Functional Evaluation Of BRCA1 & BRCA2 Unclassified Sequence Variants And Identification Of Critical Pathogenic Domains.
Funder
National Health and Medical Research Council
Funding Amount
$331,312.00
Summary
The major genes that predispose to hereditary breast cancer are called BRCA1 and BRCA2. Most mutations in these genes cause the protein product to be truncated and inactive. However there are many families in which such truncating mutations are not found, but instead there are sequence changes that slightly alter the protein product. It is often difficult to predict whether these sequence variants are likely to cause hereditary breast cancer simply by looking at the position and nature of the se ....The major genes that predispose to hereditary breast cancer are called BRCA1 and BRCA2. Most mutations in these genes cause the protein product to be truncated and inactive. However there are many families in which such truncating mutations are not found, but instead there are sequence changes that slightly alter the protein product. It is often difficult to predict whether these sequence variants are likely to cause hereditary breast cancer simply by looking at the position and nature of the sequence change. Consequently, it is not possible to offer informative genetic counselling to these women or their at-risk family members. Assessment of the potential pathogenicity and functional significance of these unclassified sequence variants will be directly useful with regard to the clinical management of these women and their families, and will develop our current understanding of how different domains of these genes contribute to their role as cancer susceptibility genes.Read moreRead less
KConFab Follow-Up Project: A Prospective Study Of Non-Genetic Risk Modifiers In Women At High Risk For Breast Cancer
Funder
National Health and Medical Research Council
Funding Amount
$726,351.00
Summary
Having a strong family history for breast cancer is one of the most important risk factors for the disease. Two major genes, BRCA1 and BRCA2, have been identified which, when abnormal, result in an inherited tendency towards developing breast cancer. Women with a strong family history of breast cancer can undergo testing for these genes via Family Cancer Centres around Australia. However in only about 20% of families with a strong family history will a gene abnormality be discovered. Women from ....Having a strong family history for breast cancer is one of the most important risk factors for the disease. Two major genes, BRCA1 and BRCA2, have been identified which, when abnormal, result in an inherited tendency towards developing breast cancer. Women with a strong family history of breast cancer can undergo testing for these genes via Family Cancer Centres around Australia. However in only about 20% of families with a strong family history will a gene abnormality be discovered. Women from families in which no abnormality has been discovered remian at high risk because they may have an abnormality in an as yet undiscovered gene which can't yet be tested for. Little is currently known bout the best ways to prevent cancer in women who are at high risk. The Kathleen Cuningham Consortium for Research Into Familial Aspects of Breast Cancer (kConFab) has been recruiting families with exceptionally strong hostories of breast cancer since 1997. kConFab is funded to collect risk factor information on such individuals only at the time of their initial recruitment. In 2000 and again in 2003, the NHMRC recognised the importance of undertaking clinical follow-up of this precious cohort of individuals and provided funding through consecutive project grants to do so. The current application is to enable us to continue that follow-up for a further 5 years. As well as continuing the follow-up, we will use the data already collected to examine the effect of prophylactic surgery, breastfeeding and use of the oral contraceptive pill as well as cigarette smoking and alcohol use on breast cancer risk in high-risk women. The results of this study will provide high-risk women with better information about what modifications they might make to their lifestyles to reduce their cancer risk.Read moreRead less
Evaluation Of Unclassified Variants Of BRCA1 And BRCA2 Using A Multifactorial Approach
Funder
National Health and Medical Research Council
Funding Amount
$456,495.00
Summary
The major genes that predispose to hereditary breast cancer are called BRCA1 and BRCA2. Most mutations in these genes cause the protein product to be truncated and inactive. However there are many families in which such truncating mutations are not found, but instead there are sequence changes that may slightly alter the protein product. It is often difficult to predict whether these sequence variants are likely to cause hereditary breast cancer simply by looking at the position and nature of th ....The major genes that predispose to hereditary breast cancer are called BRCA1 and BRCA2. Most mutations in these genes cause the protein product to be truncated and inactive. However there are many families in which such truncating mutations are not found, but instead there are sequence changes that may slightly alter the protein product. It is often difficult to predict whether these sequence variants are likely to cause hereditary breast cancer simply by looking at the position and nature of the sequence change. Consequently, it is not possible to offer informative genetic counselling to these women or their at-risk family members. Assessment of the potential pathogenicity and functional significance of these unclassified sequence variants will be directly useful with regard to the clinical management of these women and their families, and will develop our current understanding of how different domains of these genes contribute to their role as cancer susceptibility genes. In addition, some of our experiments to classify variants may be useful as a screening tool to identify carriers of mutations, and so prioritize them for mutation screening.Read moreRead less
Clinical Outcomes In Individuals With An Inherited Predisposition To Breast Cancer
Funder
National Health and Medical Research Council
Funding Amount
$606,015.00
Summary
