ANECS – Detailed Study Overview

Background
Endometrial cancer is the most common invasive gynaecological cancer in Australian women, ranking 6 th for incidence and 9 th for mortality, but numbers of cases are increasing as the population ages. Several histological subtypes are recognised and survival is poor for some of these. Although it is now clear that the aetiology of other gynaecologic cancers varies by subtype, few epidemiological studies have distinguished between different subtypes of endometrial cancer. Furthermore, very little is known regarding the role of germline genetic factors in endometrial cancer risk, except that an increased risk among relatives suggests a strong inherited component exists . A thorough examination of the genetic basis to disease within families has not been carried out, and the contribution from other lower-risk genes is unclear from studies to date.

To increase understanding of the aetiology of endometrial cancer it is essential to conduct a study large enough to evaluate risk factors separately for different subtypes, and to identify environmental and genetic risk factors for the more aggressive subtypes.

Objective
To establish an integrated, multidisciplinary approach to the study of endometrial cancer by collecting epidemiological and clinical data and biological samples from a large population-based group of women newly diagnosed with endometrial cancer, a comparable group of cancer-free women, and selected relatives of cases reporting a family history of cancer.

Specific Aims
To clarify existing and identify new modifiable risk factors, and their interaction with genetic factors, by subtype; to examine the genetic basis to disease within multiple-case families; to establish and maintain a biorepository and comprehensive epidemiological, molecular and clinical database for ongoing studies.

Research Plan Synopsis

Study Design
We are establishing a nation-wide population-based study of endometrial cancer. Incident endometrial cancer patients(~1500 consecutive) in Qld, NSW, Vic, SA, and WA will be identified through a network of clinicians in major gynaecological-oncology treatment centres, and through the state cancer registries. We will base the study on the established systems and instruments in use by the Australian Ovarian Cancer Study. Women will be approached with permission from their treating physician, while attending for treatment in the capital cities, or via letter if identified through cancer registries. With their permission, we will also endeavour to recruit relatives of patients reporting a family history of cancer (<10%). Population controls (~1500) will be sampled from the Commonwealth electoral roll, frequency matched on age and state to the case series. Potential controls will be sent an invitation letter followed by a telephone call.

Data and Sample Collection
Participants will complete questionnaires , to collect information on socioeconomic factors, medical and reproductive/hormonal history, family history of cancer, physical activity and diet. With permission, we will access medical records of cases to collect clinical information. Blood samples will be collected from cases by hospital pathology services or the study nurses, while rural cases and controls will be mailed a collection kit to take to their local pathology service or GP. Tumour blocks and/or fresh tissue will also be collected from cases.

Data Processing and Genetic Analysis
Coding, entry and checking of data will be performed on an on-going basis to maintain consistency and quality. Cases with a strong family history of endometrial and other cancers will be screened for mutations in the HNPCC and PTEN genes, and other candidate high-risk genes. Cases and controls will be genotyped using standard methodology for genetic polymorphisms in hormone pathways.

Analysis
Associations will be addressed using standard case-control analyses. For population-based analyses with 1500 cases/1500 controls and genes/exposure with a prevalence of 25% (e.g. HRT use), we will be able to detect an odds ratio (OR) of 1.3 with 90% power and 2-sided alpha=0.05.

Outcomes and Significance

This is the first large Australian population-based case-control-family study of endometrial cancer. It will provide a better understanding of causal pathways leading to the different types of endometrial cancer, and identify potentially modifiable risk factors to assist development of prevention strategies. It will also provide an assessment of the genetic basis to disease within population-based families, for development of a clinical guide to be used by genetic counsellors and other health professionals.