectal cancer risk (HR 1.45; 95% CI 1.04-2.03; p trend 0.034); while increasing low GI carbohydrate was associated with reducing risk (HR 0.73; 95% CI 0.54-0.98; p trend 0.033). High dietary GI, and high GI carbohydrate, were associated with increased risks of cancer at all colon sites (HR 1.37; 95% CI 1.00-1.88, HR 1.80;95% CI 1.22-2.65, respectively); whereas high GI carbohydrate and high GL, were associated with increased risk of proximal colon cancer (HR 1.94; 95% CI 1.18-3.16, HR 2.01; 95% CI 1.08-3.74, respectively). After stratification for waist-to-hip ratio (WHR), cancer was significantly associated with GI, and high GI carbohydrate, in those with high WHR. These findings suggest that high dietary GI, and high carbohydrate intake from high GI foods, are associated with increased risk of colorectal cancer. This article is protected by copyright. All rights reserved.
International Journal of Cancer 11/2014; · 6.20 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background
The ¿25x25¿ strategy to tackle the global challenge of non-communicable diseases takes a traditional approach, concentrating on a few diseases and their immediate risk factors. Discussion: We propose elements of a comprehensive strategy to address NCDs that takes account of the evolving social, economic, environmental and health care contexts, while developing mechanisms to respond effectively to local patterns of disease. Principles that underpin the comprehensive strategy include: (a) a balance between measures that address health at the individual and population level; (b) the need to identify evidence-based feasible and effective approaches tailored to low and middle income countries rather than exporting questionable strategies developed in high income countries; (c) developing primary health care as a universal framework to support prevention and treatment; (d) ensuring the ability to respond in real time to the complex adaptive behaviours of the global food, tobacco, alcohol and transport industries; (e) integrating evidence-based, cost-effective, and affordable approaches within the post-2015 sustainable development agenda; (f) determination of a set of priorities based on the NCD burden within each country, taking account of what it can afford, including the level of available development assistance; and (g) change from a universal ¿one-size fits all¿ approach of relatively simple prevention oriented approaches to more comprehensive multi-sectoral and development-oriented approaches which address both health systems and the determinants of NCD risk factors.SummaryThe 25x25 is approach is absolutely necessary but insufficient to tackle the the NCD disease burden of mortality and morbidity. A more comprehensive approach is recommended.
Globalization and Health 10/2014; 10(1):74. · 1.83 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Observational studies have suggested that the risks of non-communicable diseases in voluntary migrants become similar to those in the host population after one or more generations, supporting the hypothesis that these diseases have a predominantly environmental (rather than inherited) origin. However, no study has been conducted thus far to identify alterations at the molecular level that might mediate these changes in disease risk after migration.
International Journal of Epidemiology 10/2014; · 9.20 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Acrylamide, classified in 1994 by IARC as 'probably carcinogenic' to humans, was discovered in 2002 in some heat-treated, carbohydrate-rich foods. The association between dietary acrylamide intake and epithelial ovarian cancer risk (EOC) has been previously studied in one case-control and three prospective cohort studies which obtained inconsistent results, and could not further examine histological subtypes other than serous EOC. The present study was carried out in the European Prospective Investigation into Cancer and Nutrition (EPIC) sub-cohort of women (n=325,006). Multivariate Cox proportional hazards models were used to assess the association between questionnaire-based acrylamide intake and EOC risk. Acrylamide was energy-adjusted using the residual method, and was evaluated both as a continuous variable (per 10µg/day) and in quintiles; when subgroups by histological EOC subtypes were analyzed, acrylamide intake was evaluated in quartiles. During a mean follow-up of 11 years, 1,191 incident EOC cases were diagnosed. At baseline, the median acrylamide intake in EPIC was 21.3 μg/day. No associations, and no evidence for a dose-response were observed between energy-adjusted acrylamide intake and EOC risk (HR10µg/day:1.02, 95%CI:0.96-1.09; HRQ5vsQ1:0.97, 95%CI:0.76-1.23). No differences were seen when invasive EOC subtypes (582 serous, 118 endometrioid, and 79 mucinous tumors) were analyzed separately. This study did not provide evidence that acrylamide intake, based on food intake questionnaires, was associated with risk for EOC in EPIC. Additional studies with more reliable estimates of exposure based on biomarkers may be needed.
[Show abstract][Hide abstract] ABSTRACT: Genome-wide association studies (GWASs) of follicular lymphoma (FL) have previously identified human leukocyte antigen (HLA) gene variants. To identify additional FL susceptibility loci, we conducted a large-scale two-stage GWAS in 4,523 case subjects and 13,344 control subjects of European ancestry. Five non-HLA loci were associated with FL risk: 11q23.3 (rs4938573, p = 5.79 × 10(-20)) near CXCR5; 11q24.3 (rs4937362, p = 6.76 × 10(-11)) near ETS1; 3q28 (rs6444305, p = 1.10 × 10(-10)) in LPP; 18q21.33 (rs17749561, p = 8.28 × 10(-10)) near BCL2; and 8q24.21 (rs13254990, p = 1.06 × 10(-8)) near PVT1. In an analysis of the HLA region, we identified four linked HLA-DRβ1 multiallelic amino acids at positions 11, 13, 28, and 30 that were associated with FL risk (pomnibus = 4.20 × 10(-67) to 2.67 × 10(-70)). Additional independent signals included rs17203612 in HLA class II (odds ratio [ORper-allele] = 1.44; p = 4.59 × 10(-16)) and rs3130437 in HLA class I (ORper-allele = 1.23; p = 8.23 × 10(-9)). Our findings further expand the number of loci associated with FL and provide evidence that multiple common variants outside the HLA region make a significant contribution to FL risk.
