Colorectal Medicine
Bioinformatics in colorectal cancer genetics and prevention
Supervisor Professor Finlay Macrae,
Head, Colorectal Medicine and Genetics
Location Royal Melbourne Hospital, Parkville
Contact details Tel: +61 3 9347 0788 Email: finlay.macrae@mh.org.au
The Department manages a large registry of people at high risk of colorectal cancer, principally based on family history. The surveillance histories of 3000 registrants have been documented and related to their assessed level of risk. This database is now linked through Melbourne Health's Models in Molecular Medicine (MMIM) database initiative with the familial cancer database and the outcomes baseed ACCORD database which includes data on the genomics of tumours and germline information. Advanced front end enquiry facilities have been developed by MMIM allowing data linkage and searching to be done with facility, and results displayed. A collaboration with the eHealth division of the CSIRO p-Health flagship furthers enhances our capacity to explore this world class dataset. Another project in cooperation with the CSIRO searching for new genes predisposing to colorectal cancer via a genome wide SNP analysis of families presenting through outr familial bowel cancer clinic (in association with Flinders Medical Centre) is also available within this project, as well as collaboration with the US National Institutes of Health Colon Cancer Family Study (with the Centre of Genetic Epidemiology, University of Melbourne). This project will suit candidates intested in the interface between bioinformatics and clinical research, and is supported by substantial expertise in both these areas.
Examples of hypotheses being explored locally are: What is the risk to children whose both parents have colorectal cancer? What is the sensitivity of faecal occult blood tests in asymptomatic colorectal cancer and advanced adenomas? What is the yield of faecal occult blood testing done between scheduled colonoscopies in high risk pateints? What are the surveillance outcomes from mismatch repair gene carriers, by gene type and mutation location?
The Human Variome Project (HVP) and familial bowel cancer
Supervisors: Professor Finlay Macrae Head, Colorectal Medicine and Genetics, Professor Richard Cotton, Director, Genomic Disorders Research Institute, University of Melbourne
Location: Dept of Colorectal Medcine and Genetics, RMH; or GDRC, Alan Gilbert Building, Uni of Melb.
Contact: Tel: 61 3 9347 0788 E: Finlay.macrae@mh.org.au
This important project forms a component of the HVP, which aims to document all DNA variants across all genes in man. The International Society for Gastrointestinal Hereditary Tumours is well advanced in formulating processes for the vision, with committees of experts world wide working on different aspects. A range of Honours and higher degree opportunities are available within the HVP and InSIGHT's engagement with the HVP. Its efforts to position itself as a lead locus for the HVP
Dietary modulation of cancer related gene expression
Supervisor Professor Finlay Macrae,
Head, Colorectal Medicine and Genetics
Location Royal Melbourne Hospital, Parkville
Contact details Tel: +61 3 9347 0788 Email: finlay.macrae@mh.org.au
Colon cancer is the most common internal malignancy in developed countries and its incidence in Australia is increasing. Resistant starch (RS) is a major dietary determinant of large bowel function in humans and may have important implications for the risk of colon cancer. However, the full impact (both positive and negative) of these starches in the diet must be studied and understood.
Our research team has studied the role of RS in human large bowel physiology, particularly the increased production of butyrate from its colonic fermentation. Butyrate is the preferred energy source of the cells that line the large bowel and can protect against malignant change.
Some investigators report that resistant starch can cause colonocyte hyperproliferation and increased tumour formation in animal models. We have evidence that adverse outcomes may be prevented by combining RS with slowly fermented wheat bran (WB).
We have recently completed a randomised study in 20 human volunteers. A diet combining WB (12gfiber/day) with a moderate amount of RS (22g /day) produced more favourable changes in faecal variables (greater faecal bulk, more rapid transit, lower pH, lower concentrations of ammonia and phenols, and higher short chain fatty acids) than WB alone. The WBRS combination resulted in major increases in faecal butyrate and was well tolerated. Rectal biopsy specimens were stained with the mib-1 antibody (to Ki-67) to assess proliferation. Accounting for dietary intervention by group, butyrate was the only variable to correlate with proliferation on its own. Significance was found in interactions: for the control and WB diets the proliferation score tended to decrease as butyrate level increased, whereas for the WBRS diet (which produced high levels of butyrate), the score increased as butyrate (concentration and percentage) levels increased. Increases in proliferation indicate a risk of carcinogenesis as it increases the probability of DNA damage.
