[Show abstract][Hide abstract] ABSTRACT: 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.
BMC Cancer 09/2014; 14(1):708. · 3.33 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Accurate detection of characteristic proteins secreted by colon cancer tumor cells in biological fluids could serve as a biomarker for the disease. The aim of the present study was to identify and validate new serum biomarkers and demonstrate their potential usefulness for early diagnosis of colon cancer.
PLoS ONE 09/2014; 9(9):e106748. · 3.53 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: In this study we aim to identify the genes responsible for colorectal cancer (CRC) risk behind the loci identified in genome-wide association studies (GWAS). These genes may be candidate targets for developing new strategies for prevention or therapy. We analyzed the association of genotypes for 26 GWAS SNPs with the expression of genes within a 2Mb region (cis-eQTLs). Affymetrix Human Genome U219 expression arrays were used to assess gene expression in two series of samples, one of healthy colonic mucosa (n=47) and other of normal mucosa adjacent to colon cancer (n=97, total 144). Paired tumor tissues (n=97) were also analyzed, but did not provide additional findings. Partial Pearson correlation (r), adjusted for sample type, was used for the analysis. We have found Bonferroni-significant cis-eQTLs in three loci: rs3802842 in 11q23.1 associated to C11orf53, COLCA1 (C11orf92) and COLCA2 (C11orf93) (r=0.60); rs7136702 in 12q13.12 associated to DIP2B (r=0.63); and rs5934683 in Xp22.3 associated to SHROOM2 and GPR143 (r=0.47). For loci in chromosomes 11 and 12, we have found other SNPs in LD that are more strongly associated with the expression of the identified genes and are better functional candidates: rs7130173 for 11q23.1 (r=0.66) and rs61927768 for 12q13.12 (r=0.86). These SNPs are located in DNA regions that may harbor enhancers or transcription factor binding sites. The analysis of trans-eQTLs has identified additional genes in these loci that may have common regulatory mechanisms as shown by the analysis of protein-protein interaction networks.
[Show abstract][Hide abstract] ABSTRACT: A colorectal tumor is not an isolated entity growing in a restricted location of the body. The patient's gut environment constitutes the framework where the tumor evolves and this relationship promotes and includes a complex and tight correlation of the tumor with inflammation, blood vessels formation, nutrition, and gut microbiome composition. The tumor influence in the environment could both promote an anti-tumor or a pro-tumor response.
A set of 98 paired adjacent mucosa and tumor tissues from colorectal cancer (CRC) patients and 50 colon mucosa from healthy donors (246 samples in total) were included in this work. RNA extracted from each sample was hybridized in Affymetrix chips Human Genome U219. Functional relationships between genes were inferred by means of systems biology using both transcriptional regulation networks (ARACNe algorithm) and protein-protein interaction networks (BIANA software).
Here we report a transcriptomic analysis revealing a number of genes activated in adjacent mucosa from CRC patients, not activated in mucosa from healthy donors. A functional analysis of these genes suggested that this active reaction of the adjacent mucosa was related to the presence of the tumor. Transcriptional and protein-interaction networks were used to further elucidate this response of normal gut in front of the tumor, revealing a crosstalk between proteins secreted by the tumor and receptors activated in the adjacent colon tissue; and vice versa. Remarkably, Slit family of proteins activated ROBO receptors in tumor whereas tumor-secreted proteins transduced a cellular signal finally activating AP-1 in adjacent tissue.
The systems-level approach provides new insights into the micro-ecology of colorectal tumorogenesis. Disrupting this intricate molecular network of cell-cell communication and pro-inflammatory microenvironment could be a therapeutic target in CRC patients.
Molecular Cancer 03/2014; 13(1):46. · 5.13 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: 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.
PLoS ONE 01/2014; 9(5):e97045. · 3.53 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Endometrial cancer (EC), a neoplasm of the uterine epithelial lining, is the most common gynecological malignancy in developed countries and the fourth most common cancer among US women. Women with a family history of EC have an increased risk for the disease, suggesting that inherited genetic factors play a role. We conducted a two-stage genome-wide association study of Type I EC. Stage 1 included 5,472 women (2,695 cases and 2,777 controls) of European ancestry from seven studies. We selected independent single-nucleotide polymorphisms (SNPs) that displayed the most significant associations with EC in Stage 1 for replication among 17,948 women (4,382 cases and 13,566 controls) in a multiethnic population (African America, Asian, Latina, Hawaiian and European ancestry), from nine studies. Although no novel variants reached genome-wide significance, we replicated previously identified associations with genetic markers near the HNF1B locus. Our findings suggest that larger studies with specific tumor classification are necessary to identify novel genetic polymorphisms associated with EC susceptibility.
