Dr. Ostrander's laboratory is interested in the study of genes important in growth regulation, particularly as it pertains to disease states in humans and canines. Her group aims to find genes that control the morphologic body plan of the domestic dog, which shows an extraordinary level of variation between breeds, and to identify disease susceptibility genes in dogs. Her group's work also focuses on the identification of genes that relate to susceptibility to, progression of, and specific outcomes in individuals with breast and prostate cancer.
Using a strategy that exploits the breed structure of dogs to investigate the genetic basis of body morphology, Dr. Ostrander's laboratory mapped the IGF-1 locus on canine chromosome 15 as the major controller of small size. A single IGF1 haplotype is common to all small dog breeds and nearly absent from giant breeds, suggesting that the same causal sequence variant is a major contributor to body size in all small dogs. Subsequent studies have identified genes controlling leg length and fur type, as well as loci controlling leg width, skull shape, ear position, and back arch. At least four additional loci associated with controlling body size have been identified and are a major focus of ongoing fine mapping studies.
Dog pedigrees are large, multigenerational, and the result of directed matings, all of which favor the expression of recessive disorders such as cancer. The clinical presentation, histology, and biology of many canine cancers very closely parallel those of human malignancies; comparative studies of canine and human cancer will be of significant clinical benefit to the health of both humans and companion animals. Towards that end, Dr. Ostrander's group has constructed high-density comparative maps of the canine genome and, in combination with a 7.5x whole-genome assembly of the dog, has been able to map loci for bladder cancer, malignant histiocytosis, Addison's disease, osteoarthritis, and other disorders. Cancer is of particular interest to her group and is the major focus of its canine disease studies.
Dr. Ostranders laboratory is also studying human prostate cancer loci involved in susceptibility and progression in high-risk prostate cancer families, in an effort to determine the importance of those loci in increasing disease risk in the general population. Towards that end, her group has been involved in linkage studies using high-risk families, as well as genome wide association studies (GWAS) involving large numbers of cases and controls. While loci on chromosomes 8, 4, 11, 15, and 17 are also of interest, Dr. Ostrander's group has most vigorously pursued fine mapping of the locus on chromosome 22. In addition, through GWAS studies involving 43,671 SNPs in 3,650 prostate cancer cases and 3,940 controls, the laboratory has identified new loci of interest on chromosomes 2, 4, 8, 11 and 22. Many of these regions are being studied by collaborators in the International Consortium for Prostate Cancer Genetics.
Dr. Ostrander's laboratory has also analyzed candidate genes in a population-based case-control study of middle-aged men, investigating the role of several hundred candidate SNPs that may affect specific pathways of interest. Among the most interesting findings to date have been those associated with variants in megalin, an endocytic receptor expressed by prostate cells that can internalize bound active androgens. In a study of 553 Caucasian men with prostate cancer and 535 controls, Dr. Ostrander's group foundthree single nucleotide polymorphisms (SNPs) that were associated with both disease recurrence, progression and mortality. Risk of recurrence/progression alone was also associated with five additional SNPs, and six other SNPs showed evidence of modification by primary androgen deprivation therapy.
With regard to breast cancer, initial interest focused on understanding the distribution and frequency of BRCA1 and BRCA2 mutations in women drawn from the general population. The most recent study examined the prevalence and predictors of BRCA1 and BRCA2 mutations in women with breast cancer. Numerous familial and demographic factors were found to be significantly associated with BRCA1 and, to a lesser extent, BRCA2-carrier status. However when all predictors were considered together, early age of diagnosis in cases and relatives, family history of ovarian cancer, and Jewish ancestry remained strongly and significantly predictive of BRCA1 carrier status, whereas BRCA2 predictors were less clear. Dr. Ostrander's laboratory is also interested in studies that validate models for predicting BRCA1 and BRCA2 mutation status. Finally, her laboratory is conducting fine mapping studies focused on breast cancer loci of lower penetrance, such as FGFR2.
Top of page
Last Updated: May 18, 2014