Assessment Of Mismatch Repair Gene Sequence Variants For Clinical Relevance
Funder
National Health and Medical Research Council
Funding Amount
$472,659.00
Summary
Mutations in mismatch repair genes cause familial cancer. A number of families carry sequence changes that do not obviously alter the gene product, and it is difficult to predict whether these variants are the direct cause of cancer in the family. Consequently, it is not possible to offer informative genetic counselling to these families. We aim to assess the value of several web-based programs, with additional information, to predict the functional changes determined for a panel of variants.
Germline Epimutations Of Tumour Suppressor Genes In Familial Cancer
Funder
National Health and Medical Research Council
Funding Amount
$502,500.00
Summary
In the case of bowel cancer, studies of the pattern of disease in our community indicate that up to 20% of all bowel cancers has a inherited component . We now know the genetic abnormality in up to 4% of these cases. We have recently discovered a previously unrecognised cause of cancer. Individuals who are affected by this disease may have cancer in the bowel, as well as the breast and womb. In this condition the gene alphabet is correct but the genes are chemically modified. This change called ....In the case of bowel cancer, studies of the pattern of disease in our community indicate that up to 20% of all bowel cancers has a inherited component . We now know the genetic abnormality in up to 4% of these cases. We have recently discovered a previously unrecognised cause of cancer. Individuals who are affected by this disease may have cancer in the bowel, as well as the breast and womb. In this condition the gene alphabet is correct but the genes are chemically modified. This change called methylation means that certain genes are spelt incorrectly or not at all. To date we have found two individuals who have this problem. Our work has shown that these individuals have inherited a genetic change and potentially could pass this change on to their offspring. This grant application seeks to formally pursue this findng. We will study a group of people in whom the genetic cause for their cancer remains unknown. Blood samples from these individuals will be examined for methylation of their DNA. A successful project will lead to a full description of this new type of hereditary cancer, and thus serve as the basis for identifying and effectively managing people and families at risk of this disease. It is likely that identification of individuals who are 'at risk' of cancer will allow us to implement preventative screening strategies. We will also be able to provide reassurance to those family members who have not inherited the methylation abnormality.Read moreRead less
Analysis Of APC And APC Protein Complexes In Colon Cancer
Funder
National Health and Medical Research Council
Funding Amount
$110,786.00
Summary
Colorectal cancer is one of the foremost causes of death in Australia. A defective form of a protein called APC has been shown to be present in more than 80% of colon tumours. How APC contributes to colon cancer is still not known. We aim to determine the function of the APC protein by studying the APC protein and proteins that interact with APC in normal and cancerous colon epithelial cells. We will use cells derived from normal colon epithelium as well as from colon carcinomas. Once we have id ....Colorectal cancer is one of the foremost causes of death in Australia. A defective form of a protein called APC has been shown to be present in more than 80% of colon tumours. How APC contributes to colon cancer is still not known. We aim to determine the function of the APC protein by studying the APC protein and proteins that interact with APC in normal and cancerous colon epithelial cells. We will use cells derived from normal colon epithelium as well as from colon carcinomas. Once we have identified proteins that interact with APC in normal colonic cells, we will have a more complete understanding of the function of APC and its role in the development of colonic tumours.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
Role Of Chromatid Cohesion In Colon Biology And Carcinogenesis
Funder
National Health and Medical Research Council
Funding Amount
$628,422.00
Summary
Rad21 is a gene, present in many species and essential for accurate chromosome separation and DNA damage repair. Based on its known function in different species, we predict that its� dysfunction fuels cancer progression by promoting genetic instability, which is commonly associated with human cancers. This study will use unique mouse mutant models to investigate the function of this potential cancer-causing gene in colon cancer.
Using The A33 Antigen Gene Locus To Generate Novel Mouse Models Of Colon Cancer
Funder
National Health and Medical Research Council
Funding Amount
$376,320.00
Summary
Colorectal (or bowel) cancer is a major health problem in Australia. It is the most common cancer reported to Australian cancer registries and was responsible for 14% of cancer deaths in 1990, the latest year for which national figures are available. Only lung cancer, which caused 20% of cancer deaths was a more common cause of cancer death. Approximately 1 in 21 Australians will develop colorectal cancer during his-her lifetime. The risk of colorectal cancer increases with age, with risk rising ....Colorectal (or bowel) cancer is a major health problem in Australia. It is the most common cancer reported to Australian cancer registries and was responsible for 14% of cancer deaths in 1990, the latest year for which national figures are available. Only lung cancer, which caused 20% of cancer deaths was a more common cause of cancer death. Approximately 1 in 21 Australians will develop colorectal cancer during his-her lifetime. The risk of colorectal cancer increases with age, with risk rising progressively and sharply from age 50 onwards. Like all cancers, colorectal cancer results from the progressive acquisition of mutations in genes that normally ensure a balance between cell growth and cell death. Mutations which predispose individuals to colorectal cancer accumulate in the epithelial cells that provide the lining to the bowel. The progression of colorectal cancer proceeds through a number of distinct anatomical stages which can be easily recognised by pathologists. Mutations in a number of genes (known as APC, beta-catenin, Kirsten-ras, p53, SMAD2, SMAD4) are commonly found in colorectal tumours. Moreover, some of the mutations are highly associated with distinct stages of colon tumour development. As yet, however, we have no real insights into how these mutations cooperate with each other to produce full-blown (malignant) colorectal cancer. In our proposal, we are aiming to establish colorectal cancer in mice. Our approach will be to progressively introduce mutant genes into intestinal epithelial cells (singly and in combination) and study how they cooperate with each other to produce benign, and ultimately, malignant tumours in the intestines of mice. This will help us to understand which mutant genes are required for each stage in tumour development and may provide more rational approaches to bowel cancer screening and treatment.Read moreRead less
Epimutations As Germ-line Defects In Hereditary Cancer Syndromes
Funder
National Health and Medical Research Council
Funding Amount
$385,925.00
Summary
Traditionally familial cancers were thought to be caused and inherited by spelling mistakes within the genetic code of cancer prevention genes. Our group has found that a 'chemical coat' around the MLH1 gene, causing it to be switched off, can also be inherited in some cases of bowel cancer, without any mistakes within the gene's code. We will determine if this 'coat' causes other types of cancer and if this runs in families. We also hope to find out how the coat is formed and may be reversed.
Hereditary Non-Polyposis Colorectal Cancer (HNPCC) confers a high lifetime risk of developing cancer, especially colorectal and endometrial cancer. By characterising disease presentation in the patient cohort, HNPCC in an Australian context will be better defined. The aim of this proposal is to undertake a genetic investigation such that a more comprehensive personalised patient risk-assessment can be completed by identifying genes related to disease development.