Influències clíniques i ambientals en la prevalença de mutacions en l'oncogèn K-ras en pacients amb adenocarcinoma ductal de pàncrees

Descripció del recurs: 27 gener 2010Antecedents La prevenció primària de l'adenocarcinoma ductal de pàncrees (ADP) està limitada per la falta de coneixement sobre la seva etiologia. El factor de risc més ben establert és el consum de tabac, però explica només una petita proporció de casos. Es discuteix el paper d'altres factors etiològics com els antecedents patològics de diabetis i pancreatitis, la dieta, determinades exposicions ambientals o laborals, i els factors hereditaris. Mutacions puntuals en l'oncogèn K-ras, i la seva conseqüent activació, són presents en més del 80% dels casos d'ADP; és un dels esdeveniments genètics fonamentals perquè el càncer tingui lloc. L'activació d'aquest oncogèn dóna lloc a gran varietat de respostes, des de l'augment de la proliferació cel·lular fins a la inhibició de l'apoptosi, en funció del context cel·lular. Els gens Ras són dianes crítiques per als carcinògens químics; els càncers de pàncrees amb i sense mutacions en l'oncogèn K-ras probablement es desenvolupen a partir de diferents interaccions gen-ambient. Tot i això, els estils de vida i les exposicions ambientals que poden influir en la presència de mutacions en el gen K-ras són pràcticament desconeguts. L'objectiu general d'aquesta tesi és estudiar la relació entre la prevalença de mutacions en el codó 12 de l'oncogèn K-ras i diferents factors ambientals (consum de tabac i alcohol), clínics (antecedents patològics) i genètics (polimorfismes en el gen CYP1B1), en pacients amb ADP. Metodologia La tesi s'emmarca en el projecte PANKRAS II, un estudi multicèntric prospectiu sobre el paper de les mutacions en l'oncogèn K-ras i altres alteracions genètiques en el diagnòstic, el pronòstic i l'etiologia del càncer de pàncrees exocrí. Es van reclutar 602 pacients procedents de 5 hospitals generals del nord-est de la península ibèrica amb patologies relacionades amb el pàncrees, dels quals 185 eren pacients amb ADP. Es va entrevistar personalment més del 85% dels pacients per obtenir informació sociodemogràfica, clínica (antecedents patològics i història familiar de càncer) o sobre els seus estils de vida (dieta, ocupació o hàbits tòxics); paral·lelament es van revisar les històries clíniques d'aquests pacients. Finalment es van realitzar anàlisis moleculars de gens implicats en el procés de carcinogènesi pancreàtica (K-ras, TP53, p-16/CDKN2, SMAD4/DPC4, BRCA2 o CFTR). L'anàlisi de l'associació entre la prevalença de mutacions en l'oncogèn K-ras i els diferents factors clínics, ambientals i genètics s'ha realitzat mitjançant regressió logística no condicional. Resultats i discussió Tot i que el consum de tabac és el factor de risc més ben establert i les mutacions en l'oncogèn K-ras un esdeveniment fonamental en l'etiologia de l'ADP, els nostres resultats mostren que no existeix associació entre ambdós factors. Els carcinògens del tabac presents en el teixit pancreàtic, les nitrosamines, serien les responsables d'alteracions en gens que intervenen en estadis més tardans del desenvolupament del càncer; alhora, altres carcinògens del tabac amb capacitat per activar K-ras, com els hidrocarburs aromàtics policíclics, no tindrien el pàncrees com a òrgan diana. Els carcinògens del tabac intervenen en la carcinogènesi pancreàtica per vies alternatives a l'activació de K-ras. El gen citocrom P4501B1 (CYP1B1) codifica un enzim metabolitzador de carcinògens i estrògens amb un rol important en la bioactivació de procarcinògens ambientals. En les reaccions de detoxificació es generen productes capaços d'unir-se al DNA formant adductes, que poden ser els responsables de les mutacions activadores en l'oncogèn K-ras. Els nostres resultats mostren que el genotip homozigot per l'al·lel valina en el locus m1 del gen CYP1B1, augmenta de risc de tenir un ADP amb mutacions en l'oncogèn K-ras; aquest genotip estaria associat a una activitat detoxificadora més pobra i, en conseqüència, a un procés deficient de biotransformació, metabolització i eliminació de tòxics de l'organisme, que serien l'origen de mutacions en l'oncogèn K-ras. Les mutacions en l'oncogèn K-ras són presents en estadis molt inicials del procés carcinogènic pancreàtic, i també en el teixit de pacients amb pancreatitis o diabetis; ambdues patologies considerades possibles factors de risc per l'ADP. Els nostres resultats mostren que els antecedents patològics de diabetis tipus 2 (DM-2) i de pancreatitis no són més freqüents en els casos d'ADP amb mutacions a K-ras. Així doncs, en pacients d'ADP, tant els antecedents de DM-2 com els de pancreatitis semblen estar associats amb vies d'activació de la carcinogènesi pancreàtica independents de K-ras, potser lligats al dany que pateix el teixit pancreàtic com a conseqüència de la inflamació crònica a la que està sotmès i a mediadors de la resposta inflamatòria, entre d'altres. Tot i que es discuteix el paper del consum d'alcohol en la carcinogènesi pancreàtica, tant l'etanol com el seu metabòlit, l'acetaldehid, estan reconeguts com a carcinògens en humans. Els nostres resultats mostren