[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. · 5.33 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
[show abstract][hide abstract] ABSTRACT: An analysis of the contributions of "omics technologies" to human health and clinical care needs to address the relationships between internal issues (e.g., methodological shortcomings in "omics" research and clinical biology) and external influences. Among the latter, monetization of intellectual property (IP) appears to be a powerful force favoring methodological limitations and an excessive reductionism and fragmentation of biological knowledge. Following economic successes in other industries (semiconductors, software, and "dot-coms"), monetization of IP tries to market small fragments of big research "puzzles"; the strategy seems partly responsible for the biotech industry having underperformed methodological, clinical, and economic expectations. Hence, internal, purely scientific reasons can hardly explain failures in the application of long-proven principles of clinical epidemiology to the discovery and validation of diagnostic and prognostic tests. Nevertheless, this paper also sketches methodological proposals that may help integrate microbiological, clinical, and environmental evidence. Clinical and epidemiological reasoning, knowledge, and methods need to be applied on a much wider scale than until now by "omics" studies that aim at making inferences relevant for human beings. Rather than adopting the values and norms of "science business," "omics research" could apply a diversity of clinicoepidemiological models favoring integrative research.
[show abstract][hide abstract] ABSTRACT: We analyzed the relation between mutations in codon 12 of the K-ras oncogene and lifetime consumption of tobacco in patients with exocrine pancreatic cancer (EPC).
Incident cases of EPC were prospectively identified and interviewed during hospital admission about smoking and other factors. Exact logistic regression was used to compare EPC cases (N = 107) with and without K-ras mutations (case-case study).
Mutated cases were nonsignificantly less likely to have been smokers than wild-type cases: the odds ratio adjusted by age and sex was 0.54 (95% confidence interval, 0.10-2.69; P = 0.613). With respect to never smokers, adjusted odds ratios for former and current smokers were 0.79 and 0.36, respectively (P = 0.193). Pack-years smoked, years of smoking, and cigarettes smoked per year also tended to be higher in nonmutated than in mutated cases. Neither age at onset of smoking nor the time between quitting and diagnosis were associated with K-ras.
Tobacco does not play a major part in the acquisition of K-ras mutations in the pancreatic epithelium. Although both smoking and K-ras mutations have important roles in the etiopathogenesis of EPC, the 2 processes may act independently.
[show abstract][hide abstract] ABSTRACT: No studies have investigated the relation between K-ras mutations and dietary factors in exocrine pancreatic cancer (EPC), and fewer than 10 studies have done so in other neoplasms. Patients and
Incident cases of EPC were prospectively identified, and interviewed face-to-face during hospital admission. Food and nutrient intakes were measured with a food frequency questionnaire. Logistic regression was used to compare EPC cases (n = 107) with and without K-ras mutations (case-case study).
K-ras mutations were more common among daily consumers of milk and other dairy products than among non-daily consumers: the odds ratio adjusted by total energy, age, sex, smoking, alcohol and coffee consumption (ORa) was 5.1 (95% CI 1.1 to 24.5, p = 0.040). For all dairy products, including butter, the ORa for the medium and upper tertiles of intake were 5.4 and 11.6, respectively (p for trend = 0.023). The ORa for regular coffee drinkers further adjusted by dairy consumption was 4.7 (95% CI 1.1 to 20.7, p = 0.043). K-ras mutated cases reported a lower intake of vitamin E (ORa = 0.2, p for trend = 0.036), polyunsaturated fats and omega 3 fatty acids (ORa = 0.2; p for trend <0.03).
Results support the hypothesis that in EPC exposure to specific dietary components or contaminants may influence the occurrence or persistence of K-ras mutations.
Journal of Epidemiology & Community Health 07/2007; 61(7):641-9. · 3.39 Impact Factor