1994 — 1998 |
Ostrander, Elaine A |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Population Based Genetic Analysis of Breast Cancer @ Fred Hutchinson Cancer Research Center
Through epidemiological research, a consensus has been reached that environmental factors are important in the etiology of breast cancer. Genetic analysis of breast cancer pedigrees has proven that hereditary factors can also contribute to breast cancer etiology. The guiding principal of this project and its two interactive R01 partners is to discover the environmental and hereditary factors that define an individual woman's breast cancer risk. This proposal concentrates on two issues important to the genetic epidemiology of breast cancer. 1) Genes that contribute to breast cancer risk need to be discovered. Despite recent exciting advances in breast cancer genetics, the discovery of BRCA1 located on 17q, there is compelling evidence that there are additional genes to be discovered. In this proposal, we will use a population based sampling of breast cancer affected relatives to perform linkage studies. We will use APM linkage strategies because they are free of the assumptions that are required to perform likelihood linkage analysis. 2) Once breast cancer susceptibility genes are found, they must then be incorporated into epidemiological studies: efficient assays need to be developed; the population genetic characteristics need to be determined; and large numbers of individuals need to be assayed if genetic/environmental interactions are to be discovered. We will sequence cases and controls at the p53 gene concentrating on those exons that have not been analyzed by other researchers. We will also perform sequence analysis of BRCA1 if it is isolated during this granting period. Interpretation of the data will use case-control methodologies and will concentrate on the potential of finding gene/environment interactions. This proposal represents the next generation of genetic analysis. We will be searching for the genes that are more difficult to find; genes that do not present themselves in large, highly penetrant pedigrees; genes that may be more relevant to the total population incidence of breast cancer. The limitation we face at this time is not genotyping technology, but rather patient populations and analysis methods that are sufficient to the task. This requires the merging of genetics, epidemiology and biostatistics. The foundation of this proposal, and the other two interactive projects, is that we have already ascertained 1400 women who were diagnosed with breast cancer before age 45 and a similar number of matched controls. Blood samples have been collected from over half the cases and 200 controls. A relatively small amount of additional effort is required to fully transform this epidemiological resource into the resource we need for our proposed genetic studies. Application and/or development of appropriate biostatistical tools requires interaction with our partner projects.
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0.901 |
1997 — 1999 |
Ostrander, Elaine A |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Inherited Breast Cancer in Chinese Women @ Fred Hutchinson Cancer Research Center
DESCRIPTION: The goal of this study is to describe the frequency and type of mutations and polymorphisms in two autosomal dominant, highly penetrant breast cancer genes in cases and controls from a population-based series of Chinese women with breast cancer, unselected for family history. Mutations in the BRCA1 and BRCA2 genes have all been associated with breast cancer in high risk families, that include multiple cases of apparently inherited disease, often at a young age. The majority of these data derive from studies of a small number of high risk Caucasian families with unusually high frequencies of early onset breast cancer. No information is available regarding the frequency, type or presence of founder mutations in non-Caucasian populations, specifically among Asians. As a result, no information is currently available for genetic testing or screening for either Chinese women or Western women living in North America or Europe, who are of Chinese descent. This study seeks to provide and disseminate that information by: 1) determining the frequency and types of mutations in the BRCA1 genes in cases and controls from a large, population-based, case-control study of breast cancer in Shanghai; 2) developing a public data base to distribute the above information, along with information regarding the type and frequency of polymorphisms and rare sequence variants' and 3) comparing the frequency and type of mutations with suspected risk factors for breast cancer. The proposed study will be nested within a randomized, controlled trial, the Shanghai Breast Self-Examination (BSE) Trial, of 267,000 women, designed to examine the effect of breast self-examination on breast cancer mortality in Shanghai, China. Extensive epidemiologic data are already available on this cohort, which may be combined with the proposed molecular study for additional analyses. Information from the above studies could be used to formulate public health policy and diagnostic breast cancer screening strategies on subsets of Asian women, in the future.
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0.901 |
1999 — 2003 |
Ostrander, Elaine A |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Genetics of Prostate Cancer Susceptibility @ Fred Hutchinson Cancer Research Center
DESCRIPTION (Adapted from investigator's abstract): Prostate cancer is the most common cancer and the second leading cause of cancer deaths among men in the United States. Approximately 334,500 men are diagnosed every year. Despite advances in treatment and increased screening efforts, about 41,800 men each year will go on to die of the disease. This is similar to the number of women that die yearly from breast cancer. Epidemiological data support the hypothesis that strong familial components are involved in the etiology of prostate cancer, particularly in men diagnosed at young age or men with a family history of disease. Mapping and eventual cloning of such genes is likely to provide insight into the molecular mechanisms critical for prostate cancer susceptibility, and provide knowledge about the molecular mechanisms of prostate cancer initiation. This submission proposes to map prostate cancer susceptibility genes by taking advantage of an ongoing effort to collect high risk prostate cancer families that has been undertaken by Seattle investigators. This effort has led to the identification of a large number of high risk prostate cancer families and subsequent collection of DNA samples, epidemiologic and clinical data, and family history information from eligible families. Specifically, the proposal is to 1) Genotype 250 high risk prostate cancer families with 387 microsatellite-based genetic markers that span the human genome at 10cM resolution. 2) Perform linkage and nonparametric analysis to identify regions of the genome likely to contain prostate cancer susceptibility genes using the above genotyping data. This will involve stratifying families by a number of criteria for which they have collected data, such as age of onset, tumor grade and stage, PSA level, and occurrence and incidence of other cancers. 3) Expand the analysis of a prostate cancer susceptibility gene at 1q24-25 from 49 to 250 high risk families. Particular emphasis will be placed on heterogeneity analysis to best determine the subset of families for which this locus is likely to be most significant. Finally, once regions of the genome likely to contain prostate cancer susceptibility genes are localized, they will refine the region of interest by analysis of additional markers and identification of recombinants. These experiments will provide a foundation for subsequent physical mapping efforts and candidate cDNA analysis.
