Regulation Of Mutational Load By Chemopreventive Agents And Implications For Molecular Pathogenesis Of Colorectal Cancer
Funder
National Health and Medical Research Council
Funding Amount
$423,750.00
Summary
In Australia colorectal cancer is the second most common cause of cancer death, however the morbidity and mortality of colorectal cancer is currently not under control. Identification of safe and practical preventive agents should aid control. There is increasing evidence that colorectal cancer is associated with endogenous (internall) and exogenous (external) factors. They cause damage to DNA which might lead to tumour development if the damage is not repaired. This study will first identify th ....In Australia colorectal cancer is the second most common cause of cancer death, however the morbidity and mortality of colorectal cancer is currently not under control. Identification of safe and practical preventive agents should aid control. There is increasing evidence that colorectal cancer is associated with endogenous (internall) and exogenous (external) factors. They cause damage to DNA which might lead to tumour development if the damage is not repaired. This study will first identify the ability of preventive agents (aspirin-like drugs, fish oil, and antioxidants) to regulate DNA damage, then examine the effect of combination of the agents. It will finally determine the ability of agents, or combination of agents, to prevent development of colorectal cancer using two animal models. Prevention of human CRC by such a strategy should be feasible. First, evidence indicates that DNA damage is important in tumour initiation. Second, exogenous regulation of DNA damage, repair and removal seems possible. Epidemiological studies have suggested that that 30-70% of cancer can potentially be prevented with proper adjustment of diets (fat, fibre, resistant starch) and supplements of drugs (NSAIDs) or antioxidants (Vitamin, Selenium). Third, preventive strategies are likely to be feasible. At the population level, they would need to be safe and manageable in the context of dietary lifestyle, but this can be achieved through a range of food technology developments. In individuals at high risk, personalised preventive strategies become feasible through doctor-patient contact. This study focuses on regulation of DNA damage, and its repair and removal during the early stage of tumour development. The study will provide information if preventive agents, alone or in combination, provide a promising strategy for colorectal cancer through reduction of genetic damage. They might also identify new biomarkers that facilitate testing in humans.Read moreRead less
Population-based Detection Of Hereditary Non-polyposis Colorectal Cancer: Development Of New Best Practice
Funder
National Health and Medical Research Council
Funding Amount
$356,250.00
Summary
Approximately 1-2% of all large bowel cancers are thought to be caused by inherited defects in genes involved in the repair of DNA. These cancers are indistinguishable from those that occur in the general population and this has made it difficult to identify individuals and families with the defective gene. It has been estimated that only about 10-20% of individuals affected by this familial cancer syndrome are being referred to specialized genetic service centres for testing. The large majority ....Approximately 1-2% of all large bowel cancers are thought to be caused by inherited defects in genes involved in the repair of DNA. These cancers are indistinguishable from those that occur in the general population and this has made it difficult to identify individuals and families with the defective gene. It has been estimated that only about 10-20% of individuals affected by this familial cancer syndrome are being referred to specialized genetic service centres for testing. The large majority of familial colorectal cancers occur in young patients aged less than 60 years at diagnosis. Identification of these cases would allow genetic testing to be carried out on other family members who might also carry the mutant gene, thus allowing regular surveillance and a far greater likelihood of early detection and therefore cure. The aim of this project is to use a relatively simple laboratory-based method to test for the possibility that colorectal cancer in young patients (<60 years) may be inherited. From our preliminary data we expect that about 2% of all large bowel cancers, or 20 cases per year in Western Australia, may be familial. These individuals will be referred to Genetic Services WA for proper evaluation of their family history for cancer and for further DNA testing in an attempt to identify the defective gene. For positive cases, affected family members could then be tested for the gene after appropriate genetic counselling.Read moreRead less
Studies Of Genetic Predisposition To Develop Serrated Neoplasia In The Colorectum.
