Investigating The Genetic Basis Of Inherited Renal Cell Carcinoma
Lead Research Organisation:
University of Birmingham
Department Name: Clinical and Experimental Medicine
Abstract
Kidney cancer is a serious medical problem. The five year survival of patients with metastatic disease is 10%. We need to improve our understanding of kidney cancer so that we can produce more effective treatments. Some kidney cancers run in families, and although rare they have provided great insights in how kidney cancer occurs. This has led to the development of drugs that have revolutionised kidney cancer treatment. Patients with familial kidney cancer have kindly allowed us (Dr Mariam Jafri and Professor Eamonn Maher) to investigate their blood for alterations (misprints) in their DNA which may cause cancer susceptibility. As relatively few misprints have been detected in kidney cancer, there maybe other unknown alterations that maybe important in the disease. We hope to identify these alterations by looking for misprints in the genes of patients with familial cancer. We will look at particular interesting genes and use a new technique that looks at most of the genes that are contained in a person‘s DNA. Once we have identified altered genes, we will either try to use them in the treatment of kidney cancer or if we do not know about how they work, we will try and determine their function.
Technical Summary
Aims:
To gain a novel insight into the pathogenesis of renal cell carcinoma (RCC) by identifying new tumour associated genes in familial kidney cancer.
Objectives:
1. Investigate candidate genes for mutations in a cohort of non-syndromic familial renal cell carcinoma (NSFRCC) patients.
2. Perform whole exome sequencing on germline DNA from NSFRCC patients to identify novel inherited renal cancer gene(s)
3. Investigate the role of novel NSFRCC genes in sporadic RCC.
4. Initiate functional/therapeutic investigations
Methodology:
Initially, I will use conventional and second generation DNA sequencing methodologies to identify mutations in candidate genes in a panel of 50 NSFRCC germline DNA samples. I have already investigated two candidate genes, and have compiled a list of other candidate genes from published data, and unpublished epigenetic studies.
Whole exome sequencing will be performed on a subgroup of patients with NSFRCC who do not harbour mutations in known or candidate inherited RCC genes to identify novel inherited RCC gene(s). Having prioritised candidate mutations, I will perform analyses to validate the candidate as a novel inherited RCC gene. Furthermore, I will investigate its contribution to the pathogenesis of NSFRCC and to sporadic RCC (by sequencing and CpG island methylation analysis as appropriate).
Further investigations of a novel inherited RCC gene will be dependent on knowledge of the gene of interest. If the gene is well characterised and part of a well defined pathway, I will investigate the effect of potential therapeutic agents on the proliferation of RCC cell lines defective for the novel RCC gene to determine if genetic status might be used to guide targeted therapy (I have experience of using siRNA treatments to identify new targets in VHL +/- isogenic cell lines).
Scientific and Medical Opportunities
Insights from familial RCC have led to significant developments in the treatment of RCC. Segregation analysis studies indicate NSFRCC is inherited in an autosomal dominant manner. Most NSFRCC kindreds are not accounted for by known inherited RCC genes. A combined strategy of candidate gene and exome sequencing is likely to identify novel genes, and to provide better insight into the pathology of kidney cancer.
To gain a novel insight into the pathogenesis of renal cell carcinoma (RCC) by identifying new tumour associated genes in familial kidney cancer.
Objectives:
1. Investigate candidate genes for mutations in a cohort of non-syndromic familial renal cell carcinoma (NSFRCC) patients.
2. Perform whole exome sequencing on germline DNA from NSFRCC patients to identify novel inherited renal cancer gene(s)
3. Investigate the role of novel NSFRCC genes in sporadic RCC.
4. Initiate functional/therapeutic investigations
Methodology:
Initially, I will use conventional and second generation DNA sequencing methodologies to identify mutations in candidate genes in a panel of 50 NSFRCC germline DNA samples. I have already investigated two candidate genes, and have compiled a list of other candidate genes from published data, and unpublished epigenetic studies.
Whole exome sequencing will be performed on a subgroup of patients with NSFRCC who do not harbour mutations in known or candidate inherited RCC genes to identify novel inherited RCC gene(s). Having prioritised candidate mutations, I will perform analyses to validate the candidate as a novel inherited RCC gene. Furthermore, I will investigate its contribution to the pathogenesis of NSFRCC and to sporadic RCC (by sequencing and CpG island methylation analysis as appropriate).
Further investigations of a novel inherited RCC gene will be dependent on knowledge of the gene of interest. If the gene is well characterised and part of a well defined pathway, I will investigate the effect of potential therapeutic agents on the proliferation of RCC cell lines defective for the novel RCC gene to determine if genetic status might be used to guide targeted therapy (I have experience of using siRNA treatments to identify new targets in VHL +/- isogenic cell lines).
Scientific and Medical Opportunities
Insights from familial RCC have led to significant developments in the treatment of RCC. Segregation analysis studies indicate NSFRCC is inherited in an autosomal dominant manner. Most NSFRCC kindreds are not accounted for by known inherited RCC genes. A combined strategy of candidate gene and exome sequencing is likely to identify novel genes, and to provide better insight into the pathology of kidney cancer.