The American Journal of Human Genetics 10/2014; 95(4):462-71. · 10.99 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Hypertensive disorders in pregnancy are among the leading causes of maternal and perinatal death in low-income countries, but the aetiology remains unclear. We investigated the relationship between salinity in drinking water and the risk of (pre)eclampsia and gestational hypertension in a coastal community.
PLoS ONE 09/2014; 9(9):e108715. · 3.53 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Previous epidemiological studies suggest an inverse association between allergies, marked by elevated IgE levels, and non-Hodgkin lymphoma (NHL) risk. The evidence, however, is inconsistent and prospective data are sparse. We examined the association between pre-diagnostic total (low: <20; intermediate: 20 to 100; high >100 kU/l) and specific IgE (negative: <0.35; positive ≥0.35 kU/I) concentrations against inhalant antigens and lymphoma risk in a study nested within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. 1021 incident cases and matched controls of NHL, multiple myeloma (MM) and Hodgkin lymphoma (HL) with a mean follow-up time of 7 years were investigated. Multivariate adjusted odds ratios (ORs) with 95% confidence intervals (CI) were calculated by conditional logistic regression. Specific IgE was not associated with the risk of MM, B-NHL and B-NHL subtypes. In contrast, total IgE levels were inversely associated with the risk of MM (high level: OR=0.40 [95%CI=0.21-0.79]) and B-NHL (intermediate level: OR=0.68 [95%CI=0.53-0.88]; high level: OR=0.62 [95%CI=0.44-0.86]), largely on the basis of a strong inverse association with chronic lymphocytic leukaemia (CLL) (intermediate level: OR=0.49 [95%CI=0.30-0.80]; high level: OR=0.13 [95%CI=0.05-0.35]) risk. The inverse relationship for CLL remained significant for those diagnosed 5 years after baseline. The findings of this large prospective study demonstrated significantly lower prediagnostic total IgE levels among CLL and MM cases compared to matched controls. This corresponds to the clinical immunodeficiency state often observed in CLL patients prior to diagnosis. No support for an inverse association between prediagnostic levels of specific IgE and NHL risk was found.
[Show abstract][Hide abstract] ABSTRACT: Diffuse large B cell lymphoma (DLBCL) is the most common lymphoma subtype and is clinically aggressive. To identify genetic susceptibility loci for DLBCL, we conducted a meta-analysis of 3 new genome-wide association studies (GWAS) and 1 previous scan, totaling 3,857 cases and 7,666 controls of European ancestry, with additional genotyping of 9 promising SNPs in 1,359 cases and 4,557 controls. In our multi-stage analysis, five independent SNPs in four loci achieved genome-wide significance marked by rs116446171 at 6p25.3 (EXOC2; P = 2.33 × 10(-21)), rs2523607 at 6p21.33 (HLA-B; P = 2.40 × 10(-10)), rs79480871 at 2p23.3 (NCOA1; P = 4.23 × 10(-8)) and two independent SNPs, rs13255292 and rs4733601, at 8q24.21 (PVT1; P = 9.98 × 10(-13) and 3.63 × 10(-11), respectively). These data provide substantial new evidence for genetic susceptibility to this B cell malignancy and point to pathways involved in immune recognition and immune function in the pathogenesis of DLBCL.
[Show abstract][Hide abstract] ABSTRACT: Background: Shorter telomere length (TL) has been reported to be associated with increased risk of early death in elder individuals. Telomere shortening has been also related to chromosomal instability, that may possibly contribute to the development of several types of digestive or urogenital system cancers and smoking-related tumors. Therefore, we investigated the impact of TL on bladder cancer survival. Methods: TL was measured in leukocyte DNA from whole peripheral blood using quantitative real-time PCR in 463 bladder cancer patients from a total 726 cases who were followed for up to 18 years. Results: Patients with muscle-invasive tumor/any grade had shorter telomere than patients with non-muscle-invasive tumor/high-grade and with non-muscle-invasive tumor/non high-grade (TL reference 0.7±0.2; vs. respectively, 0.8±0.2, P=3.4x10-2 and 0.8±0.2, P=3.6x10-2). Moreover, patients in the lowest quartiles of TL were associated with decreased survival after diagnosis (log-rank test, P=3.9x10-4). A Cox regression adjusted by age, cancer aggressiveness, BCG, radical cystectomy, radiotherapy and chemotherapy showed an independent effect of TL on bladder cancer survival (HR=3.9; 95% CI, 1.7-9.1; P=1.2x10-3). Conclusions: Our results suggest that leukocyte TL is only partly related to tumor aggressiveness and that shorter telomeres act as independent prognostic predictor of survival in bladder cancer patients. TL information may allow to better select therapeutic approaches in patients with the same stage and grade. Impact: Blood leukocyte TL levels could provide an additional non-invasive prognostic marker to better predict survival and personalize therapies in bladder cancer patients.