Finding Genes for Cancer Susceptibility and Growth Regulation

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Dr. Ostranders research interests are in the area of genetic mapping of complex traits and genomics. We have two main areas of study. First, we are mapping and identifying genetic variants that increase susceptibility to breast and prostate cancer in humans. Both family and population-based studies are underway. Second, we are interested in the development of the canine system for understanding the role of genetic variation in complex traits. Traits of interest include those related to both disease susceptibility and morphology. With regard to prostate cancer, we completed and published a genome wide scan of 255 human prostate cancer families and identified several loci of interest. Stratification of our now complete dataset by features such as aggressiveness of disease has highlighted a region of chromosome 22 where we have been doing extensive fine-mapping. We have reduced the region of linkage to 1.35 Mb and using recently generated SNP data are focused on less then 3 genes in a region that provides the strongest statistical evidence for a locus in our own data set, and in a parallel and collaborative study with the Mayo Clinic. We are now working on mutation scanning. In addition to the above, we have completed genotyping of approximately 1000 single nucleotide polymorphisms (SNPs) that interrogate over 100 candidate genes for association with prostate cancer risk and progression in a large population-based, case control study of middle and older aged men. Analysis of these data is ongoing, but thus far we have found interesting SNPs associated with several genes. For instance, several SNPs at 8q24 show as association with prostate cancer and we have published several papers summarizing this data. Additionally SNPs in genes such as megalin and the TMPR322 gene fusion have proven interesting and papers summarizing these findings recently published. With regard to megalin the risk of recurrence and progression is strongly associated with five SNPs. With regard to the TMPR322 fusion we find that reduced prostate cancer specific survival occurs in cases whose tumor has multiple copies of the fusion. We have also completed a detailed study of the role of BRCA2 and prostate cancer, showing a minimal contribution to familial and sporadic disease. Finally, we have been involved in a study of statin use and prostate cancer risk and prognosis. We recently published our results showing that obese men who used statins had an increased risk of prostate cancer (OR = 1.5, 95% CI: 1.0, 2.2) relative to obese nonusers, with a stronger association for longer-term use. With regard to breast cancer we have focused on understanding the role of the breast cancer susceptibility genes BRCA1 and BRCA2 in women drawn from the general population. Our most recent collaborative study, published in Cancer Research has focused on a large data set of nearly 3000 women, nearly 1/3 of whom are African American, to define profiles of women likely to be at increased risk for being a BRCA1 or BRCA2 carrier. As a follow up, we are taking an evolutionary approach to understanding the role of missense changes in BRCA1/BRCA2, with a long term goal of identifying subtle variants of low genetic penetrance that are associated with increased disease risk. We are working to summarize all missense changes found in our case control study, particularly as they relate to African American women, and using a variety of lab based, statistical and evolutionary approaches determine the ones most likely to be disease-associated. We have also put considerable effort into determining the role of various SNPs in the TNRC9 and FGFR5 genes and breast cancer risk for African American women. Manuscripts are in preparation summarizing those three projects. Our canine studies canine studies focus on finding genes important in disease susceptibility and growth regulation. This work is accomplished by collaboration with dog owners, breeders and kennel clubs and not by breeding or housing any dogs on site. Several high profile papers have resulted from these efforts to date. With regard to morphology determine that IGF-1 is a major regulatory in distinguishing body size in dogs. A single ancient allele has been under strong selection in small dog breeds and, as was described in a high profile paper in Science, plays a major role in controlling overall body size in dog breeds. Since publication of that paper we have expanded our study genotyping 1000 dogs of 85 breeds with the Affymetrix SNP chip and defined a set of five additional genes that contribute to overall body size control. Major efforts are ongoing in the lab to characterize those loci. Other morphologic traits have also been under investigation and we now understand the genetic control of several. Asymmetrical dwarfism (Corgi, Bassett Hound, Dachshund, etc) appears to be controlled by a single complex mutation. We have also investigated hair growth and found the genes controlling hair growth pattern, curl of fur, and length. For two of those the variant form of the gene have been found (long versus short, fringes versus not). Again, manuscript preparation is underway. With regard to disease gene mapping we have been interested in taking advantage of the population structure of modern dogs to improve power for whole genome association studies. We have completed and now published an expanded study of nearly 135 dog breeds and used clustering algorithms to better understand the relationship of the breeds one to another. This data is useful for grouping affected dogs of different breeds which may share a common ancient disease allele as demonstrated in a recent Genome Research paper where we identified the mutation for collie eye anomaly, a disorder of herding breeds that as features reminiscent of human macular degeneration. We are continuing our series of whole genome association studies aimed at finding loci for cancer susceptibility in the dog. Ongoing studies include mapping loci for transitional cell carcinoma (TCC) of the bladder in the Scottish terrier and west highland white terrier, malignant histiocytosis (MH) in the Bernese mountain dog and squamous cell carcinoma (SCC) of the digit in the poodle and the giant schnauzer. A locus on canine chromosome 11 has been unambiguously identified as associated with MH in the Bernese mountain dog and positional cloning efforts are underway. Positional cloning efforts have been successful in the case of the SCC in the Standard Poodle, Gordon Setter, and Giant Schnauzer. Final mutation scanning is now proceeding for that disease. We are also planning to scan DNA from a cohort of human subjects with the same disorder to see if the same gene plays a role in human forms of the disease. In summary, our work is aimed at understanding the role of genetic variation in regulating phenotypes contributing to both morphology and disease susceptibility. In humans our studies focus on two cancers, breast and prostate, and rely on both family-based linkage studies and whole genome association studies. The past year has been met with considerable success, and groundwork laid for additional studies in the coming year. In the canine system we continue to explore the organization of the genome. We are applying our findings to studies of disease susceptibility, with an emphasis on cancer, and to understanding the portfolio of genes important in growth regulation. Again, we have met with considerable success finding genes for both growth regulation at least one form of cancer. Extensive preliminary studies suggest that this coming year is apt to be a banner year with multiple long term studies completed.