Molecular Epidemiology And Clinical Outcome In Epithelial Ovarian Cancers

Ovarian cancer kills between 4 and 5,000 women a year in the UK. It is one of the more lethal cancers in that when a women is diagnosed with the disease, she usually has a low chance of surviving more than 5 years. This statistic has changed very little in 4 decades. One approach to reducing death caused by cancer is to detect the disease at its earliest stages of development, when it is most treatable. However, many of the symptoms of early stage ovarian cancer are vague and there is no national screening programme that targets the detection of these cancers. If we could identify the proportion of the population that is a greatest risk of getting the disease, one could use a targeted strategy to screen these women and find any early signs of cancer as it develops. A person?s genetic make-up can increase their chance of getting one of many common diseases including diabetes, heart disease and breast cancer. By screening several million letters of DNA code that show variation from person to person, it is possible to find those letters that appear to be more common in individuals with certain diseases. This is what we have been doing for ovarian cancer; comparing the DNA code of thousands of women with the disease to women without disease. We now plan to take this information and find the handful of letters that seem to suggest a woman is at greatest risk of getting ovarian cancer. We will also test whether there are factors in her lifestyle- for example whether or not she has had children, or used the oral contraceptive pill- that also changes her risk of getting ovarian cancer. Once we have done this, we will be able to test whether it is feasible to use the markers we find to screen for the highest risk women throughout the whole population. To do these studies requires a large international effort, because we have to screen several thousands of women with disease and volunteers that have taken part in these studies. We are using the combined power of 11 different studies from around the world in order to perform this research. It is hoped that the findings will not only have an impact in the UK, but in other countries where ovarian cancer is also a major health problem

Epithelial ovarian cancer is responsible for 4-5,000 deaths in the UK each year. The disease is assoicated with a particularly poor outcome after diagnosis compared to other common cancers and the survival rates have improved little in 40 years. Identifying genetic and/or environmental risk factors for ovarian cancer in the population, could lead to improvements in clinical outcome through strategies aimed at early detection and prevention of the disease. Similarly, by identifying profiles of genetic changes that take place during ovarian tumour development, it may be possible to predict which patients are likely to respond to different treament regimens and to establish targeted intervention strategies based on these predictions.
The known ovarian cancer susceptibility genes are thought to explain 40% of the excess familial risk of the disease. The residual familial risks are thought to be driven by variants at multiple loci, each conferring more moderate disease risks ? the so called ?common disease common variant? hypothesis. The last year has seen a plethora of studies published that have identified several new genetic susceptibility loci for common diseases including breast, prostate and colorectal cancers; and so it is likely that similar common genetic susceptibility variants exist for ovarian cancer.
As part of an international collaboration of 11 studies comprising more than 7,000 ovarian cancer cases and 7,000 controls, we have performed a genome wide association study (GWAS) to identify moderate/low penetrance ovarian cancer susceptibility allele and have found strong evidence that multiple genetic susceptibility loci exist (11 loci with a P-value less than 10-7).
The goal of this research proposal is to use the combined power in sample numbers achieved by this collaboration to follow-up on the data emerging from this GWAS to address the following aims: (1) To identify the putative causal variants associated with ovarian cancer risk by fine mapping the genetic variation at candidate susceptibility loci. (2) To evaluate the interaction between genetic variation and known ovarian cancer reproductive/lifestyle factors. (3) To evaluate the interactions between germline genetic variation and somatic genetic features of ovarian tumours following DNA profiling of 2,000 invasive ovarian cancers. (4) To evaluate associations between germline genetic variation and somatic genetic variation in tumours with clinical characteristics of disease (e.g. tumour sub-type; patient outcome). Positive findings from this study will be validated in two large, well-established consortia: the international Ovarian Cancer Association Consortium (OCAC) and the European wide Collaborative Oncological Gene-environment Study (COGS).