Table of Contents

Rationale

The European Prospective Investigation on Cancer (EPIC) is a cohort study involving ten European countries | © dkfz.de

After the completion of the human genome sequence, attention has turned to the identification of germline genetic variants that are associated with altered risk of cancers, and/or interact with common environmental exposures to cause or protect against these diseases. It is expected that a large fraction of genetic cancer susceptibility is due to polymorphisms common in the population and conferring small or moderate risk of disease. The main objective of our group is to study the role of genetic polymorphisms in relation to susceptibility to human cancers, in the context of large-scale population-based epidemiological studies, such as the European Prospective Investigation on Cancer (EPIC). We currently focus on a candidate gene approach, i.e. an exhaustive study of genetic variants in the key genes belonging to specific biochemical and regulatory pathways with high prior probability of association with cancer risk, due to their biological significance. As technology allows genetic analysis at higher throughput, we will perform also whole genome scans based on linkage disequilibrium to identify new genetic cancer risk factors.

Hormone metabolizing gene variants, gene-environment interactions, and breast and prostate cancer risk

Breast and prostate cancer are the most common cancers among men and women, respectively, in the developed world. Despite extensive evidence for the role of hormones, the relative importance of genetic and environmental factors and their interactions in causing these cancers is unknown.
The National Cancer Institute of the U.S.A. has funded the creation of a consortium of prospective cohort studies to evaluate these relationships. Cohorts from Europe and the U.S.A. that include over 790,000 men and women have agreed to participate, and provided 6,160 incident cases of breast cancer and 8,850 cases of prostate cancer for the first study. The studies use available prospectively collected serum samples and genetic material, from the majority of the cases and matched controls from the cohorts, as well as anthropometric measurements, and extensive questionnaire data on diet, physical activity, exogenous hormone use, smoking, and other lifestyle factors. They are larger than any previous studies of endogenous hormones and cancer risk. Our studies thus allow the simoultaneous investigation of genetic predisposition factors (polymorphisms in specific candidate genes), lifestyle factors, and related levels of circulating steroid hormones, as risk factors for these hormone-related cancers.
Two pathways have been selected, due to the vast amount of evidence for their involvement in the etiology of breast and prostate cancer: synthesis/metabolism of steroid hormones and synthesis/metabolism of insulin-like growth factor-I. Over 50 genes from these two pathways have been chosen and thoroughly resequenced in DNA samples from multiple ehtnic backgrounds. A complete catalogue of genetic variation in the candidate genes has thus been established and used to select haplotype tagging single nucleotide polymorphisms. These are being currently genotyped in all the breast and prostate cancer cases and controls. Prediagnostic hormone levels are also being measured in a subset of cases and controls. We will thus be able to measure to what extent genetic variability influences hormone levels and cancer risk.
Our group is involved in the European Prospective Investigation on Cancer (EPIC), one of the participating cohorts, and more specifically we are in charge of performing genotyping for the breast cancer component of EPIC (about 2,000 cases and 3,000 controls), and we are involved in the analysis of results and preparation of manuscripts.

Genetic variability of fatty acid metabolism, arachidonic acid metabolism and inflammation mediators and colorectal cancer risk

In collaboration with Dr. Alexandra Nieters, Molecular Tumor Epidemiology Group, Division of Clinical Epidemiology

The aim of this study is to assess the effects of genetic variability in crucial metabolic genes involved in the metabolism of arachidonic acid and other mediators of inflammation on the risk for colorectal cancer (CRC). This goal will be achieved through a case-contol study nested within the European Prospective Investigation on Cancer (EPIC), a prospective cohort study which involves ten European countries (Norway, Sweden, Denmark, United Kingdom, Germany, Netherlands, France, Spain, Italy and Greece).
Nutritional factors are established risk factors for CRC, however, the individual variability in fatty acid metabolism is recognised but not well understood. Arachidonic acid (AA) metabolism is one metabolic pathway directly influenced by the amount and quality of dietary fatty acids which leads to the generation of important bioactive molecules with relevance in tumorigenesis. The main enzymatic factors involved in AA metabolism are phospholipases, cyclooxygenases and lipoxygenases. AA is converted into prostaglandins, leukotriens and thromboxanes, molecules that have an important role in inflammation. The involvement of inflammation in CRC is becoming an established concept. Inflammatory diseases of the colon, such as Crohn's disease and ulcerative colitis, substantially increase the risk of CRC. Morevoer, aspirin and other non-steroid inflammatory drugs, which inhibit cyclooxygenases, the enzymes that convert AA into prostaglandins, contribute to reduce the risk of CRC.
We will therefore establish a list of genes involved in the metabolism of dietary long-chain fatty acids, arachidonic acid and prostaglandins. We will also include other genes involved in inflammation. We will select genetic polymorphisms in these genes according to the following criteria: 1) established or likely functional impact on gene function or regulation; 2) haplotype tagging polymorphisms.
We will genotype at first a set of samples from 850 CRC cases and 1700 controls from EPIC for a subset of polymorphisms. Depending on the availability of funding, we will then expand the number of samples (an additional 800 cases are projected) and polymorphisms to investigate. We will use state-of-the-art hardware and software to generate the genotype data and perform statistical analyses to determine the impact of the selected genetic variants on cancer risk.