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 both a microsatellite and SNP-based 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 completed extensive fine-mapping. We refine this locus to a 15 kb region that spans one major gene by performing family-based association analyses with the use of 150 prostate cancer cases from 42 families (from two sources), each linked to the 22q12.3 region, and 506 unrelated population controls. The two independent family collections analyzed in this study independently identified the same locus as well as the same SNPs as having the strongest associations, with the most robust results coming from a combined analysis of all 42 families. In addition to the above, we have completed genotyping of approximately 1000 single nucleotide polymorphisms (SNPs) that include 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, we find that a SNP in cav-1 and one in cav-2 were associated with risk of overall PC and aggressive PC: ORCT+CC=1.57, 95%CI=1.20,2.06; ORGA+AA=1.40, 95%CI=1.05,1.86). We also found modest evidence for associations with variants in the cav-1 and cav-2 genes and risk of overall PC and aggressive PC, which merit further study. Of perhaps even great interest are SNPs associated with mismatch repair genes. Specifically, 19 SNPs were evaluated in the key MMR genes: five in MLH1, 10 in MSH2, and 4 in PMS2. Among Caucasian men, one SNP in MLH1 was associated with: overall PC risk (OR=1.21, 95% CI=1.02, 1.44; p=0.03), more aggressive PC (OR=1.49, 95% CI=1.15-1.91; p<0.01), and PC recurrence (HR=1.83, 95% CI=1.18, 2.86; p<0.01), but not PC-specific mortality. A non-synonymous coding SNP in MLH1 was also found to be associated with more aggressive disease. SNPs associated with circadian rhythm have also revealed interesting results. This analysis found that at least one SNP in each of nine different circadian rhythm-associated genes was significantly associated with susceptibility to prostate cancer and the risk of four SNPs in three genes varied by disease aggressiveness. Results from several other genes families are either published or analysis is ongoing. Finally, we are also working with a large collaborative group to identify and validate new loci using GWAS-based approaches. With regard to breast cancer we have focused this year on understanding the role of non BRCA1 and BRCA2 susceptibility genes. In a follow-up from a large collaborative GWAS study, we show a significant association with breast cancer risk was replicated for SNPs FGFR2-32 and FGFR2-13 (per-allele ORs and P-values adjusted for age at diagnosis and family history 1.21 (1.02-1.44) P=0.025, 1.24 (1.04-1.47) P=0.014). Additionally, for both these SNPs the effect was stronger in estrogen receptor (ER) positive cases as well as in progesterone positive (PR) cases compared to ER negative and PR negative cases, respectively, although the differences were not significant (P-Heterogeneity both >0.05). We have also showed significant evidence of an association between genotype and breast cancer survival was observed for a polymorphism in he COMT gene. Studies of other loci are ongoing. 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. For instance, using a multi-breed association analysis we showed that a recently acquired fgf4 retrogene causes chondrodysplasia, a short-legged phenotype that defines several common dog breeds including the dachshund, corgi and basset hound. The discovery that a single evolutionary event underlies a breed-defining phenotype for 19 diverse dog breeds demonstrates the importance of unique mutational events in constraining and directing phenotypic diversity in the domestic dog. We have also explored ways to understand the genetic control of seemingly complex phenotypes using the dog system. We show, for instance that varirant in three genes, Rspo2, FGF5, and Krt71, in combination, account for the majority of observed coat phenotypes among purebred dogs in the United States. These findings show how an array of varied and seemingly complex phenotypes can be reduced to the combinatorial effects of only three genes. We have also continued to work on genetics of body size, and defined a set of four genes that contribute to overall body size control. Efforts are ongoing in the lab to characterize those loci. We also continue to be interested in genetics of dog breeds, and have genotyped a set of 1000 domestic dogs, representing over 85 breeds as well as 300 wild canids. In collaboration with others, analysis of that data is revealing interesting information about the organization of the canid species and individual genomes. That data set also continues to be analyzed for the identification of other loci controlling morphologic features in the dog. We are also continuing our series of GWAS 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 and very recently the Sheltie, malignant histiocytosis (MH) in the Bernese mountain dog and squamous cell carcinoma (SCC) of the digit in the poodle and the giant schnauzer. Also we just began a study of gastric cancer in the Chow Chow. We have found a locus for 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 and mutations scanning in collaboration with investigators at NISC using next generation sequencing technologies is underway. The GWAS for gastric cancer is just beginning. We have completed an initial scan for TCC and provisionally identified two loci. Fine mapping and additional chip genotyping is underway. We have established a collaboration with investigators working on human bladder cancer to test the importance of identified loci identified in the dog. In summary, our work is aimed at understanding the role of genetic variation in regulating phenotypes contributing to both morphology and disease susceptibility. The past year has been met with considerable success with the publication of multiple high profile papers.