que el consum d'alcohol al llarg de la vida està associat amb la presència de mutacions en l'oncogèn K-ras en pacients amb ADP. Els efectes carcinogènics i mutagènics de l'etanol i l'acetaldehid podrien jugar un paper important en l'aparició de les mutacions en l'oncogèn K-ras en l'epiteli pancreàtic.Background The primary prevention of pancreatic ductal adenocarcinoma (PDA) cancer is hampered by limited knowledge on its etiology. Tobacco consumption is the best established risk factor, but it explains only a small fraction of cases. It is currently being discussed the role of other etiologic factors including diet, medical history, environmental and occupational exposures, or genetic susceptibility. Activating point mutations in the K-ras oncogene are one of the fundamental genetic events leading to PDA; at diagnosis, about 80% of PDA cases harbour mutations in codon 12 of K-ras. Depending on the cellular and molecular context, oncogenic K-ras activation can result in a wide variety of responses ranging from the activation of a senescence programme to an increased cell proliferation and inhibition of apoptosis. Ras genes are critical targets for chemical carcinogens; K-ras-mutated and wild-type cancers may develop through pathways involving different gene-environment interactions. Although mutations in K-ras are the most frequent alteration of oncogenes in human cancer, the potential lifestyle and environmental influences on their occurrence and persistence are largely unknown. The main objective of the present thesis is to assess the relationship between activating mutations in codon 12 of the K-ras oncogene and environmental, clinical, and genetic factors, (specifically tobacco and alcohol consumption, medical history and genetic polymorphisms in CYP1B1) in patients with PDA. Methodology This thesis is developed in the context of the PANKRAS II project, a multicentre prospective study on the role of mutations in the K-ras oncogene and other genetic alterations in the diagnosis, prognosis and etiology of exocrine pancreatic cancer. A total of 602 subjects were recruited at five general hospitals in the eastern Mediterranean part of Spain; among them, 185 were incident cases of PDA. Over 85% of the patients were interviewed face-to-face during hospital stay, close to the time of diagnosis. Interviews included questions about lifestyle, past clinical history, symptoms, occupation, diet, coffee, alcohol and tobacco consumption. A structured form was used to collect clinicopathological information from medical records, including details on diagnostic procedures, laboratory results and follow-up care. Molecular analyses of genes involved in pancreatic carcinogenesis were also undertaken (i.e., K-ras, TP53, p-16/CDKN2, SMAD4/DPC4, BRCA2 or CFTR). The association between the presence of K-ras mutations and clinical, environmental and genetic factors was assessed by unconditional logistic regression. Results and discussion While both smoking and K-ras mutations have important roles in the etiopathogenesis of PDA, our results show no association between the presence of K-ras mutations and tobacco consumption in PDA patients; the two processes may act independently in pancreatic carcinogenesis. Carcinogens from tobacco smoke detected in pancreatic tissue (nitrosamines) might be the responsible of other genetic alterations that act late in the carcinogenic process. On the other hand, pancreatic tissue is not a target organ for tobacco carcinogens that could activate oncogenic K-ras (such as polycyclic aromatic hydrocarbons). Tobacco does not play a major part in the acquisition of K-ras mutations in the pancreatic epithelium. Cytochrome P4501B1 (CYP1B1) is a carcinogen and estrogen-metabolizing enzyme with an important role in the bioactivation of some environmental procarcinogens. The oxidant steps catalyzed by this enzyme create more reactive intermediates that are able to bind with DNA, leading to DNA adduct formation and genetic mutations. Our results suggest that CYP1B1 polymorphisms might influence interindividual differences in susceptibility to pancreatic cancer by the acquisition of K-ras mutations. Val/Val genotype increases the probability of having a K-ras mutated PDA; this genotype might be associated with poor detoxification activity and, consequently, with an impaired elimination of some environmental toxics that can react with DNA to form stable adducts, which may favor mutations in K-ras. Activating point mutations in the K-ras oncogene are present in early stages of the PDA development, and have been also detected in pancreatic tissue from patients with diabetes and pancreatitis, both considered as risk factors for PDA. Our results show no association between the presence of K-ras mutations and medical history of diabetes or pancreatitis in PDA patients. Medical history of pancreatitis and diabetes may favor pancreatic carcinogenesis through pathways independent of K-ras activation; chronic inflammation causes a gradual damage of pancreatic tissue that might contribute to carcinogenic transformation of acinar pancreatic cells through molecular alterations not involving K-ras mutations