Changes in proliferation must be interpreted in context with changes in apoptosis as it is a decrease in cell death relative to proliferation that may increase the risk of DNA damage and decrease the probability of repair. Genes regulating apoptosis, either pro-apoptotic or anti-apoptotic, include bcl-2, bax and bak. Activation or suppression of these genes has been shown to be important in controlling neoplastic processes. Other key genes potentially modulated by diet along the pathway to cancer include: APC (a tumour suppressor gene); p21 (a differentiation marker); MSH2 and MLH1 (mismatch repair genes); COX-2 (inflammation and growth) and hTERT (telomerase).
The Hypothesis in the current study available for BSC(Hons) students is that the fermentation-dependent events observed in our completed study will be related to the expression of cancer-related genes in the colonic mucosa.
Methodology has been established through our collaborators in South Carolina, who developed the techniques under a grant from the US National Cancer Institute. Rectal biopsies from our trial have been sectioned and stained with Mib-1 (for Ki-67), bcl-2, bax, and p21. Mib-1 sections have been counted and results analysed. These biomarkers are currently being analysed using an Image Analysis System with a dedicated ‘Hemicrypt’ macro program. Enough biopsy samples from the study remain for examination of the other biomarkers including: APC, COX-2, p21, MSH2, MSH1, bak and hTERT. These additional biomarkers tissue will be sectioned and stained before counting using the ‘Hemicrypt’ program.
The project will provide an unparalleled opportunity to study the expression of these cancer related genes in response to dietary intervention.
Confocal endomicroscopy
Supervisor: Professor Finlay Macrae, Head, Colorectal Medicine and Genetics
Location: Royal Melbourne Hospital, Parkville
Contact: Tel: +61 3 9347 0788 E: finlay.macrae@mh.org.au
Aim: To assess distribution of disease in patients with known or historical microscopic colitis,
Inclusion: Clinical need for colonoscopy in patients with known microscopic colitis
Dysplasia in Ulcerative colitis and Barrett's Oesophagus
Intervention: Confocal Endomicroscopy
Correlation with conventional histology; diagnostic accutracy dcompared with random biopsy protocols
Progress: Unlimited places available, Funding: Optiscan - covers endoscopy costs and confocal
Ethics: Approved Cabrini Health
Biogrid and IBD data basing
Supervisor: Professor Finlay Macrae, Head, Colorectal Medicine and Genetics
Location: Royal Melbourne Hospital, Parkville
Contact: Tel: +61 3 9347 0788 E: finlay.macrae@mh.org.au
The development of a common database for recording clinical management and outcomes for IBD clinics in Melbourne is being coordinated through the Department of Colorectal and Genetics. Henry Gasko, for the Australian BioGrid, is assisting with this. http://www.biogrid.org.au
Functional Foods in colorectal cancer prevention
Supervisor: Professor Finlay Macrae, Head, Colorectal Medicine and Genetics
Location: Royal Melbourne Hospital, Parkville
Contact: Tel: +61 3 9347 0788 E: finlay.macrae@mh.org.au
Evolving project. Please let me know if any interest.
Dietary prevention of adenomas in familial adenomatous polyposis
Supervisor: Professor Finlay Macrae, Head, Colorectal Medicine and Genetics
Location: Royal Melbourne Hospital, Parkville
Contact: Tel: +61 3 9347 0788 E: finlay.macrae@mh.org.au
This is a randomised controlled trial of a new resistant starch preparation capable of releasing large quantities of butyrate for chemoprevention in the colon. The trial will measure adenoma formation of FAP patients through their regular surveillance, comparing activity with placebo study agents. In partnership with CSIRO.