A Randomised Trial Of A Decision Aid For Women At Increased Risk For Ovarian Cancer
Funder
National Health and Medical Research Council
Funding Amount
$115,110.00
Summary
Epithelial ovarian cancer is the leading cause of death from gynaecological malignancy in Australia. The majority of women with ovarian cancer are diagnosed with advanced disease, and the chance of cure is low. The strongest risk factor for ovarian cancer identified to date is a family history of ovarian cancer, and up to 5% of all ovarian cancers are thought to be due to dominantly inherited mutations in a small number of ovarian-cancer-related genes. National guidelines on surveillance and pro ....Epithelial ovarian cancer is the leading cause of death from gynaecological malignancy in Australia. The majority of women with ovarian cancer are diagnosed with advanced disease, and the chance of cure is low. The strongest risk factor for ovarian cancer identified to date is a family history of ovarian cancer, and up to 5% of all ovarian cancers are thought to be due to dominantly inherited mutations in a small number of ovarian-cancer-related genes. National guidelines on surveillance and prophylactic strategies have recently been ratified. These are largely based on expert opinion. Because of the uncertain efficacy of ovarian cancer screening and the high mortality associated with ovarian cancer, prophylactic oophorectomy is considered an option for women at high risk. Decisions about optimal care are difficult for both women and their doctors. Efforts to improve services for women who are trying to make informed decisions about screening and prophylactic strategies under conditions of uncertainty must be informed by sound knowledge of the efficacy of educational interventions. Decision aids have been developed as adjuncts to practitioners' counselling to prepare patients for decision-making. The proposed randomised controlled trial will compare the efficacy of a general educational pamphlet and that of a tailored decision aid. A total of 120 women at risk for ovarian cancer who are attending one of five familial cancer clinics will be included in the trial to determine the efficacy of different educational interventions in preparing women for decision-making about screening and prophylactic options.Read moreRead less
The Role And Inheritance Of Constitutional Epimutations In Early-onset Colorectal Cancer.
Funder
National Health and Medical Research Council
Funding Amount
$347,551.00
Summary
Traditionally familial cancers are thought to be caused by spelling mistakes within the genetic code of cancer prevention genes. Our group has found that chemical attachments to one gene (MLH1) stops it working, even where there is no spelling mistake, and that those chemical changes can be inherited in families with bowel cancer. We will determine how frequently this type of defect occurs in bowel cancer patients, how and why it arises, and if other cancer genes are similarly affected.
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.
Mapping And Identification Of Novel Breast Cancer Susceptibility Genes
Funder
National Health and Medical Research Council
Funding Amount
$354,419.00
Summary
Breast cancer is one of Australia?s major cancer problems, but we still do not fully understand why certain people are at higher risk of the disease than others. In recent years two genes have been shown to be abnormal in a small number of people with strong family history of breast cancer and-or ovarian cancer. This study will search for the identity of other genes of this kind. It will take advantage of a large network of researchers which has been working to recruit women with a strong family ....Breast cancer is one of Australia?s major cancer problems, but we still do not fully understand why certain people are at higher risk of the disease than others. In recent years two genes have been shown to be abnormal in a small number of people with strong family history of breast cancer and-or ovarian cancer. This study will search for the identity of other genes of this kind. It will take advantage of a large network of researchers which has been working to recruit women with a strong family history of breast cancer from around Australia over the last two years. In this short time such large numbers of women have come forward that a study of this kind will be among the largest in the world. The results of this research, in terms of location of possible new genes causing high risk of breast cancer, will be shared with other researchers in Europe and the US who are working toward the same goals. This will ensure that progress is as rapid as possible. Based on experience with the two previously discovered breast cancer genes, this research will also shed light on the types of changes that drive the malignancy of breast cancer cells. It will have implications for improved prevention, diagnosis and treatment of breast cancer.Read moreRead less
Regulation And Assembly Of Nuclear DNA Repair Centres
Funder
National Health and Medical Research Council
Funding Amount
$457,267.00
Summary
