The Role Of Differentially Methylated Genes In The Initiation And Progression Of Colorectal Cancers
Funder
National Health and Medical Research Council
Funding Amount
$361,527.00
Summary
Most colorectal cancers develop from polyps in the lining of the bowel. The bulk of cancers develop from adenomatous polyps, but we have found that a second type of polyp called a hyperplatic polyp can also be associated with the development of cancer. During our studies of these polyps we found that a particular gene was inactivated in all of these polyps. We have called this gene HPP1. HPP1 was also found to be inactivated in adenomatous polyps and about 50% of colorectal cancers, indicating t ....Most colorectal cancers develop from polyps in the lining of the bowel. The bulk of cancers develop from adenomatous polyps, but we have found that a second type of polyp called a hyperplatic polyp can also be associated with the development of cancer. During our studies of these polyps we found that a particular gene was inactivated in all of these polyps. We have called this gene HPP1. HPP1 was also found to be inactivated in adenomatous polyps and about 50% of colorectal cancers, indicating that it may be an important player in the early stages of colorectal cancer and hence may allow opportunity for prevetive intervention. This grant proposal will investigate the function of HPP1 in the genesis of colorectal polyps and cancers.Read moreRead less
Characterisation Of Precursor Lesions In Colorectal Cancers With DNA Instability
Funder
National Health and Medical Research Council
Funding Amount
$60,190.00
Summary
It is now generally accepted that most colorectal cancers arise from previously benign lesions in the mucosal lining of the large bowel. These lesions are called adenomatous polyps. They have been extensively studied as have the cancers which evolve from them with regard to the type of cancer causing genetic changes they bear. Recently, it has been found that colorectal cancer is not a single disease in that there exists a subgroup comprising 15% of colorectal cancers which is an entirely differ ....It is now generally accepted that most colorectal cancers arise from previously benign lesions in the mucosal lining of the large bowel. These lesions are called adenomatous polyps. They have been extensively studied as have the cancers which evolve from them with regard to the type of cancer causing genetic changes they bear. Recently, it has been found that colorectal cancer is not a single disease in that there exists a subgroup comprising 15% of colorectal cancers which is an entirely different type wwith respect to genetic changes and biological behaviour. This subgroup contains cancers with a high level of microsatellite instability (MSI-high) and the cancers which comprise this group show none of the common genetic changes which can be demonstrated in both adenomatous polyps and the 85% of colon cancers which develop from them. The MSI-high colorectal cancers do however share some striking similarities to a type of polyp (hyperplastic) which has until quite recently been considered of little consequence. Our research group and others have shown an association with colorectal cancer in those patients in whom hyperplastic polyps are unusually large or numerous, especially if present in the right side of the large bowel, where the bulk of MSI-high colorectal cancers arise. The current proposal will investigate the hyperplastic polyp as a precursor lesion in the genesis of MSI-high cancers.Read moreRead less
Characterisation Of Candidate Colorectal Cancer Genes Identified By Microarray And SSH Analysis
Funder
National Health and Medical Research Council
Funding Amount
$417,750.00
Summary
Bowel cancer is one of the leading causes of cancer death in Australia today. If diagnosed early, surgery cures most patients. Unfortunately, symptoms often are not present until the cancer is advanced. In these cases surgery is still performed but sometimes all the cancer cannot be removed or it comes back after surgery. We need better ways to identify patients in whom the cancer is likely to return and better chemotherapy drugs to treat cancer not able to be removed surgically. Recently it has ....Bowel cancer is one of the leading causes of cancer death in Australia today. If diagnosed early, surgery cures most patients. Unfortunately, symptoms often are not present until the cancer is advanced. In these cases surgery is still performed but sometimes all the cancer cannot be removed or it comes back after surgery. We need better ways to identify patients in whom the cancer is likely to return and better chemotherapy drugs to treat cancer not able to be removed surgically. Recently it has been recognised that there are different subgroups of bowel cancer. One of these subgroups contains changes in the DNA called microsatellite instability, MSI-H for short. MSI-H cancers are less likely to come back after surgical removal and there is some evidence that they respond differently to chemotherapy. All cancers develop due to changes in their genetic material which make the cancer cells behave more aggressively than normal cells. We think that MSI-H bowel cancers have different changes in their genetic material compared to non-MSI-H bowel cancers. Understanding what these differences are would allow a better understanding of why bowel cancers do or do not come back after surgery. It would also allow chemotherapy treatments to be individualised according to genetic changes in the cancer. We have already used DNA chip technology to identify a large number of genetic differences between MSI-H and non-MSI-H bowel cancers. In this project we want to examine the most important of these in more detail. We will replicate these changes in cells cultured in the laboratory to see if the changes really do affect the behaviour of cancer cells. We will then look for what kind of genetic damage has led to the change. For key genetic changes, we will then examine our large tumour bank of bowel cancers collected with patients' consent over many years. We will look to see if the genetic changes really do predict the cancers' behaviour and response to treatment.Read moreRead less
Haplotype Variation At The Dopamine Transporter Gene (SLC6A3): Effects On Function, Endo-phenotypes, Cognition And ADHD
Funder
National Health and Medical Research Council
Funding Amount
$585,894.00
Summary
We will investigate variation in the dopamine transporter gene. Variation in this gene will be characterised to a deeper level than has been previously possible using the latest sequencing technology, its biological function will be investigated using biochemical and neuroimaging methods directly in human subjects, and its effects on a clinically important cognitive measure and a common psychiatric condition (attention deficit/hyperactive disorder) will we determined.