Association Between Oxytocin Receptor Genotype, Maternal Care, and Eating Disorder Behaviours in a Community Sample of Women

Abstract This study aimed to investigate associations between oxytocin receptor gene (OXT‐R) polymorphisms (rs53576 and rs2254298), their interaction with maternal care (GxE), and ED behaviours in a community sample. We studied 3698 women from the Avon Longitudinal Study of Parents and Children (ALSPAC) who participated in a two‐phase prevalence study of lifetime ED and had genotype data. The GG rs53576 genotype was associated with binge eating and purging, and the rs2254298 AG/AA genotype with restrictive eating lifetime. In addition, the rs2254298 AG/AA genotype interacted with poor maternal care to increase the odds of binge eating and purging (odds ratio = 4.40 (95% confidence intervals: 1.11–17.4)). This study replicates previous findings of an association between OXT‐R polymorphisms and ED, and it is the first to show an interaction between OXT‐R genotype and poor maternal care. As such, these findings highlight the important role of oxytocin in understanding the pathophysiology of ED. © 2016 The Authors European Eating Disorders Review published by Eating Disorders Association and John Wiley & Sons Lt

Genetically predicted telomere length and its relationship with neurodegenerative diseases and life expectancy

Telomere length (TL) is a biomarker of biological aging. Shorter telomeres have been associated with mortality and increased rates of age-related diseases. However, observational studies are unable to conclude whether TL is causally associated with those outcomes. Mendelian randomization (MR) was developed for assessing causality using genetic variants in epidemiological research. The objective of this study was to test the potential causal role of TL in neurodegenerative disorders and life expectancy through MR analysis. Summary level data were extracted from the most recent genome-wide association studies for TL, Alzheimer's disease (AD), Parkinson's disease, Frontotemporal dementia, Amyotrophic Lateral Sclerosis, Progressive Supranuclear Palsy and life expectancy. MR estimates revealed that longer telomeres inferred a protective effect on risk of AD (OR = 0.964; adjusted p-value = 0.039). Moreover, longer telomeres were significantly associated with increased life expectancy (beta(IVW) = 0.011; adjusted p-value = 0.039). Sensitivity analyses suggested evidence for directional pleiotropy in AD analyses. Our results showed that genetically predicted longer TL may increase life expectancy and play a protective causal effect on AD. We did not observe significant causal relationships between longer TL and other neurodegenerative diseases. This suggests that the involvement of TL on specific biological mechanisms might differ between AD and life expectancy, with respect to that in other neurodegenerative diseases. Moreover, the presence of pleiotropy may reflect the complex interplay between TL homeostasis and AD pathophysiology. Further observational studies are needed to confirm these results. (C) 2022 The Author(s). Published by Elsevier B.V. on behalf of Research Network of Computational and Structural Biotechnology. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/)

