Research Grants Awarded
Genetic Characterization Of Breast Cancer Risk In Families
Investigator Initiated Research
It is clear from numerous epidemiologic studies that BRCA1 and BRCA2 mutations account for only a small portion of familial susceptibility to breast cancer. Although shared environment may account for some of the remaining familiality of the disease, consistent recurrence patterns in distant relatives indicate that simple additive or dominant genetic factors account for much of the variability in susceptibility. Identification of additional susceptibility alleles is critically important for reducing the risk of breast cancer in women with positive family histories of disease, by allowing for early intensive screening, chemoprevention, and/or surgical prophylaxis. Moreover, the identification of additional susceptibility alleles is likely to lead to an improved understanding of mechanisms of carcinogenesis in the breast, and the identification of potential drug targets for prevention and treatment.
Our specific aims are to:
1.Conduct a genome-wide association study of breast cancer in high-risk families identified through the Utah Population Database. We will genotype 290 breast cancer cases and 290 controls drawn from 80 high-risk cancer families, using high-density (~1,000,000) SNP arrays. Because our samples come from high-risk families descended from known common ancestors within six to eight generations, ancestral haplotypes containing disease-causing variants are almost certain to span multiple SNPs on a high-density array. We have completed a preliminary genome scan based on a small number of microsatellite markers. To date, we have identified 17 loci suggestively (false discovery rate (FDR) < 0.2; 7 with FDR < 0.1) associated with susceptibility to breast cancer. Although these results show that our analysis so far has been productive, the 10 cM intervals between microsatellite loci are large in relation to the expected lengths of the chromosomal segments shared by affected relatives after many generations have passed. The availability of high-density genotyping arrays containing hundreds of thousands of single-nucleotide polymorphism (SNP) markers makes it possible for us to definitively map the primary variants responsible for excess familial cancer risk in the Utah population.
2. Conduct confirmatory analyses using the National Cancer Institute?s Cancer Genetic Markers of Susceptibility (CGEMS) database, the National Center for Biotechnology Information?s database of Genotype and Phenotype (dbGaP), and data from other published association studies as available.
While identification of the BRCA1 and BRCA2 genes has certainly led to an improved understanding of cellular mechanisms for maintaining DNA integrity, neither gene has proved critical to breast carcinogenesis in general, and the existence of strong patents on both genes has probably hampered research in certain areas. The identification of new susceptibility variants will lead to the identification of new diagnostic and screening procedures, new mechanisms of carcinogenesis, and new targets for intervention.
Increased knowledge of the entire landscape of breast cancer susceptibility will result in more accurate prediction of breast cancer risks, which can lead to more informed choices about screening and prevention options for women who are concerned about how a family history of breast cancer might affect their chances of having breast cancer.
While the familiality of many forms of cancer is well established, and several genes with important impacts on familial cancer risk have been identified, abundant evidence suggests that the great majority of genes that affect cancer risk have not yet been found. Early efforts to identify cancer susceptibility genes concentrated on large families with very high risks, especially at young ages; these studies were generally successful in identifying the genes and mutations responsible for elevated risks in the target families. In the last decade, a much greater effort has gone into the study of affected sib pairs and other small-family designs, with less impressive results. The apparent lack of success of recent studies has led to speculation that few susceptibility genes with large effects remain to be discovered, although the epidemiologic evidence seems to indicate otherwise.
We suspect that numerous genetic variations that have important effects on breast cancer risks, remain to be discovered. Small-family study designs are poorly suited to the identification of genes that contribute to relatively common, late-onset, heterogeneous diseases like cancer. On the other hand, large families with multiple breast cancer cases have been getting hard to find. Genetic association studies that require little or no familial information are now becoming feasible, but the power of these studies to find genetic variants that are not common remains quite limited.
Population-wide genealogical databases provide us with an opportunity to identify very large families that contain many affected individuals related to varying degrees and paths of relationship within ten generations or less. Cases drawn from these very large families (VLFs), and the varieties of kinship among them, can be employed in genetic association studies and greatly increase the power of a study to detect susceptibility alleles regardless of their population frequency.
From the Utah Population Database, we have identified 80 very large families at significant excess risk of cancer. These families range in size from 524 to 21,653 members, and from them we have collected lymphocyte and DNA samples from 1,479 members (290 affected by breast cancer). We have completed a preliminary genome scan based on a small number of markers. To date, we have identified 17 different regions of the human genome that are likely to harbor genetic variants that predispose women to breast cancer.
We intend to use modern, highly informative, genotyping methods to increase the amount of genetic information we have on our families by a factor of about 2,500, in order to maximize our chances of finding the genetic variants that are most important in affecting breast cancer risk in women. If we find the genetic variations responsible for making some women much more likely to get breast cancer than others, we can be much more effective in designing and deploying screening programs to detect cancer early, and we may also gain valuable insights into the disease process that will help in designing drugs or other tools for preventing and curing breast cancer.