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0.901 |
2001 — 2004 |
Ostrander, Elaine A |
K05Activity Code Description: For the support of a research scientist qualified to pursue independent research which would extend the research program of the sponsoring institution, or to direct an essential part of this research program. |
Genetics of Cancer Susceptibility--Multisystem Approach @ Fred Hutchinson Cancer Research Center
DESCRIPTION (provided by applicant): We are interested in the identification and analysis of genes which increase susceptibility to cancer and are taking a three-pronged approach to addressing the problem. We have used linkage analysis to look for highly-penetrant Plostate cancer susceptibility loci by performing a ganomc-wide scan in 266 high-riskI prostate cancer families, preliminary results from this scan implicate multiple lociof interest, and ongoing efforts focus on fine mapping of the regions identified and positional cloning of the affected genes. We have used population-based case/control studies to determine the role played in sporadic breast cancer of mutations in the highly-penetrant genes BRCA1 and BRCA2. Work to date has focused on a population of women in Western Washington State, and ongoing efforts center around 2 much larger studies, 1 in the U.S. and 1 in Shanghai, China, and also on understanding the effects of non-genetic factors on panetrance of BRCA1 and 2 mutations. Our human work has underscored the difficulties of studying a genetically complex disease in human families. We have therefore developed the domestic dog as a uniquely powerful system for advancing cancer genetics, taking advantage of both the large family size as well as the closed breeding populations (breeds) that characterize purebred dogs. To date, we have developed a map of the dog genome and demonstrated the utility of the canine system for simplifying the locus heterogeneity associated with mapping complex traits. In the process we have mapped several disease genes, including a kidney cancer locus, of interest to the human genetics community. The next key step is to integrate our throe approaches. Cloning prostate cancer susceptibility loci identified in high risk families and analysis of mutation frequency and distribution will allow us to determine the significance of these genes in the general population, much as we have done in our studies of breast cancer. Mapping and cloning of canine cancer loci will accelerate identification both of highly penetrant genes and of less penerrant genetic modifier loci, and will permit us to test the hypothesis that genes we identify in dogs are equally relevant in human disease, as suggested by a variety of prior studies. This K05 will provide the resources, and particularly the time, necessary to provide guidance and mentoring to students and postdocs in my lab as they pursue the new avenues of research that will achieve the integration of our efforts.
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0.901 |
2002 — 2003 |
Ostrander, Elaine A |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
A High Density Gene Map of the Canine Genome @ Fred Hutchinson Cancer Research Center
[unreadable] DESCRIPTION (provided by applicant):The identification of disease susceptibility genes in human families and populations to date has focused on the mapping and cloning of autosomal dominant highly penetrant genes, identified by linkage mapping studies using extreme, "high risk families." Such families are rare and because of their small size often provide limited genetic information, particularly if key family members are deceased or have not produced offspring. In addition, inherent limitations in the structure of human populations, such as a long generation time and outbreeding mean that genes which are weakly penetrant, give rise to variable phenotypes, or act in concert with other genes to produce complex phenotypes are extremely difficult to map. This is particularly true for diseases like cancer, in which a multitude of low penetrant alleles are believed to account for a significant percentage of disease in the population.We hypothesized previously that the domestic dog offers several key advantages over other systems for mapping genes relevant to human disease. Obvious advantages include the large family size of dogs, as well as founder effects and narrow population bottlenecks that result in limited locus heterogeneity for common disorders among purebred dogs.In this grant, three experienced and interactive groups will expand their ongoing collaborations to develop the infrastructure for positional cloning in dogs, thus establishing the domestic dog as the model system of choice for mapping cancer susceptibility genes, as well as other common disease alleles. Previously we developed an integrated 1800 marker meiotic linkage/radiation hybrid (RH) map of the dog, composed of microsatellites, ESTs, and BAC-ends that spans over 95 percent of the genome. We have demonstrated the utility of these maps by mapping loci for several diseases, including canine renal cancer and four types of retinal degeneration. In this proposal we will set the stage for positional cloning of these and other disease genes of interest in the dog by 1) Identifying fragments from greater than 10,000 canine genes, suitable for RH mapping, from the 1x canine genome sequence being made available by The Institute for Genomic Research (TIGR); 2) Mapping fragments from 10,000 canine genes using a newly developed, high resolution (10,000-rad) RH panel; and 3) Developing and making readily available to the genomics community a canine RH map inclusive of these and additional data currently under generation.
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0.901 |