Endometrial Tumor Classification by Histomorphology and Biomarkers in the Nurses’ Health Study

Objective: Endometrial cancers have historically been classified by histomorphologic appearance, which is subject to interobserver disagreement. As molecular and biomarker testing has become increasingly available, the prognostic significance and accuracy of histomorphologic diagnoses have been questioned. To address these issues for a large, prospective cohort study, we provide the results of a centralized pathology review and biomarker analysis of all incidental endometrial carcinomas occurring between 1976 and 2012 in the Nurses' Health Study. Methods: Routine histology of all (n = 360) cases was reviewed for histomorphologic diagnosis. Cases were subsequently planted in a tissue microarray to explore expression of a variety of biomarkers (e.g., ER, PR, p53, PTEN, PAX2, AMACR, HNF1β, Napsin A, p16, PAX8, and GATA3). Results: Histologic subtypes included endometrioid (87.2%), serous (5.6%), carcinosarcoma (3.9%), clear cell (1.7%), and mixed type (1.7%). Biomarker results within histologic subtypes were consistent with existing literature: abnormal p53 was frequent in serous cases (74%), and HNF1β (67%), Napsin A (67%), and AMACR (83%) expression was frequent in clear cell carcinomas. Our dataset also allowed for examination of biomarker expression across non-preselected histologies. The results demonstrated that (1) HNF1β was not specific for clear cell carcinoma, (2) TP53 mutations occurred across many histologies, and (3) GATA3 was expressed across multiple histotypes, with 75% of positive cases demonstrating high-grade features. Conclusions: Our findings establish the subtypes of endometrial cancer occurring in the Nurses' Health Study, corroborate the sensitivity of certain well-established biomarkers, and call into question previously identified associations between certain biomarkers (e.g., HNF1B) and particular histotypes

In pancreatic ductal adenocarcinoma blood concentrations of some organochlorine compounds and coffee intake are independently associated with KRAS mutations

8 pages, 4 pages.-- PMID: 19797353 [PubMed].-- Printed version published Nov 2009.While KRAS activation is a fundamental initiating event in the aetiopathogenesis of pancreatic ductal adenocarcinoma (PDA), environmental factors influencing the occurrence and persistence of KRAS mutations remain largely unknown. The objective was to test the hypothesis that in PDA there are aetiopathogenic relationships among concentrations of some organochlorine compounds (OCs) and the mutational status of the KRAS oncogene, as well as among the latter and coffee intake. Incident cases of PDA were interviewed and had blood drawn at hospital admission (N = 103). OCs were measured by high-resolution gas chromatography with electron capture detection. Cases whose tumours harboured a KRAS mutation had higher concentrations of p,p′-dichlorodiphenyltrichloroethane (DDT), p,p′-dichlorodiphenyldichloroethene (DDE) and polychlorinated biphenyls (PCBs) 138, 153 and 180 than cases with wild-type KRAS, but differences were statistically significant only for p,p′-DDT and PCBs 138 and 153. The association between coffee intake and KRAS mutations remained significant (P-trend < 0.015) when most OCs where accounted for. When p,p′-DDT, PCB 153, coffee and alcohol intake were included in the same model, all were associated with KRAS (P = 0.042, 0.007, 0.016 and 0.025, respectively). p,p′-DDT, p,p′-DDE and PCB 138 were significantly associated with the two most prevalent KRAS mutations (Val and Asp). OCs and coffee may have independent roles in the aetiopathogenesis of PDA through modulation of KRAS activation, acquisition or persistence, plausibly through non-genotoxic or epigenetic mechanisms. Given that KRAS mutations are the most frequent abnormality of oncogenes in human cancers, and the lifelong accumulation of OCs in humans, refutation or replication of the findings is required before any implications are assessed.Government of Catalonia (2009 SGR 1350); ‘Red temática de investigación cooperativa de centros en Cáncer’ (C03/10); ‘Red temática de investigación cooperativa de centros en Epidemiología y salud pública’ (C03/09); CIBER de Epidemiología y Salud Pública, Instituto de Salud Carlos III, Madrid, Government of Spain.Peer reviewe