Funder
National Health and Medical Research Council
Funding Amount
$308,291.00
Summary
Colorectal Cancer was once believed to develop only from a certain kind of polyp in the colon called the adenoma. However, recently another type of polyp called the hyperplastic polyp was found to also be capable of producing a cancer. In this proposal, we will look at the possibility that the predisposition to form hyperplastic polyps may be inherited in families.
Molecular Markers Of The Progression Of Intestinal Metaplasia To Gastric Cancer
Funder
National Health and Medical Research Council
Funding Amount
$556,618.00
Summary
Gastric cancer (GC) is the second most common cause of cancer-related death globally. It is a surgically treatable disease that has good prognosis if detected at an early stage. The majority of patients in our community are detected at a late stage, where less than 20% of patients survive 5 years. The majority of GC is preceded by distinct histological stages that follow a progression from gastric mucosal inflammation, intestinal metaplasia (IM) and eventually cancer. These stages are characteri ....Gastric cancer (GC) is the second most common cause of cancer-related death globally. It is a surgically treatable disease that has good prognosis if detected at an early stage. The majority of patients in our community are detected at a late stage, where less than 20% of patients survive 5 years. The majority of GC is preceded by distinct histological stages that follow a progression from gastric mucosal inflammation, intestinal metaplasia (IM) and eventually cancer. These stages are characterised by genetic events that are largely unknown and occur over a period that can take years. It is also evident, especially in countries where GC is not as prevalent, that only a proportion of individuals will eventually develop GC. The long latency from the develpoment of IM and diagnosis of GC offers an opportunity to intervene and study the changes that lead to GC as well as find genes that may predict which individuals will progress. IM is the stage in which intervention is obvious. It is very easily diagnosed, is present for a long time and, for certain individuals, will eventually accumulate enough genetic events that will mandate progression to GC. Targeted screening of these individuals will enable a feasible strategy to find early GC, and avoid costly non-targeted screening. This proposal seeks to find key genetic events responsible for the transition of IM to GC. The first step utilises Affymetrix arrays to detect genes expressed in IM and specifically linked to GC. These candidates will be validated and used to study their role in the progression to GC using a mouse model of GC. This study is designed to find genes responsible for GC that can be used as: 1) a marker of progression in humans that will be used as a tool to stratify individuals into a screening protocol; 2) candidates to be tested in animal studies to study the pathogenesis of GC and potentially used as preventative or therapeutic targets.Read moreRead less
CpG Island Methylation In Microsatellite Stable Colorectal Cancers: Epigenetics Or Epiphenomenon?
Funder
National Health and Medical Research Council
Funding Amount
$245,402.00
Summary
For years researchers have known that changes in the sequence of DNA in genes within a cell can lead to cancer, particularly when those changes are passed on to daughter cells. This has lead to massive research interest in the field of cancer genetics. In the last few years, it has become clear that as well as changes in DNA, other more subtle changes can be passed on. These changes, which do not directly involve changes in DNA sequence, are referred to as epigenetic changes. One of the most com ....For years researchers have known that changes in the sequence of DNA in genes within a cell can lead to cancer, particularly when those changes are passed on to daughter cells. This has lead to massive research interest in the field of cancer genetics. In the last few years, it has become clear that as well as changes in DNA, other more subtle changes can be passed on. These changes, which do not directly involve changes in DNA sequence, are referred to as epigenetic changes. One of the most commonly recognised epigenetic changes is known as methylation. Methylation of genes can switch that gene off, meaning that the protein normally made is no longer present in the cell. This can have profound effects on the way cells behave, and importantly may be involved in the development of cancer. In this study, we will look at a group of colorectal cancers that show abnormally high amounts of DNA methylation , to test our hypothesis that these cancers share a common origin that is distinct from the usual type of bowel cancer. The findings will be important, as they may allow us to show that all bowel cancers are not the same, and that simple gene testing may be able to identify the different subtypes. If bowel cancers can be classified according to the way in which they have developed, then this will help us to understand what causes them why some are more aggressive than others, and why some may respond differently to existing or future cancer treatments.Read moreRead less