Statistical Methods For Identifying Structural Variation In Tumour Genomes Using Next Generation Sequencing
Funder
National Health and Medical Research Council
Funding Amount
$243,458.00
Summary
New DNA sequencing technology can sequence a tumour genome affordably in 2 weeks. This re-sequencing data can be used to find small mutations and large-scale chromosomal rearrangements that together are the drivers of cancer. These may one day be used to guide cancer therapy. This project will develop new algorithms for finding mutations and apply these to discover the genetic basis of drug resistance in a model lymphoma system.
Genome-wide SNP Analysis Of Fibroblasts Juxtaposed Or Distant From Epithelial Breast And Ovarian Tumours
Funder
National Health and Medical Research Council
Funding Amount
$401,763.00
Summary
In the past it was believed that the driving factor in the process of cancer devlopment was the cancer tissue itself. More recently however, it has become clear that the process is far more complex and that many aspects of human biology can profoundly influence both an individuals presiposition to cancer and the severity of disease. Many laboratories, including our own, have shown that gene mutations frequently occur in cancer tissue but recent studies have suggested that the apparently normal t ....In the past it was believed that the driving factor in the process of cancer devlopment was the cancer tissue itself. More recently however, it has become clear that the process is far more complex and that many aspects of human biology can profoundly influence both an individuals presiposition to cancer and the severity of disease. Many laboratories, including our own, have shown that gene mutations frequently occur in cancer tissue but recent studies have suggested that the apparently normal tissue surrounding the cancer (often referred to stroma) may also contain mutations. This so called 'cancer associated stroma'(CAS) is also thought to harbour genetic mutations and some studies have shown that without these mutations the cancer cannot survive. At present we have only had glimpses of the genetic alterations that may occur in CAS and there is an urgent need to fully understand the interplay between CAS and frankly cancerous tissue. Our laboratory will utilise high density, genome-wide screening technologies to search for novel mutations in CAS from breast and ovarian cancers. A complete understanding of the role stroma plays in cancer development is likely to lead to novel ways of treating and preventing cancer. Consequently, the identification of the full repertoire of stroma-derived cancer promoting genes is emerging as one of the most important areas in cancer research. The identification of these genes could lead to the development of novel diagnostic markers for use in cancer detection, diagnosis and-or prognosis.Read moreRead less
Physiological Genomic Analysis Of Lvm-1 - A Genetic Locus That Determines Left Ventricular Mass
Funder
National Health and Medical Research Council
Funding Amount
$356,540.00
Summary
As many as one in ten healthy individuals have big hearts. Careful scientific investigation has revealed that the bigger one's heart, the greater the risk of dying from cardiovascular disease. This is true even in the absence of known causes of heart disease. Unlike high blood pressure or cholesterol, the size of the heart is not easily measured and enlargement often goes undetected. We were among the first internationally to discover genetic clues to enlarged hearts. We identified regions on ra ....As many as one in ten healthy individuals have big hearts. Careful scientific investigation has revealed that the bigger one's heart, the greater the risk of dying from cardiovascular disease. This is true even in the absence of known causes of heart disease. Unlike high blood pressure or cholesterol, the size of the heart is not easily measured and enlargement often goes undetected. We were among the first internationally to discover genetic clues to enlarged hearts. We identified regions on rat chromosomes that harbour the gene or genes that influence heart size. The aim of these studies is to identify the exact gene responsible and to understand how that gene produces its effects. The experiments involve testing DNA samples already obtained from many hundreds of rats and breeding animals to study the consequences of the genetic abnormality in greater detail. The experiments are critical steps towards the prevention of big hearts and their complications in humans. In time, genetic tests will offer earlier detection and facilitate targeted and tailored treatments.Read moreRead less
Genetic Analysis Of Type 2 Diabetes In Indigenous Australian Pedigrees.
Funder
National Health and Medical Research Council
Funding Amount
$502,500.00
Summary
Type 2 diabetes is a major world health problem. With 300 million people expected to be affected worldwide by 2025 it is a major economic burden. It is a leading cause of kidney failure, blindness, heart attacks, strokes and amputations. Over 7% of the general Australian population have type 2 diabetes, whilst up to 30% of the population in some indigenous communities are affected by this condition. Very few Australians have not been touched in some way by the shadow of diabetes. The precise cau ....Type 2 diabetes is a major world health problem. With 300 million people expected to be affected worldwide by 2025 it is a major economic burden. It is a leading cause of kidney failure, blindness, heart attacks, strokes and amputations. Over 7% of the general Australian population have type 2 diabetes, whilst up to 30% of the population in some indigenous communities are affected by this condition. Very few Australians have not been touched in some way by the shadow of diabetes. The precise cause of diabetes is unknown, however we do know that it tends to run in families, indicating that inherited tendency is important. This research program will find genes which cause diabetes by searching for them in indigenous Australian pedigrees in which many of the family members are affected by diabetes. Finding the genes which cause diabetes will have significant impact in at least three major ways. Firstly, it will increase our understanding of the disease process. Secondly, it will be possible to develop tests to identify people at risk of diabetes at a very early stage so that therapy can be introduced and complications averted. Thirdly, it will be possible to develop new and more effective approaches for the prevention and treatment of type 2 diabetes.Read moreRead less
Phosphatidylinositol 3-kinase Mutations Associated With Ovarian, Colon And Breast Tumours
Funder
National Health and Medical Research Council
Funding Amount
$154,000.00
Summary