Mediterranean diet and telomere length in Nurses’ Health Study: population based cohort study

Objective: To examine whether adherence to the Mediterranean diet was associated with longer telomere length, a biomarker of aging. Design: Population based cohort study. Setting: Nurses’ Health Study, an ongoing prospective cohort study of 121 700 nurses enrolled in 1976; in 1989-90 a subset of 32 825 women provided blood samples. Participants: 4676 disease-free women from nested case-control studies within the Nurses’ Health Study with telomere length measured who also completed food frequency questionnaires. Main outcome measure Association between relative telomere lengths in peripheral blood leukocytes measured by quantitative real time polymerase chain reaction and Alternate Mediterranean Diet score calculated from self reported dietary data. Results: Greater adherence to the Mediterranean diet was associated with longer telomeres after adjustment for potential confounders. Least squares mean telomere length z scores were −0.038 (SE 0.035) for the lowest Mediterranean diet score groups and 0.072 (0.030) for the highest group (P for trend=0.004). Conclusion: In this large study, greater adherence to the Mediterranean diet was associated with longer telomeres. These results further support the benefits of adherence to the Mediterranean diet for promoting health and longevity

Association Between Egg Consumption and Dementia Risk in the EPIC-Spain Dementia Cohort

Current evidence suggests that egg composition might have potential neuroprotective effects. Our aim was to determine the association between egg consumption and the risk of dementia in a Mediterranean population. MethodsThis study was carried out in 3 centers from the European Prospective Investigation into Cancer and Nutrition (EPIC)-Spain Dementia Cohort, i.e., 25,015 participants aged 30-70 years, recruited in 1992-1996, and followed up for a mean of 21.5 years. ResultsA total of 774 incident dementia cases were diagnosed and validated, of which 518 were Alzheimer's disease (AD). Data on egg consumption were estimated using a validated dietary history questionnaire at recruitment. Cox proportional hazards models, adjusted for confounders, were used in the analyses. No association was observed between egg consumption and either total dementia [hazard ratio between extreme quartiles (HRQ4vs.Q1: 1.05; 95% CI 0.85-1.31; p-trend = 0.93)] or AD (HRQ4vs.Q1 0.93; 95% CI 0.72-1.21; p-trend = 0.50) risks. After dividing the population by adherence to the relative Mediterranean diet (rMED) score, a borderline inverse association was found between egg intake and both total dementia (HRQ4vs.Q1: 0.52; 95% CI 0.30-0.90; p-trend = 0.10) and AD (HRQ4vs.Q1: 0.52; 95% CI 0.27-1.01; p-trend = 0.13) risks within participants with low adherence to rMED score. However, no association was observed in participants with medium and high adherence to rMED score. ConclusionThis prospective study suggests that egg consumption is associated with a reduced risk of dementia, and specifically of AD, in the adult population with low adherence to rMED score; whereas it has no impact in subjects with moderate and high MD adherence

Polymorphisms in alcohol metabolism genes ADH1B and ALDH2, alcohol consumption and colorectal cancer