[Show abstract][Hide abstract] ABSTRACT: 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.
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.
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.
PLoS ONE 01/2013; 8(11):e80158. · 3.53 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Colorectal cancer (CRC) is a leading cause of cancer death worldwide. Epidemiological risk factors for CRC included dietary fat intake; consequently, the role of genes in the fatty acid biosynthesis and metabolism pathways is of particular interest. Moreover, hyperlipidaemia has been associated with different type of cancer and serum lipid levels could be affected by genetic factors, including polymorphisms in the lipid metabolism pathway. The aim of this study is to assess the association between single-nucleotide polymorphisms (SNPs) in fatty acid metabolism genes, serum lipid levels, body mass index (BMI) and dietary fat intake and CRC risk; 30 SNPs from 8 candidate genes included in fatty acid biosynthesis and metabolism pathways were genotyped in 1780 CRC cases and 1864 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. Several LIPC (lipase, hepatic) polymorphisms were found to be associated with CRC risk, although no particular haplotype was related to CRC. The SNP rs12299484 showed an association with CRC risk after Bonferroni correction. We replicate the association between the T allele of the LIPC SNP rs1800588 and higher serum high-density lipoprotein levels. Weak associations between selected polymorphism in the LIPC and PPARG genes and BMI were observed. A path analysis based on structural equation modelling showed a direct effect of LIPC gene polymorphisms on colorectal carcinogenesis as well as an indirect effect mediated through serum lipid levels. Genetic polymorphisms in the hepatic lipase gene have a potential role in colorectal carcinogenesis, perhaps though the regulation of serum lipid levels.
[Show abstract][Hide abstract] ABSTRACT: The development of genotyping technologies has allowed for wider screening for inherited causes of variable outcomes following drug administration. We have performed a genome-wide association study (GWAS) on 221 colorectal cancer (CRC) patients that had been treated with 5-fluorouracil (5-FU), either alone or in combination with oxaliplatin (FOLFOX). A validation set of 791 patients was also studied. Seven SNPs (rs16857540, rs2465403, rs10876844, rs10784749, rs17626122, rs7325568 and rs4243761) showed evidence of association (pooled P-values 0.020, 9.426E-03, 0.010, 0.017, 0.042, 2.302E-04, 2.803E-03) with adverse drug reactions (ADRs). This is the first study to explore the genetic basis of inter-individual variation in toxicity responses to the administration of 5-FU or FOLFOX in CRC patients on a genome-wide scale.The Pharmacogenomics Journal advance online publication, 7 February 2012; doi:10.1038/tpj.2012.2.
The Pharmacogenomics Journal 02/2012; · 5.13 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: INTRODUCTION: The traditional staging system is inadequate to identify those patients with stage II colorectal cancer (CRC) at high risk of recurrence or with stage III CRC at low risk. A number of gene expression signatures to predict CRC prognosis have been proposed, but none is routinely used in the clinic. The aim of this work was to assess the prediction ability and potential clinical usefulness of these signatures in a series of independent datasets. METHODS: A literature review identified 31 gene expression signatures that used gene expression data to predict prognosis in CRC tissue. The search was based on the PubMed database and was restricted to papers published from January 2004 to December 2011. Eleven CRC gene expression datasets with outcome information were identified and downloaded from public repositories. Random Forest classifier was used to build predictors from the gene lists. Matthews correlation coefficient was chosen as a measure of classification accuracy and its associated p-value was used to assess association with prognosis. For clinical usefulness evaluation, positive and negative post-tests probabilities were computed in stage II and III samples. RESULTS: Five gene signatures showed significant association with prognosis and provided reasonable prediction accuracy in their own training datasets. Nevertheless, all signatures showed low reproducibility in independent data. Stratified analyses by stage or microsatellite instability status showed significant association but limited discrimination ability, especially in stage II tumors. From a clinical perspective, the most predictive signatures showed a minor but significant improvement over the classical staging system. CONCLUSIONS: The published signatures show low prediction accuracy but moderate clinical usefulness. Although gene expression data may inform prognosis, better strategies for signature validation are needed to encourage their widespread use in the clinic.