Genetic defects in DNA repair genes are associated with increased cancer risk in humans. For example, BRCA1 and BRCA2 gene mutations are the most common causes of familial breast cancer, and MLH1 gene mutations are the most common cause of familial non-polyposis colorectal cancer. We have identified a novel human DNA repair protein termed ASCIZ that performs a similar function to BRCA1 and BRCA2 in that it regulates the concentration of the RAD51 repair protein in specific DNA repair centres in ....Genetic defects in DNA repair genes are associated with increased cancer risk in humans. For example, BRCA1 and BRCA2 gene mutations are the most common causes of familial breast cancer, and MLH1 gene mutations are the most common cause of familial non-polyposis colorectal cancer. We have identified a novel human DNA repair protein termed ASCIZ that performs a similar function to BRCA1 and BRCA2 in that it regulates the concentration of the RAD51 repair protein in specific DNA repair centres in the cell nucleus. However, ASCIZ performs this function in response to different types of DNA damage than BRCA1-BRCA2, and it acts in concert with the MLH1 protein. Here we want to study how ASCIZ regulates the assembly of DNA repair centres, and if it does so with support by the BRCA1-BRCA2 proteins. We also want to know if DNA repair functions of the RAD51 protein are diminished when it is not located in repair centres, and we want to identify novel proteins involved in this process. Our preliminary data show that cells that lack ASCIZ become dramatically hypersensitive to DNA damaging agents that are similar to clinically used chemotherapy drugs. We hope that our studies may identify possible approaches to develop drugs against ASCIZ and related proteins in order to kill cancer cells more effectively.Read moreRead less
DNA Lesions Involved In Chemotherapy Responses And Their Repair
Funder
National Health and Medical Research Council
Funding Amount
$399,142.00
Summary
The integrity of the human genome is constantly threatened by spontaneous DNA damage from products of normal metabolism, for example DNA oxidation, or environmental mutagens and carcinogens such as UV light. Improperly repaired DNA damage is a major contributing factor to the onset of cancer. To prevent this, human cells have a multitude of specialised DNA repair mechanisms to repair distinct lesions in the best possible way. As a consequence, mutations in DNA repair genes lead to increased canc ....The integrity of the human genome is constantly threatened by spontaneous DNA damage from products of normal metabolism, for example DNA oxidation, or environmental mutagens and carcinogens such as UV light. Improperly repaired DNA damage is a major contributing factor to the onset of cancer. To prevent this, human cells have a multitude of specialised DNA repair mechanisms to repair distinct lesions in the best possible way. As a consequence, mutations in DNA repair genes lead to increased cancer risk. Common examples for cancer-associated DNA repair gene mutations include the BRCA1 and BRCA2 breast cancer genes, and the MLH1 gene mutated in familial non-polyposis colorectal cancer. We have identified a novel human DNA repair protein termed ASCIZ that performs a function similar to BRCA1 and BRCA2 in that it regulates the concentration of the RAD51 repair protein in specific DNA repair centres in the cell nucleus. However, compared to BRCA1-BRCA2, ASCIZ performs this function in response to different types of DNA damage and acts in concert with the MLH1 protein. Here we want to investigate what the specific DNA lesions are that are repaired by ASCIZ, and we want to determine if the repair involves a copy mechanism that utilises intact genes as repair templates. In addition, we want to generate animals in which the ASCIZ gene is mutated, as a model to study its role in cancer development in humans. Cells that lack ASCIZ are dramatically hypersensitive to DNA damaging agents that are similar to clinically used chemotherapy drugs. We hope that our studies may identify possible approaches to develop drugs against ASCIZ and related proteins in order to kill cancer cells more efficiently.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
Germline Mutations In Mismatch Repair Genes: Prevalence, Risk Of Cancer, And Environmental Modifiers Of Risk.
Funder
National Health and Medical Research Council
Funding Amount
$216,750.00
Summary
Aims: 1. Develop a model that will predict who has a mutation in a group of genes that cause cancer 2. Estimate risk of cancer in people who have a mutation in these genes (carriers) 3. Determine if cancer risk in carriers can be reduced People who inherit a mutation in a group of genes called 'mismatch repair genes' are at increased risk of cancer, particularly cancer of the colon and rectum. If these carriers can be identified they can take preventive measures such as screening to reduce their ....Aims: 1. Develop a model that will predict who has a mutation in a group of genes that cause cancer 2. Estimate risk of cancer in people who have a mutation in these genes (carriers) 3. Determine if cancer risk in carriers can be reduced People who inherit a mutation in a group of genes called 'mismatch repair genes' are at increased risk of cancer, particularly cancer of the colon and rectum. If these carriers can be identified they can take preventive measures such as screening to reduce their risk of cancer and death. We will develop a model using data from the Colon Cancer Family Registry (CFR), the world's largest dataset of carriers and non-carriers which has already recruited and genetically tested over 4,000 families from Australasia, USA and Canada. The model will allow clinicians to predict who is a likely be a carrier based so they can be tested for the mutation. We know the risk of cancer is high in carriers, but we don't have precise estimates. We will use the Colon CFR applying sophisticated statistical methods required to answer this question. This data is critical for genetic counselling so appropriate decisions can be made by the patient and the doctor as to what preventive measures to take. We will also use the Colon CFR data to find out what how the carriers who develop cancer differ from those who stay cancer free using their completed lifestyle questionnaires which includes questions on diet, smoking, alcohol consumption, exercise, aspirin use, and oral contraceptive pill use. We may identify risk factors that carriers can avoid (or take up if they reduce cancer risk) to reduce their risk of cancer.Read moreRead less