Genes have recently been identified which, when abnormal, result in an inherited tendency towards developing breast cancer (BC). It is now possible to undergo testing for abnormalities in these genes. However, there is little known about the best ways to prevent cancer or detect it early in individuals with such a gene abnormality. In addition, it is possible that BCs occuring in women with a gene abnormality might behave differently (have a different prognosis and thus require different treatme ....Genes have recently been identified which, when abnormal, result in an inherited tendency towards developing breast cancer (BC). It is now possible to undergo testing for abnormalities in these genes. However, there is little known about the best ways to prevent cancer or detect it early in individuals with such a gene abnormality. In addition, it is possible that BCs occuring in women with a gene abnormality might behave differently (have a different prognosis and thus require different treatment) from other BCs. Answers to these important questions are essential for women to be able to make informed decisions about how best to reduce their risk of developing, or dying from, BC. This study will examine the clinical outcomes of individuals (both those who have not yet developed cancer and those who have) with an inherited tendency to BC. The study has 2 components; each builds on one of 2 existing Australian studies of hereditary BC 1) Is the likely clinical outcome (prognosis) different for BC patients with a gene abnormality compared to those without? The cancer and treatment details of BC patients in Melbourne and Sydney who are already enrolled in the Australian Breast Cancer Family Study will be examined to determine whether those with a gene abnormality have a better or worse outcome than those without. 2) What factors impact on the clinical outcome (development of cancer) in well individuals with an inherited tendency to BC? An Australia-wide study of inherited BC (kConFab) has recruited families with a strong family history of BC. The family history, lifestyle, exposure to female hormones, cancer screening and preventive surgery details of all individuals in the study will be collected 3 years following study entry. Ultimately this information should help determine how best to prevent cancer in such individuals.Read moreRead less
Risk Factors, Screening, Prophylaxis And Outcomes In Individuals From Breast Cancer Families: KConFab Follow-Up Study
Funder
National Health and Medical Research Council
Funding Amount
$510,675.00
Summary
Having a strong family history of breast cancer is one of the most important risk factors for the disease. Two major genes, BRCA1 and BRCA2, have been identified which, when abnormal, result in an inherited tendency towards developing breast cancer. Women with a strong family history of breast cancer can undergo testing for these gene abnormalities via Family Cancer Centres around Australia. However, once a gene abnormality is found, little is known about the best ways to prevent cancer or detec ....Having a strong family history of breast cancer is one of the most important risk factors for the disease. Two major genes, BRCA1 and BRCA2, have been identified which, when abnormal, result in an inherited tendency towards developing breast cancer. Women with a strong family history of breast cancer can undergo testing for these gene abnormalities via Family Cancer Centres around Australia. However, once a gene abnormality is found, little is known about the best ways to prevent cancer or detect it early. The Kathleen Cuningham Consortium for Research into Familial Aspects of Breast Cancer (kConFab) has been recruiting families with exceptionally strong histories of breast cancer since 1997. kConFab is funded to collect epidemiological information and biological specimens on such individuals only at the time of their initial recruitment. In 2000 the NHMRC recognised the importance of undertaking clinical follow-up of this precious cohort of individuals, and provided funding through a 3 year project grant to commence the first round of 3 yearly follow-up on this cohort (NHMRC Project Grant #145684). The first 2 years of this follow-up has been completed successfully and the current is application is for a renewal of funding (to commence in 2004) to enable us to undertake further follow-up of the now much larger cohort. In the short term we will examine the screening and preventive surgery behaviours of high risk women within this study to determine whether they are optimal. The ultimate aim of this long term follow-up of individuals in kConFab is to determine what factors impact on the development of cancer in well individuals with a genetic predisposition to breast cancer.Read moreRead less
Investigation Of An LMO4- And BRCA1 -containing Complex Involved In Breast Cancer
Funder
National Health and Medical Research Council
Funding Amount
$440,250.00
Summary
Breast cancer will affect one in twelve Australian women and a quarter of those will die from breast cancer. At present we still know little about what causes the disease, and there is currently a lot of activity in the field of breast cancer research that will ultimately increase our ability to both detect its development at early stages and to provide effective treatments for the disease. We do know that losing the function of a few genes (breast cancer susceptibility genes) leads to a very hi ....Breast cancer will affect one in twelve Australian women and a quarter of those will die from breast cancer. At present we still know little about what causes the disease, and there is currently a lot of activity in the field of breast cancer research that will ultimately increase our ability to both detect its development at early stages and to provide effective treatments for the disease. We do know that losing the function of a few genes (breast cancer susceptibility genes) leads to a very high likelihood of developing cancer, and we know that the normal roles of the proteins that are produced from these genes are to prevent cancers from occurring in a spontaneous fashion. However, the inheritance of mutations in breast cancer susceptibility genes accounts for only a few percent of breast cancer cases. A recently discovered protein, known as LMO4, has been found at abnormal levels in over 50% of non-inherited breast tumors. This protein has been found to both interact with the protein from the most commonly occurring breast cancer susceptibility gene, known as BRCA1, and to prevent the normal activity of BRCA1. Thus, if we could develop reagents that prevent LMO4 from interacting with BRCA1, we could use those reagents as lead compounds for the development of anti-breast cancer drugs. Before we can develop such reagents we need to fully understand both what these proteins look like and how they interact. We already know that two other proteins, known as ldb1 and CtIP are involved in the LMO4:BRCA1 interaction. We will investigate the ways in which all of these proteins interact, from determining how strong each interaction is, to getting atomic level information about which surfaces of the proteins make the most contribution to each interaction. This should let us identify good targets for the design and development of anti-breast cancer drugs.Read moreRead less