PLoS ONE 01/2012; 7(11):e48877. · 3.53 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: As cancer is a complex disease, the representation of a malignant cell as a protein-protein interaction network (PPIN) and its subsequent analysis can provide insight into the behaviour of cancer cells and lead to the discovery of new biomarkers. The aim of this review is to help life-science researchers without previous computer programming skills to extract meaningful biological information from such networks, taking advantage of easy-to-use, public bioinformatics tools. It is structured in four parts: the first section describes the pipeline of consecutive steps from network construction to biological hypothesis generation. The second part provides a repository of public, user-friendly tools for network construction, visualisation and analysis. Two different and complementary approaches of network analysis are presented: the topological approach studies the network as a whole by means of structural graph theory, whereas the global approach divides the PPIN into sub-graphs, or modules. In section three, some concepts and tools regarding heterogeneous molecular data integration through a PPIN are described. Finally, the fourth part is an example of how to extract meaningful biological information from a colorectal cancer PPIN using some of the described tools.
Clinical and Translational Oncology 01/2012; 14(1):3-14. · 1.28 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: 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.
[Show abstract][Hide abstract] ABSTRACT: Surprisingly different frequencies and patterns of K-ras mutations are observed in human adenocarcinomas of the pancreas, colorectum and lung. Their respective relationships with smoking are apparently paradoxical. We evaluated all the available types of clinical and epidemiological studies on the relationship between tobacco smoking and the occurrence of K-ras mutations in human adenocarcinomas of the pancreas, colorectum and lung. We identified 8, 7 and 12 studies that analyzed the relationship between K-ras mutations and tobacco smoking in human neoplasms of the pancreas, colorectum and lung, respectively. A meta-analysis was undertaken for each site separately. In pancreatic adenocarcinomas lifetime history of tobacco consumption was not significantly associated with the frequency of K-ras mutations (OR=1.26; 95% CI=0.82-1.94). Similarly, no association was observed between smoking and K-ras mutations in colorectal adenocarcinomas (OR=0.94; CI=0.79-1.12), neither when colorectal adenomas and adenocarcinomas were jointly analyzed (OR=0.96; 95% CI=0.83-1.13). In lung adenocarcinoma, where only 15-25% of cases harbor a K-ras mutation, tumors from smokers were more likely to have K-ras mutations than tumors from non-smokers (OR=3.67; 95% CI=2.47-5.45). Furthermore, in lung adenocarcinomas K-ras mutations have a pattern different from that in pancreatic and colorectal adenocarcinomas. Results support the hypothesis that smoking influences the risk of pancreatic cancer - and possibly colorectal cancer - through events other than K-ras mutations. In adenocarcinoma of the lung, smoking may play a role in the occurrence of K-ras mutations. If the influence of tobacco products in the induction, acquisition and persistence of K-ras mutations had some tissue specificity, or was dependent on different factors in different organs, the corresponding mechanisms would deserve detailed research.
Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis 08/2009; 682(2-3):83-93. · 3.90 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: In pancreatic ductal adenocarcinoma (PDA), evidence on the etiopathogenic role of alcohol consumption in the occurrence of K-ras mutations is scant, and the role of alcohol in pancreatic carcinogenesis is not well established. We analyzed the relation between lifetime consumption of alcohol and mutations in codon 12 of the K-ras oncogene in patients with PDA.
Incident cases of PDA were prospectively identified and interviewed face-to-face during hospital admission about lifetime alcohol consumption and other lifestyle factors. Logistic regression was used to compare PDA cases (N = 107) with mutated and wild-type K-ras tumors (case-case study).
Mutated cases were moderate or heavy drinkers more frequently than wild-type cases: the odds ratio adjusted by age, sex, smoking, and history of pancreatitis (ORa) was 3.18 (95% confidence interval: 1.02-9.93; P = 0.046). Total grams of alcohol and years of consumption were higher in mutated than in wild-type cases: the ORa for lifetime alcohol consumption over 507,499 g was 3.35 (95% CI: 0.81-13.88); and for more than 40 years of alcohol consumption it was 4.47 (95% CI: 1.05-19.02). Age at onset of alcohol consumption and years of abstinence were also associated with the presence of K-ras mutations. There were no significant differences in alcohol dependency.
