Biomarkers of environmental exposure: genetic and epigenetic approaches

Exposure assessment in cancer epidemiological studies relies on measurable intermediate molecular biomarkers with high sensitivity and specificity in order to prevent common problems due to misclassification of exposure. Studies on the early stages of carcinogenesis have helped to identify molecular changes that are detectable in pre-cancerous lesions and that are thought to occur as the result of specific exposures such as tobacco smoking. More recently, in vitro evidence started to support the potential cancer-protective role of various micronutrients acting through epigenetic and genetic mechanisms. Somatic mutations in “master” cancer genes and modifications of epigenetic patterns in the promoter region of specific genes involved in cell cycle, apoptosis or DNA repair may prove good candidates of carcinogenic and dietary exposure even if the evidence that these changes may be present and detectable in “normal” tissue are still scarce (due in part to the practical and ethical difficulty to conduct experimental prospective studies in healthy individuals). In this thesis, I have developed two projects exploring the application of TP53, KRAS, EGFR mutations and of DNA methylation changes as biomarkers of exposure to tobacco smoking, in experimental and observational study designs. Somatic mutations were analysed by dHPLC, ME-PCR, RFLP and sequencing and DNA-methylation analysis was performed by pyrosequencing. Moreover, somatic mutations were analysed in a prospective context of lung cancer recurrence; also the capacity of dietary polyphenols and isothiocyanates to modify methylation patterns in smokers was assessed in an intervention trial. The results show that somatic mutations are good markers of different forms of tobacco-related lung cancers but have limited short-term prognostic value, with the exception of KRAS mutations in adenocarcinoma. Methylation data suggested that a specific short-term dietary intervention may stabilize global epigenetic (LINE1 DNA methylation) patterns in peripheral white blood cells

Body fatness and cancer - viewpoint of the IARC working group

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European Code against Cancer 4th Edition:Obesity, body fatness and cancer

AbstractIt is estimated that over half the population of the European Union (EU) is overweight or obese due to an imbalance between energy expenditure and energy intake; this is related to an obesogenic environment of sociocultural, economic and marketing challenges to the control of body weight. Excess body fat is associated with nine cancer sites – oesophagus, colorectum, gall bladder, pancreas, postmenopausal breast, endometrium, ovary, kidney and prostate (advanced) – and 4–38% of these cancers (depending on site and gender) can be attributed to overweight/obesity status. Metabolic alterations which accompany excess body weight are accompanied by increased levels of inflammation, insulin, oestrogens and other hormonal factors. There are some indications that intentional weight loss is associated with reduced cancer incidence (notably in postmenopausal breast and endometrial cancers). Excess body weight is also a risk factor for several other diseases, including diabetes and heart disease, and is related to higher risk of premature death.In reviewing the current evidence related to excess body fat and cancer, the European Code against Cancer Nutrition Working Group has developed the following recommendation: ‘Take action to be a healthy body weight’

Alcohol intake and breast cancer in the European prospective investigation into cancer and nutrition

Alcohol intake has been associated to breast cancer in pre and postmenopausal women; however results are inconclusive regarding tumor hormonal receptor status, and potential modifying factors like age at start drinking. Therefore, we investigated the relation between alcohol intake and the risk of breast cancer using prospective observational data from the European Prospective Investigation into Cancer and Nutrition (EPIC). Up to 334,850 women, aged 35-70 years at baseline, were recruited in ten European countries and followed up an average of 11 years. Alcohol intake at baseline and average lifetime alcohol intake were calculated from country-specific dietary and lifestyle questionnaires. The study outcomes were the Hazard ratios (HR) of developing breast cancer according to hormonal receptor status. During 3,670,439 person-years, 11,576 incident breast cancer cases were diagnosed. Alcohol intake was significantly related to breast cancer risk, for each 10 g/day increase in alcohol intake the HR increased by 4.2% (95% CI: 2.7-5.8%). Taking 0 to 5 g/day as reference, alcohol intake of >5 to 15 g/day was related to a 5.9% increase in breast cancer risk (95% CI: 1-11%). Significant increasing trends were observed between alcohol intake and ER+/PR+, ER-/PR-, HER2- and ER-/PR-HER2- tumors. Breast cancer risk was stronger among women who started drinking prior to first full-time pregnancy. Overall, our results confirm the association between alcohol intake and both hormone receptor positive and hormone receptor negative breast tumors, suggesting that timing of exposure to alcohol drinking may affect the risk. Therefore, women should be advised to control their alcohol consumption. What's new? Although it is now established that alcohol consumption increases breast cancer risk, many questions remain. Using a prospective study design with 11,576 incident breast cancer cases across 10 European countries, the authors confirmed the increased risk of alcohol on breast cancer development. They further show that women who started drinking before their first full-term pregnancy have a higher risk than women who started afterwards. These effects were observed in hormone-receptor positive and -negative tumors pointing to non-hormonal pathways that need to be further investigated

European code against cancer 4th edition: 12 ways to reduce your cancer risk

This overview describes the principles of the 4th edition of the European Code against Cancer and provides an introduction to the 12 recommendations to reduce cancer risk. Among the 504.6 million inhabitants of the member states of the European Union (EU28), there are annually 2.64 million new cancer cases and 1.28 million deaths from cancer. It is estimated that this cancer burden could be reduced by up to one half if scientific knowledge on causes of cancer could be translated into successful prevention. The Code is a preventive tool aimed to reduce the cancer burden by informing people how to avoid or reduce carcinogenic exposures, adopt behaviours to reduce the cancer risk, or to participate in organised intervention programmes. The Code should also form a base to guide national health policies in cancer prevention. The 12 recommendations are: not smoking or using other tobacco products; avoiding second-hand smoke; being a healthy body weight; encouraging physical activity; having a healthy diet; limiting alcohol consumption, with not drinking alcohol being better for cancer prevention; avoiding too much exposure to ultraviolet radiation; avoiding cancer-causing agents at the workplace; reducing exposure to high levels of radon; encouraging breastfeeding; limiting the use of hormone replacement therapy; participating in organised vaccination programmes against hepatitis B for newborns and human papillomavirus for girls; and participating in organised screening programmes for bowel cancer, breast cancer, and cervical cancer