Colorectal and breast cancers are the two most common registrable cancers in Australia and are second only to lung cancer in the total number of cancer deaths each year (4,678 and 2,612 deaths in 1997 for colorectal and breast, respectively). Ovarian cancer kills a further 740 women each year (Source: Cancer in Australia 1997, AIHW and AACR 2000). Thus, on average, one Australian dies of colorectal, breast or ovarian cancer every hour! Clearly, these are major diseases with a significant impact ....Colorectal and breast cancers are the two most common registrable cancers in Australia and are second only to lung cancer in the total number of cancer deaths each year (4,678 and 2,612 deaths in 1997 for colorectal and breast, respectively). Ovarian cancer kills a further 740 women each year (Source: Cancer in Australia 1997, AIHW and AACR 2000). Thus, on average, one Australian dies of colorectal, breast or ovarian cancer every hour! Clearly, these are major diseases with a significant impact on our society. Unfortunately, though, we still do not understand the basic molecular and-or biochemical abnormalities that initiate and-or drive the development of these cancers. Recent functional and genetic studies in a number of different tumour types (including colon and ovarian) have suggested that members of the phosphatidylinositol 3-kinase (PI3K) enzyme family may be oncogenes (cancer-causing genes). However, strong evidence confirming a causal role for PI3K in human cancer is yet to be reported. Our research proposal outlines a study to address this issue. We have preliminary data demonstrating mutations in at least one member of this enzyme family in a number of tumours. We now propose to undertake a comprehensive analysis of the spectrum, and frequency, of PI3K mutations that occur in colon, breast and ovarian tumours. These studies will allow us to make a definitive assessment of the role of PI3K in the development human cancer. In addition to furthering our understanding of the processes involved in the initiation and progression of human tumours, this project also has the potential to identify new markers for the early detection of cancer and novel targets for new anti-cancer therapies.Read moreRead less
Cleavage Methods Of Mutation Detection: Improvement And Application In Cardiovascular Disease
Funder
National Health and Medical Research Council
Funding Amount
$1,044,349.00
Summary
Genes contain the information to build our body and keep it operating normally. These genes are inherited from our parents and number around 100,000. Faults in these genes can cause inherited diseases such as cystic fibrosis, cancers and common disorders such as Asthma and diabetes. These genes need detecting so that particular genes can be identified as causing the disease and also so that patients can have their disease properly diagnosed so that proper therapy and information can be given to ....Genes contain the information to build our body and keep it operating normally. These genes are inherited from our parents and number around 100,000. Faults in these genes can cause inherited diseases such as cystic fibrosis, cancers and common disorders such as Asthma and diabetes. These genes need detecting so that particular genes can be identified as causing the disease and also so that patients can have their disease properly diagnosed so that proper therapy and information can be given to the patients. In future similar changes (but changes not causing disease) may be searched for in patients to overcome the side effects of drugs. Our centre specializes in the methods of detecting faults and their application. Two of our methods are being used around the world and one is being sold as simple kit. These methods still have drawbacks and the work proposed is to overcome some of these. We propose to apply our and other methods to faults in genes which have recently been shown to cause diseases of the artery. This is an exciting new development that shows that this disease is similar to cancer. We are fortunate to have attracted Dr Paula Bray from the laboratory which discovered this. This new finding needs to be studied in more detail and may identify life-style factors which cause coronary heart disease. Our studies will also assist in gene therapy when it becomes available.Read moreRead less
Genome-wide Study Of Loss Of Heterozygosity Using High Density SNP Arrays To Identify Breast Cancer Predisposition Genes
Funder
National Health and Medical Research Council
Funding Amount
$542,599.00
Summary
The genes responsible for the majority of breast cancer families remain unknown. The genes BRCA1 and BRCA2 can prevent the development of cancer and represent a class of gene known collectively as 'tumor suppressors'. One of the hallmarks of these genes is that they show loss of the normal copy of the gene in tumors that arise in individual carrying one inherited, mutated copy. The broad aim of this proposal is to exploit this phenomenon to identify novel tumor suppressor genes that predispose t ....The genes responsible for the majority of breast cancer families remain unknown. The genes BRCA1 and BRCA2 can prevent the development of cancer and represent a class of gene known collectively as 'tumor suppressors'. One of the hallmarks of these genes is that they show loss of the normal copy of the gene in tumors that arise in individual carrying one inherited, mutated copy. The broad aim of this proposal is to exploit this phenomenon to identify novel tumor suppressor genes that predispose to familial breast cancer. This will be done by analyzing tumors from families that do not have either BRCA1 or BRCA2 mutations. Candidate tumor suppressor genes will be identified when tumors from different individuals in the same family all appear to have lost one copy of a gene, and retained the same copy, in a particular chromosomal region. We study tumours from non-BRCA1-2 breast cancer families using genetic techniques that are able to rapidly and accurately identify which parts of the chromosomes have been lost. Families will be identified in which all the tumors have lost exactly the same part of the chromosome. Next, we will exploit the fact that the entire sequence of the human genome is completed to find out which genes are located within the candidate region. We will then apply other technologies to identify which of these 'candidate genes' is actually responsible for the cancer in that family. Following this, we will investigate other families with a history of breast cancer to see how many can be accounted for by mutations in this gene. It is possible that we may identify more than on breast cancer gene using this powerful approach. Identification of new breast cancer predisposition genes would have major clinical relevance to the families directly affected, and much wider relevance if the same gene (or pathway) is later found to be involved in the causes of other familial or sporadic breast cancers.Read moreRead less