Alcohol consumption is weakly associated with an increased risk of having a K-ras mutated PDA. To confirm or to refute the hypothesis that ethanol, acetaldehyde or other alcohol-related substances might influence the acquisition or persistence of K-ras mutations in the pancreatic epithelium, large and unselected studies are warranted.
Environmental and Molecular Mutagenesis 04/2009; 50(5):421-30. · 3.71 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: In pancreatic ductal adenocarcinoma (PDA) evidence on the etiopathogenic role of past medical conditions in the occurrence and persistence of K-ras mutations is scant.
Incident cases of PDA were interviewed face-to-face about past medical history and other factors. Logistic regression was used to compare PDA cases (n = 120) with wild-type and mutated K-ras tumors (case-case study).
Patients with wild-type K-ras tumors were more likely to have a prior diagnosis of pancreatitis (Odds ratio [OR] = 6.11, p = 0.041). Diabetes mellitus (DM) was non-significantly more common among cases with a K-ras wild-type tumor, and the OR for DM of >6 years of duration was 4.54 (p = 0.39). Patients with wild-type K-ras were significantly more likely to have had a surgically treated peptic ulcer (OR = 9.03, p = 0.027). The probability of having a K-ras wild-type tumor increased with the number of medical conditions (p for trend = 0.012); the corresponding OR for two or more medical conditions was 4.46 (95% CI: 1.37-14.50).
Results raise the hypothesis that pancreatitis and possibly peptic ulcer might influence pancreatic carcinogenesis through pathways independent of K-ras mutation, perhaps related to growth factors or mediators of the inflammatory response. Large unselected studies should be conducted to refute or replicate our findings.
Cancer Causes and Control 12/2008; 20(5):591-9. · 3.20 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Disease-induced changes in blood concentrations of lipids may bias etiologic studies. We analyzed the influence of clinical factors and timing of blood extraction on serum concentrations of cholesterol and triglycerides in exocrine pancreatic cancer (EPC).
Subjects were 144 incident cases of EPC prospectively recruited in five teaching hospitals in eastern Spain.
Higher concentrations of cholesterol, triglycerides, and total lipids were observed among patients with a shorter interval from first symptom of cancer to blood extraction (IES); but concentrations were lower in patients with longer IES. The relationship between cholesterol and tumor stage was "n-shaped." Jaundice and other components of the cholestatic syndrome increased cholesterol and triglycerides. Invasive diagnostic tests were associated with lower cholesterol. All these factors were related to changes >50mg/dl in cholesterol (P<0.05), even when adjusting by stage. Statistical models including IES, number of invasive diagnostic tests, jaundice, weight loss, and stage explained over 28% of the variation in lipid concentrations.
Restriction and adjustment by stage may be insufficient to prevent biases related to disease progression. Multivariate analyses may allow to control to some extent the influence of clinical symptoms, procedures, and timing of blood extraction in studies on the etiological significance of lipids and lipophilic compounds, either risk factors or protective agents.
Journal of Clinical Epidemiology 08/2008; 61(7):695-704. · 5.48 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The frequency of CYP1B1 polymorphisms in pancreatic cancer has never been reported. There is also no evidence on the relationship between CYP1B1 variants and mutations in ras genes (K-, H- or N-ras) in any human neoplasm. We analyzed the following CYP1B1 polymorphisms in 129 incident cases of pancreatic ductal adenocarcinoma (PDA): the m1 allele (Val to Leu at codon 432) and the m2 allele (Asn to Ser at codon 453). The calculated frequencies for the m1 Val and m2 Asn alleles were 0.45 and 0.68, respectively. CYP1B1 genotypes were out of Hardy-Weinberg equilibrium; this was largely due to K-ras mutated PDA cases. The Val/Val genotype was over five times more frequent in PDA cases with a K-ras mutation than in wild-type cases (OR = 5.25; P = 0.121). In PDA, polymorphisms in CYP1B1 might be related with K-ras activation pathways.
Digestive Diseases and Sciences 06/2008; 53(5):1417-21. · 2.26 Impact Factor