Background: Colorectal cancer (CRC) is a leading cause of cancer death worldwide. Epidemiological risk factors for CRC included alcohol intake, which is mainly metabolized to acetaldehyde by alcohol dehydrogenase and further oxidized to acetate by aldehyde dehydrogenase; consequently, the role of genes in the alcohol metabolism pathways is of particular interest. The aim of this study is to analyze the association between SNPs in ADH1B and ALDH2 genes and CRC risk, and also the main effect of alcohol consumption on CRC risk in the study population. Methodology/Principal Findings: SNPs from ADH1B and ALDH2 genes, included in alcohol metabolism pathway, were genotyped in 1694 CRC cases and 1851 matched controls from the Molecular Epidemiology of Colorectal Cancer study. Information on clinicopathological characteristics, lifestyle and dietary habits were also obtained. Logistic regression and association analysis were conducted. A positive association between alcohol consumption and CRC risk was observed in male participants from the Molecular Epidemiology of Colorectal Cancer study (MECC) study (OR = 1.47; 95%CI = 1.18-1.81). Moreover, the SNPs rs1229984 in ADH1B gene was found to be associated with CRC risk: under the recessive model, the OR was 1.75 for A/A genotype (95%CI = 1.21-2.52; p-value = 0.0025). A path analysis based on structural equation modeling showed a direct effect of ADH1B gene polymorphisms on colorectal carcinogenesis and also an indirect effect mediated through alcohol consumption. Conclusions/Significance: Genetic polymorphisms in the alcohol metabolism pathways have a potential role in colorectal carcinogenesis, probably due to the differences in the ethanol metabolism and acetaldehyde oxidation of these enzyme variants

Exome-Wide Association Study of Endometrial Cancer in a Multiethnic Population

Endometrial cancer (EC) contributes substantially to total burden of cancer morbidity and mortality in the United States. Family history is a known risk factor for EC, thus genetic factors may play a role in EC pathogenesis. Three previous genome- wide association studies (GWAS) have found only one locus associated with EC, suggesting that common variants with large effects may not contribute greatly to EC risk. Alternatively, we hypothesize that rare variants may contribute to EC risk. We conducted an exome-wide association study (EXWAS) of EC using the Infinium HumanExome BeadChip in order to identify rare variants associated with EC risk. We successfully genotyped 177,139 variants in a multiethnic population of 1,055 cases and 1,778 controls from four studies that were part of the Epidemiology of Endometrial Cancer Consortium (E2C2). No variants reached global significance in the study, suggesting that more power is needed to detect modest associations between rare genetic variants and risk of EC

Large differences in global transcriptional regulatory programs of normal and tumor colon cells

Background: Dysregulation of transcriptional programs leads to cell malfunctioning and can have an impact in cancer development. Our study aims to characterize global differences between transcriptional regulatory programs of normal and tumor cells of the colon. Methods: Affymetrix Human Genome U219 expression arrays were used to assess gene expression in 100 samples of colon tumor and their paired adjacent normal mucosa. Transcriptional networks were reconstructed using ARACNe algorithm using 1,000 bootstrap replicates consolidated into a consensus network. Networks were compared regarding topology parameters and identified well-connected clusters. Functional enrichment was performed with SIGORA method. ENCODE ChIP-Seq data curated in the hmChIP database was used for in silico validation of the most prominent transcription factors. Results: The normal network contained 1,177 transcription factors, 5,466 target genes and 61,226 transcriptional interactions. A large loss of transcriptional interactions in the tumor network was observed (11,585; 81% reduction), which also contained fewer transcription factors (621; 47% reduction) and target genes (2,190; 60% reduction) than the normal network. Gene silencing was not a main determinant of this loss of regulatory activity, since the average gene expression was essentially conserved. Also, 91 transcription factors increased their connectivity in the tumor network. These genes revealed a tumor-specific emergent transcriptional regulatory program with significant functional enrichment related to colorectal cancer pathway. In addition, the analysis of clusters again identified subnetworks in the tumors enriched for cancer related pathways (immune response, Wnt signaling, DNA replication, cell adherence, apoptosis, DNA repair, among others). Also multiple metabolism pathways show differential clustering between the tumor and normal network. Conclusions: These findings will allow a better understanding of the transcriptional regulatory programs altered in colon cancer and could be an invaluable methodology to identify potential hubs with a relevant role in the field of cancer diagnosis, prognosis and therapy