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    Research Grants Awarded

    Genomic study of familial DCIS and invasive breast cancer to discover susceptibility genes

    Study Section:
    RISK and Prevention, Epidemiology

    Scientific Abstract:
    It is important to develop methods to identify women at increased risk of breast cancer to effectively target early detection and prevention strategies. Although several high-risk susceptibility genes have been discovered, only 5-10% of breast cancer is hereditary. About 15-20% of breast cancer occurs in familial clusters but the etiology remains largely unexplained. We believe that heterogeneity of genetic and environmental risk factors is the main reason why the discovery of breast cancer susceptibility alleles has been so elusive. Our strategy to circumvent this problem is to group tumors into smaller families or “molecular portraits” according to their global pattern of gene expression. We propose to apply gene expression profiling to the study of familial DCIS and invasive breast cancer in order to enrich for and identify candidate breast cancer susceptibility genes. We hypothesize that genes which are causally related to the development of familial breast cancer will be discernable among the larger set of genes which define breast cancer subtypes. Aim 1: Perform gene expression profiling on sporadic invasive breast carcinomas and sporadic DCIS samples. We will use computer programs to cluster genetically similar tumors together, analyze the association with clinical parameters such as rec eptor status, and utilize publicly available data to later detect novel tumor types in familial tumors. Aim 2: Perform gene expression profiling on familial invasive breast carcinomas and familial DCIS. Aim 3: Compare invasive breast tumors and DCIS from within families, i.e. sister-sister or sister-mother pairs. Aim 4: Select candidate genes based on experimental data from Aims 1-3, and information on biological role in breast cancer and genetic variants. A measure of success for this study will be the identification of previously discovered susceptibility genes. Ultimate proof regarding new susceptibility genes will depend on the results of genetic association studies, as part of future work, using microarray-based genotyping. The impact of this work will be broad as our objective is to identify the genetic determinants of breast cancer. Ultimately we envision a comprehensive risk evaluation using a panel of genetic markers, an environmental exposure history that is informed by gene pathway analysis, and a prescription of lifestyle behaviors, screening, and prevention tailored to a woman’s underlying risks.

    Lay Abstract:
    It is important to develop ways to identify women at increased risk of breast cancer in order to focus early detection and prevention efforts on these individuals. Although some high-risk breast cancer genes have been discovered, only 5-10% of breast cancer is hereditary. About 15-20% of breast cancer occurs in familial clusters. The causes of familial breast cancer remain largely unexplained. It is thought that a broad mix of genetic and environmental risk factors contributes to familial breast cancer. We believe that the complexity of these risk factors explains why the discovery of familial breast cancer genes has been so elusive. Our strategy to circumvent this problem is to group tumors into smaller families or “molecular portraits” according to their global pattern of gene expression. Tumors with a similar biology cluster together into subtypes which reflect common patterns of gene expression. We predict that shared patterns of gene expression are in part determined by the genetic predisposing factors that tumors of the same subtype share in common. We propose to apply gene expression profiling to the study of familial DCIS and familial invasive breast cancer in order to enrich for and identify candidate breast cancer susceptibility genes. We hypothesize that genes which cause familial breast cancer will be discernable among the larger set of genes which define breast cancer subtypes. Aim 1: Perform gene expression profiling on sporadic invasive breast carcinomas and sporadic DCIS samples. We will use computer programs to cluster genetically similar tumors together, analyze the association with clinical parameters such as receptor status, and utilize publicly available data to later detect novel tumor types in familial tumors. Aim 2: Perform gene expression profiling on familial invasive breast carcinomas and familial DCIS. Aim 3: Compare invasive breast tumors and DCIS from within families, i.e. sister-sister or sister-mother pairs. Aim 4: Select candidate genes based on experimental data from Aims 1-3, and information on biological role in breast cancer and genetic variants. A measure of success for this study will be the identification of previously discovered susceptibility genes. Ultimate proof regarding new susceptibility genes will depend on the results of genetic association studies, as part of future work, using microarray-based genotyping. The impact of this work will be broad as our objective is to identify the genetic causes of breast cancer. Genetic susceptibility likely underlies not only familial, but also sporadic breast cancer. Ultimately we envision a comprehensive risk evaluation using a panel of genetic markers, an environmental exposure history that is informed by gene pathway analysis, and a prescription of lifestyle behaviors, screening, and prevention tailored to a woman’s underlying risks.