The recent cloning of the breast cancer predisposition gene, BRCA1 had an unexpected consequence. Whereas mutations were found in affected individuals from families showing a predisposition to breast and ovarian cancer, mutations were not identified in breast cancers from individuals with no family history. We have identified a type of change called an epigenetic change affecting BRCA1 in breast and ovarian cancers. Epigenetic changes are mechanisms which act at a gene without causing mutations ....The recent cloning of the breast cancer predisposition gene, BRCA1 had an unexpected consequence. Whereas mutations were found in affected individuals from families showing a predisposition to breast and ovarian cancer, mutations were not identified in breast cancers from individuals with no family history. We have identified a type of change called an epigenetic change affecting BRCA1 in breast and ovarian cancers. Epigenetic changes are mechanisms which act at a gene without causing mutations but nevertheless have the stability of genetic change. We plan to examine breast tumours for further epigenetic changes. This project has important implications for our understanding of the development of breast cancer. This new understanding may in turn suggest new strategies for the treatment of breast cancer.Read moreRead less
Histopathological, Magnetic Resonance (MR) And Ultrasound Correlates Of Mammographic Density In BRCA1-2 Mutation Carriers
Funder
National Health and Medical Research Council
Funding Amount
$345,931.00
Summary
Mammographic density (MD), is a major risk factor for breast cancer. The nature of breast tissue underlying MD is not clear. The study will clarify the nature of breast tissue underlying MD as well as determining the breast MRI and ultrasound features that correlate with MD. These findings will enhance knowledge of breast cancer development, and should help to avoid mammography to screen young, high risk women and fulfil a priority objective of Cancer Australia
Regulation Of BRCA1 And APC Tumour Suppressor Functions By Nuclear Export
Funder
National Health and Medical Research Council
Funding Amount
$433,500.00
Summary
Cancer cells are unique, in that their ability to divide and grow is no longer controlled. Moreover, the DNA of cancer cells is less stable, and vital control genes often gain small mutations which culminate in a more aggressive or malignant cancer cell. Cancers from different tissues progress and respond in different ways to treatment, and the eventual development of tailored treatments or therapies will require a detailed understanding of how cancers from different tissues arise. Our laborator ....Cancer cells are unique, in that their ability to divide and grow is no longer controlled. Moreover, the DNA of cancer cells is less stable, and vital control genes often gain small mutations which culminate in a more aggressive or malignant cancer cell. Cancers from different tissues progress and respond in different ways to treatment, and the eventual development of tailored treatments or therapies will require a detailed understanding of how cancers from different tissues arise. Our laboratory studies two proteins, BRCA1 and APC, which are encoded by the genes most often associated with breast and colon cancer, respectively. We have made important discoveries linking the movement and location of these proteins inside the cell with their cancer-causing activity. In this project, we will continue to study how and why APC and BRCA1 move between different compartments inside cancer cells, and how this movement can sometimes signal cancer cells to die. Detailed understanding of these processes is essential for the eventual design of drug, peptide or gene therapies aimed at correcting defects in the expression or localisation of APC or BRCA1 in breast or colon cancer cells, and hopefully provide clues for that magic bullet that specifically targets and kills cancer cells.Read moreRead less
Identification Of New Mutations That Contribute To Breast Cancer
Funder
National Health and Medical Research Council
Funding Amount
$323,825.00
Summary
Breast cancer affects approximately one in ten women and is therefore a major health problem. In order to improve the diagnosis, treatment and prognosis of this disease, it is critical to understand the genetic defects that contribute to disease initiation and progression. Although a number of breast cancer susceptibility genes have been identified, the contribution each of these genes makes to breast cancer susceptibility is currently unclear. This is partly due to limitations in current diagno ....Breast cancer affects approximately one in ten women and is therefore a major health problem. In order to improve the diagnosis, treatment and prognosis of this disease, it is critical to understand the genetic defects that contribute to disease initiation and progression. Although a number of breast cancer susceptibility genes have been identified, the contribution each of these genes makes to breast cancer susceptibility is currently unclear. This is partly due to limitations in current diagnostic processes and an incomplete understanding of all of the genetic elements for which disruption can lead to loss of gene function. This proposal aims to identify regulatory pathways that are critical for the expression of an important breast cancer gene called BRCA1. Furthermore, it aims to determine the status of these pathways in breast cancer patients, thus expanding our knowledge of the actual contribution that disruption of this gene makes to this disease. It also aims to determine the potential for trans-acting factors to regulate the expression of BRCA1 and thus activity of the BRCA1 pathway. The predicted outcome of this research is an improved ability to perform presymptomatic diagnostic testing for breast cancer and the ultimately the development of more effective drugs to treat certain breast tumours.Read moreRead less