European Code against Cancer 4th Edition:Breastfeeding and cancer

Breast cancer is the most frequent cancer in women, and incidence rates have been rising in European Union (EU) countries over recent decades due in part to a sharp decline in breastfeeding practices. Evidence for a protective association between breastfeeding and the risk of breast cancer at all ages is convincing, and modest protective relationships between breastfeeding and the risk of endometrial and ovarian cancers have been suggested. The reduction in breast cancer risk is estimated at 2% for an increase of 5 months of lifetime breastfeeding. The longer women breastfeed, the more they are protected against breast cancer. In addition, breastfeeding is associated with several health benefits for both the mother and the breastfed child. Taking all this evidence into account, the 4th edition of the European Code against Cancer recommends: ‘‘Breastfeeding reduces the mother’s cancer risk. If you can, breastfeed your baby’’

European Code against Cancer 4th Edition: Alcohol drinking and cancer.

Alcohol consumption is the third leading risk factor for disease and mortality in Europe. As evaluated by the International Agency for Research on Cancer (IARC) Monographs, a causal relationship is established for consumption of alcoholic beverages and cancers of the oral cavity, pharynx, larynx, oesophagus, liver, colorectum and female breast, even at low and moderate alcohol intakes. The higher the amount of alcohol consumed, the higher the risk of developing cancer. In Europe, an estimated 10% (95% CI: 7%-13%) of all cancer cases in men and 3% (95% CI: 1%-5%) of all cancer cases in women are attributable to alcohol consumption. Several biological mechanisms explain the carcinogenicity of alcohol; among them, ethanol and its genotoxic metabolite, acetaldehyde, play a major role. Taking all this evidence into account, a recommendation of the 4th edition of European Code against Cancer is: "If you drink alcohol of any type, limit your intake. Not drinking alcohol is better for cancer prevention.

European Code against Cancer 4th Edition:Diet and cancer

AbstractLifestyle factors, including diet, have long been recognised as potentially important determinants of cancer risk. In addition to the significant role diet plays in affecting body fatness, a risk factor for several cancers, experimental studies have indicated that diet may influence the cancer process in several ways. Prospective studies have shown that dietary patterns characterised by higher intakes of fruits, vegetables, and whole-grain foods, and lower intakes of red and processed meats and salt, are related to reduced risks of death and cancer, and that a healthy diet can improve overall survival after diagnosis of breast and colorectal cancers. There is evidence that high intakes of fruit and vegetables may reduce the risk of cancers of the aerodigestive tract, and the evidence that dietary fibre protects against colorectal cancer is convincing. Red and processed meats increase the risk of colorectal cancer. Diets rich in high-calorie foods, such as fatty and sugary foods, may lead to increased calorie intake, thereby promoting obesity and leading to an increased risk of cancer. There is some evidence that sugary drinks are related to an increased risk of pancreatic cancer.Taking this evidence into account, the 4th edition of the European Code against Cancer recommends that people have a healthy diet to reduce their risk of cancer: they should eat plenty of whole grains, pulses, vegetables and fruits; limit high-calorie foods (foods high in sugar or fat); avoid sugary drinks and processed meat; and limit red meat and foods high in salt

Biomarkers of environmental exposure : genetic and epigenetic approaches

Exposure assessment in cancer epidemiological studies relies on measurable intermediate molecular biomarkers with high sensitivity and specificity in order to prevent common problems due to misclassification of exposure. Studies on the early stages of carcinogenesis have helped to identify molecular changes that are detectable in pre-cancerous lesions and that are thought to occur as the result of specific exposures such as tobacco smoking. More recently, in vitro evidence started to support the potential cancer-protective role of various micronutrients acting through epigenetic and genetic mechanisms. Somatic mutations in “master” cancer genes and modifications of epigenetic patterns in the promoter region of specific genes involved in cell cycle, apoptosis or DNA repair may prove good candidates of carcinogenic and dietary exposure even if the evidence that these changes may be present and detectable in “normal” tissue are still scarce (due in part to the practical and ethical difficulty to conduct experimental prospective studies in healthy individuals). In this thesis, I have developed two projects exploring the application of TP53, KRAS, EGFR mutations and of DNA methylation changes as biomarkers of exposure to tobacco smoking, in experimental and observational study designs. Somatic mutations were analysed by dHPLC, ME-PCR, RFLP and sequencing and DNA-methylation analysis was performed by pyrosequencing. Moreover, somatic mutations were analysed in a prospective context of lung cancer recurrence; also the capacity of dietary polyphenols and isothiocyanates to modify methylation patterns in smokers was assessed in an intervention trial. The results show that somatic mutations are good markers of different forms of tobacco-related lung cancers but have limited short-term prognostic value, with the exception of KRAS mutations in adenocarcinoma. Methylation data suggested that a specific short-term dietary intervention may stabilize global epigenetic (LINE1 DNA methylation) patterns in peripheral white blood cells.EThOS - Electronic Theses Online ServiceGBUnited Kingdo