Epigenetics is a term that describes modification of gene expression without a change to the DNA sequence, through processes that involve chemical changes to the DNA such as DNA methylation and binding of specific proteins. It is now well established that epigenetics plays a major role in cancer development, but one of the important questions still to be resolved is the mechanism that is responsible for epigenetic changes. Our recent work has uncovered a new mechanism of epigenetic gene silencin ....Epigenetics is a term that describes modification of gene expression without a change to the DNA sequence, through processes that involve chemical changes to the DNA such as DNA methylation and binding of specific proteins. It is now well established that epigenetics plays a major role in cancer development, but one of the important questions still to be resolved is the mechanism that is responsible for epigenetic changes. Our recent work has uncovered a new mechanism of epigenetic gene silencing in cancer that can effect large chromosomal regions. We have found that both methylated and unmethylated genes can be silenced by changes to the pattern of proteins that bind to the DNA in a cancer cell. Our data also indicates that this silencing can be reversed using epigenetic drugs. This finding represents a new paradigm in epigenetic control and has major implications not only on cancer diagnostics but also cancer epigenetic therapy. In this grant we propose to further characterise and understand the mechanism involved in long range epigenetic silencing and to determine its prevalence in cancer. This proposal will shed light onto the process underlying long range epigenetic gene silencing in cancer and will provide potential novel targets for cancer detection, prognosis and therapy.Read moreRead less
Cohesin Dysfunction: Potential New Route To Tumourigenesis
Funder
National Health and Medical Research Council
Funding Amount
$386,511.00
Summary
This proposal aims to investigate the role of a newly-discovered chromosomal and DNA repair protein, Rad21, in breast cancer. Rad21 is a gene, present in many species and essential for accurate chromosome separation. Based on its' known function in different species, it is conceivable that its' dysfunction could fuel cancer progression by promoting genetic instability, eg. gains or losses of chromosomes, commonly associated with human cancers. No definitive data currently exists as regards the p ....This proposal aims to investigate the role of a newly-discovered chromosomal and DNA repair protein, Rad21, in breast cancer. Rad21 is a gene, present in many species and essential for accurate chromosome separation. Based on its' known function in different species, it is conceivable that its' dysfunction could fuel cancer progression by promoting genetic instability, eg. gains or losses of chromosomes, commonly associated with human cancers. No definitive data currently exists as regards the potential role of this gene in cancer development. This study is thus the first systematic investigation towards understanding the function of this potential cancer-causing gene. Although the proposed study focuses on breast cancers, it could, in principle, apply to other cancer types in which its' overactivity has recently be oberserved. This study could also have implications for the response of humans to radio- and chemo-therapy for cancer treatmentRead moreRead less
This proposal will focus on determining the effect that disruption of molecules involved in repairing DNA has on development of adverse reactions following cancer radiation treatment. Radiation is efective for cancer but tissues that reside next to the tumour are also exposed to radiation (which can damage DNA) during radiotherapy. About 1-5% of radiotherapy patients develop unexpectedly severe side effects in their normal tissues. The dose of radiation used for treatment to the rest of patients ....This proposal will focus on determining the effect that disruption of molecules involved in repairing DNA has on development of adverse reactions following cancer radiation treatment. Radiation is efective for cancer but tissues that reside next to the tumour are also exposed to radiation (which can damage DNA) during radiotherapy. About 1-5% of radiotherapy patients develop unexpectedly severe side effects in their normal tissues. The dose of radiation used for treatment to the rest of patients (>95%) is restrained to assure only a small proportion risk developing severe reactions. If one could predict which individuals were more susceptible to these reactions, then their large dose could be lowered to avoid the problem, and importantly, the dose could be increased for the majority of the patients, which would lead to a higher cancer cure rate. There are over 130 genes involved in repairing DNA. We hypothesize that dysfunctional DNA repair molecules are likely candidates to cause radiosensitivity in these individuals. In fact, a few of these genes have already been found to cause radiosensitivity, but we aim to assess all of the DNA repair genes in samples from patients that have had severe reactions to radiotherapy. Here we will use biospecimens, unique to our study and obtained from clinically radiosensitive cancer patients. We will use very sensitive, state-of-the-art procedures to test RNA and protein levels in our patients' cells and the latest technology to test what happens when candidate DNA repair molecule levels are altered. Additionally, we will determine the changes in DNA repair molecule numbers in response to different doses of radiation. We anticipate that results from these experiments will lead to the development of a clinical assay to test the likelihood of an individual having a severe reaction to radiotherapy, thus allowing individualization of treatment and, reducing radiotherapy side effects ultimately increasing cancer cure rates.Read moreRead less
Breast Cancer is a very common disease in women and although huge progress has been made in the last two decades, much remains to be done to improve our understanding of different types of breast cancer and its management. This program brings together the expertise of three senior researchers: 2scientists and 1 medical scientist. Dr Trench has an interest in identifying genes involved in cancers arising in patients who have a strong family history. She will use molecular methods and cohorts of p ....Breast Cancer is a very common disease in women and although huge progress has been made in the last two decades, much remains to be done to improve our understanding of different types of breast cancer and its management. This program brings together the expertise of three senior researchers: 2scientists and 1 medical scientist. Dr Trench has an interest in identifying genes involved in cancers arising in patients who have a strong family history. She will use molecular methods and cohorts of patients enrolled with Kathleen Cunningham Foundation for Research into Familial Breast and Ovarian Cancer to identify the genes responsible, assess their distribution in the population and determine whether these genes also play a role in non-familial cancers. Dr Khanna's work examines the complex array of enzymes that are responsible for maintaining the integrity of the DNA, and investigates how failure of these mechanisms leads to damage of the genetic material which ultimately results in cancer. It is known that genes involved in familial predisposition code for proteins that work as DNA repair enzymes. It is also known that different types of breast cancer exist, each with differing behaviour and response to treatment and that they are associated with specific genetic changes, including those associated with a familial predisposition. Prof Lakhani's interest lies in using microscopy and the latest molecular tools to refine the classification of these different types of breast tumour so that they can be managed appropriately by his surgical and oncological colleagues. A better understanding of the genetic changes and underlying biology of different types of breast cancer will lead to individualised and specific therapy for patients. This program brings together a unique combination, nationally and internationally, that investigates cancers at the level of genes and cells and translates the information to the clinic for the benefit of patient management.Read moreRead less
Molecular Identification Of Causative Genetic And Epigenetic Alterations That Induce And Promote Colorectal Cancer
Funder
National Health and Medical Research Council
Funding Amount
$381,821.00
Summary
The majority of mouse models currently employed to study colorectal cancer have two failings. The first is that they tend to focus on small intestinal cancers rather than colorectal cancers. It is important to note that small intestinal cancers are in the minority of gastrointestinal cancers in humans. The second problem is that the genetic lesions introduced into mice are mostly in all cells throughout development. This is a poor representation of the random nature of genetic changes that under ....The majority of mouse models currently employed to study colorectal cancer have two failings. The first is that they tend to focus on small intestinal cancers rather than colorectal cancers. It is important to note that small intestinal cancers are in the minority of gastrointestinal cancers in humans. The second problem is that the genetic lesions introduced into mice are mostly in all cells throughout development. This is a poor representation of the random nature of genetic changes that underpin the probable cause of colon cancer. We therefore propose to genetically engineer unique mouse models that focus on colon cancer to most closely replicate the situation in human disease. These models will then be available to others and us to develop and test therapies to prevent and-or treat colorectal cancer that will ultimately be used in patients.Read moreRead less