High blood pressure affects 1 in 5 Australian adults and is a leading cause of mortality and morbidity from heart attack and stroke. The condition tends to run in families and genetic predisposition, in the face of environmental factors, leads to the elevation in blood pressure. My Lab has demonstrated the capacity of a cohort of affected hypertensive sibships we have collected to find loci for essential hypertension at a level that has achieved genome-wide statistical significance and has been ....High blood pressure affects 1 in 5 Australian adults and is a leading cause of mortality and morbidity from heart attack and stroke. The condition tends to run in families and genetic predisposition, in the face of environmental factors, leads to the elevation in blood pressure. My Lab has demonstrated the capacity of a cohort of affected hypertensive sibships we have collected to find loci for essential hypertension at a level that has achieved genome-wide statistical significance and has been published in a leading molecular genetics journal. Moreover, this previous work, which included fine-mapping after finding a suggestive locus following a scan of chromosome 1, not only demonstrated significant linkage, but also went on to compare gene markers between a different cohort of (unrelated) hypertensive subjects with 2 affected parents (and early-onset, moderate to severe hypertension) and control normotensive matched subjects with unaffected parents, to identify a likely candidate gene. This same approach will be used to complete the rest of the genome. The discovery of all of the genes for essential hypertension will be an important prelude to: (1) developing new, more effective treatments, since the gene products responsible will be able to be targetted by novel therapeutics, (2) genotyping individuals early in life in order to advise them what their risk is, and thus allow couselling about lifestyle modification, (3) more logically apply existing treatment strategies according to the volume-neural-vasoconstrctor component of the contribution to high blood pressure.Read moreRead less
Fine Scale Mapping And Identification Of The IBD1 Gene On Chromsosome 16
Funder
National Health and Medical Research Council
Funding Amount
$483,849.00
Summary
One of the greatest challenges facing contemporary gastroenterology is to understand the causes of the inflammatory bowel diseases (IBD). Studies on the prevalence, incidence and cost of IBD indicate that these diseases have considerable impact in Australia. On average, patients lose more than 13 days from work each year, and in hospital, IBD in-patients accounted for 7% of total admissions and 10% of total bed days at an average cost of $2600 per admission. We estimate that there may be more th ....One of the greatest challenges facing contemporary gastroenterology is to understand the causes of the inflammatory bowel diseases (IBD). Studies on the prevalence, incidence and cost of IBD indicate that these diseases have considerable impact in Australia. On average, patients lose more than 13 days from work each year, and in hospital, IBD in-patients accounted for 7% of total admissions and 10% of total bed days at an average cost of $2600 per admission. We estimate that there may be more than 10,000 Australians who suffer from IBD. The existence of a genetic predisposition to IBD is now well established, and there is strong evidence that the disease is complex, resulting from the interaction of a number of different genes. To date, one genetic localisation on chromosome 16 has been established in several different populations, and we have confirmed the importance of this localisation in the Australian population. We will further refine the localisation by fine scale mapping in the pericentromeric region of chromosome 16 by identifying and studying the inheritance of novel markers in the region. We will then identify and characterise the gene itself using several complementary appoaches that rely on differences at the molecular level between disease and normal tissue. This work is part of the international effort to identify all IBD susceptibility genes. Once that is achieved, approaches to explaining the interactions between the genes, their protein products and environmental triggers can be determined. Only when the mechanisms of these interactions are understood will the expectation of rational therapies based on an understanding of disease aetiology be possible.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