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The aetiology of prostate cancer is largely unknown. In prospective analyses and individual participant meta-analyses we have shown that a high circulating concentration of insulin-like growth factor-I (IGF-I) is associated with prostate cancer risk, and elevated circulating IGF-I remains the only established and potentially modifiable risk factor. We have also found that protein intake may be positively associated with risk, and diets high in protein can increase circulating IGF-I. Metabolomics may help to clarify the mechanisms underlying these associations and may identify novel risk factors for prostate cancer. For example, dietary amino acids may affect cancer risk through effects on the synthesis of IGF-I and/or by stimulation of the mTOR pathway, which integrates signals from nutrients and growth factors and is an important mediator of cancer progression. In a pilot metabolomics study we have shown that strict vegetarians, who have low protein intakes and circulating IGF-I, have relatively low circulating concentrations of several essential amino acids. These include lysine and methionine, which may be important for IGF-I synthesis, and the branched-chain amino acids leucine and valine, which may be important in stimulating mTOR.
We plan to conduct a nested case-control study comparing the metabolomic profile of prediagnostic samples from prostate cancer cases and controls in order to examine the hypothesis that concentrations of amino acids and other plasma metabolites are associated with risk for prostate cancer. We will also test the hypotheses that plasma amino acid concentrations are related to the source of dietary protein and to IGF levels.
A case-control study nested within the European Prospective Investigation into Cancer and Nutrition. 180 plasma metabolites (amino acids, acylcarnitines, biogenic amines, hexoses, phospho- and sphingolipids) will be measured using a targeted metabolomic approach (the Biocrates AbsoluteIDQ p180 assay, a mass spectrometry-based metabolomics kit) in prediagnostic plasma samples from 1250 men who were subsequently diagnosed with prostate cancer and 1250 control participants. Cases will be matched to controls on recruitment centre, age, follow-up time, fasting status and time of blood collection. Conditional logistic regression analyses will be used to calculate odds ratios for prostate cancer in relation to individual metabolite concentrations and metabolite patterns. Partial correlation analyses and analyses of variance will be used to examine the relationships between diet, plasma metabolites and circulating IGF-I concentration.
This study will provide prospective data on the relationships between plasma metabolites, including amino acids, and prostate cancer risk, and will advance our understanding of the relationships between diet, circulating hormones and risk for the disease, as well as the underlying mechanisms. The identification of potentially modifiable metabolomic profiles associated with risk, and of correlated dietary and hormonal factors, may inform the future design of effective public health policies aimed at prostate cancer prevention.
Lay Title: Nutritional Markers in the Blood and Prostate Cancer Risk. Prostate cancer is the second most common cancer among men with more than 40,000 cases diagnosed in the United Kingdom each year, yet little is known about the causes of the disease. Age, family history of prostate cancer and ethnicity are known to influence prostate cancer risk. However, the only known risk factor for the disease that is potentially modifiable is having a high blood level of the hormone insulin-like growth factor (IGF)-I. Diets that are high in protein, especially protein from dairy foods, have been linked to high blood levels of IGF-I, and in some studies to risk of developing prostate cancer. The reason for this is unclear but may involve specific amino acids in the dietary protein. In a pilot study of amino acids measured in blood, we have found differences in the levels of several amino acids between individuals with different dietary patterns, including strict vegetarians.
We aim to determine whether blood levels of amino acids and other small molecules (known as metabolites) are associated with the risk of developing prostate cancer by comparing levels of metabolites in blood samples from men who went on to develop prostate cancer and men who did not. We will also investigate whether blood amino acid levels are related to dietary protein intake and to blood levels of the hormone IGF-I.
The proposed study will include men who are participating in the European Prospective Investigation into Cancer and Nutrition. Approximately 150 metabolites (including amino acids) will be measured in blood samples using an approach known as targeted metabolomics at the laboratory of the International Agency for Research on Cancer. Metabolite levels in samples from 1250 men who were subsequently diagnosed with prostate cancer will be compared to those from 1250 men who did not develop the disease but who were similar with respect to a number of other characteristics, such as recruitment centre, age, and time of day of blood collection. We will calculate the risk of developing cancer in men with high compared to low levels of each metabolite. To investigate the possible determinants of any metabolites found to be associated with prostate cancer risk, we will examine the blood levels of metabolites in relation to diet and lifestyle characteristics, inherited genetic variation and blood IGF-I level.
This study aims to increase our understanding of how diet affects hormones and thus prostate cancer risk and to identify new risk factors for the disease. The project will provide novel information on a wide range of blood metabolites, including amino acids, in relation to prostate cancer risk. The identification of potentially modifiable metabolite levels associated with risk, and of correlated dietary and hormonal factors, may inform the future design of effective public health policies aimed at prostate cancer prevention.