Chief & NIH Distinguished Investigator

Cancer Genetics and Comparative Genomics Branch

Education

B.S. University of Washington, 1981

Ph.D. Oregon Health Sciences University, 1987

Biography

Dr. Elaine Ostrander is chief of the Cancer Genetics and Comparative Genomics Branch at the National Human Genome Research Institute of NIH. She also heads the Section of Comparative Genetics. Dr. Ostrander received her Ph.D. from the Oregon Health Sciences University, and did her postdoctoral training at Harvard. She then went to UC Berkeley and the Lawrence Berkeley National Labs, where, with collaborators, she began the canine genome project, and built the canine linkage and radiation hybrid maps. She was at the Fred Hutchinson Cancer Research Center and University of Washington for 12 years, rising to the rank of member in the Human Biology and Clinical Research Divisions, and head of the Genetics Program.  She moved to NIH in 2004. 

Dr. Ostrander's lab at NIH works in both human and canine genetics.  Her lab is using state of the art genomic approaches to identify prostate cancer susceptibility genes. She is best known, though, for her studies of the domestic dog as a well-phenotyped species with an extensively documented population structure that offers unique opportunities for solving fundamental biological problems. Her lab developed the primary genomic mapping resources for the canine genetics field, and applied them to studies of disease and morphology.  For instance, she and her collaborators were the first to map genes for canine epilepsy, Addison's disease, kidney, squamous cell and histiocytic cancers. All are now candidates for comparable human disorders. In recent years, Ostrander's experiments have revealed how modifications in small numbers of genes produce the enormous differences in canine body shape and size that characterize the spectrum of breeds.

Dr. Ostrander has published over 285 papers. She has won multiple awards including the American Cancer Society Junior Faculty Award, Burroughs Welcome Award for Functional Genomics, Asa Mays Award, Lifetime Achievement Awards for both her prostate cancer and canine genetics work, and in the 2013 Genetics Society of America Medal.

Scientific Summary

The Ostrander lab is interested, first, in expanding the vocabulary of growth control related genes. As such, the researchers are building on the extensive genomic infrastructure we developed for the dog to identify genes associated with breed-specific differences in morphology. The team seeks, secondly, to find genes associated with cancer susceptibility in dogs, where breed predilection likely reflects the selective pressures used to develop and enhance specific traits. Their interest in cancer extends beyond dogs to human prostate cancer (PC), where they are working both independently and within consortia to find genes associated with susceptibility and progression to aggressive forms of PC.

Dogs

Canine Morphology: The Ostrander lab has long championed the canine system (Ostrander NEJM, 2012) for the study of complex traits by building maps (e.g. Guyon et al., PNAS 2003; Hitte et al., Nat Rev Genet 2005), organizing sequencing of the canine genome (Lindblad-Toh et al., Nature2005), and studying population structure (Parker et al., Science2004; Genome Res 2007), domestication (VonHoldt et al., Nature 2010), and performance (Mosher et al., PLoS Genet 2007). In doing so they have demonstrated the power of breed structure for mapping traits that are have proven intractable through human studies (e.g. Parker et al., Genome Res2007). The lab's ability to map the genetic underpinnings of body size (Sutter et al., Science 2007), pelage (Cadieu et al., Science 2009), leg length (Parker et al., Science 2009), skull shape (Schoenebeck et al., PLoS Genetics 2012; Schoenebeck et al., Genetics 2013), and other phenotypes has provided unique insights into the fundamental biology of natural phenotypic variation in mammals, offering a completely new lens for viewing these processes in humans. They have built a large data set for such studies encompasing 85 breeds and over 1000 dogs, all of which they have genotyped with a dense SNP chip. Using that data, their GWAS analyses of canine skull morphologies, for instance, has identified a new role for the BMP3 gene in early skull formation. Next-generation sequencing of multiple dogs has further identified a highly conserved amino acid change that is strongly associated with the bracychephalic skull shape observed in breeds such as the bulldog. They have also focused on body size, identifying eight major size genes in dogs, the first of which was IGF-1 (Sutter et al., Science 2007). Their research suggests that these newly identified genes interact in a non-additive fashion to determine breed size, which ranges from 2-200 pounds (Rimbault et al., Genome Res 2013). In theory, variants at several additional loci fine-tune the system, accounting for the continuum of size observed in modern breeds. The lab's near term aims focus on fine mapping and functional studies for the remaining body size and skull shape loci.

Canine Cancer: Cancer mapping studies in humans often fail due to sample size limitations and locus heterogeneity; factors the Ostrander lab argues can often be overcome in canines (Parker et al., Annu Rev Genet 2010). Dogs generally develop cancer in the same organs and respond to similar therapies as humans. However, predisposition to cancer type is often breed-specific. The lab first demonstrated the utility of dogs for cancer genetics by mapping kidney cystadeno- carcinoma in German Shepherds, prior to its localization in humans (Jonasdottir et al., PNAS 2000). They subsequently showed that mutations in the folliculin gene are causative, as they are in humans (Lingaas et al., Hum Mol Genet 2003).

The group subsequently tackled other cancers. Their GWAS for histocytic carcinoma identifies two loci, the first of which spans CDKN2A, an important cell cycle regulator, while the second region includes several candidates (Shearin et al., CEBP, 2012). RNAseq and ChiPseq data are being done to characterize transcripts and regulatory regions. They have also made progress in studies of squamous cell carcinoma of the digit (SCC), a breed-specific nail bed cancer occurring primarily in poodles, briards and giant schnauzers. They identified KIT ligand (KITLG) as one of the genes associated with the disorder (Karyadi et al., PLoS Genet 2013). Additional work suggests that variant forms of MC1R and MITF are protective. Interestingly, mutations in MC1R, KIT and MITF are associated with some melanomas in humans. The group's hypothesis is that for human acral (palm, soles, or nail bed) melanoma the oncogenic potential of the KIT pathway requires a functional MC1R, and that SCC may serve as a precursor model. Other studies focus on canine gastric and bladder cancer.

Prostate Cancer: PC is a major cause of human morbidity and mortality, and no good naturally occurring animal models exist. Finding genes associated with aggressive disease has been minimally successful (Schaid et al., Hum Genet 2007; FitzGerald et al., CEBP2011). The Ostrander lab has collaborated with Janet Stanford, Ph.D., from the Fred Hutchinson Cancer Research Center, Seattle, to identify PC loci using two lines of investigation. First, the group has performed multiple genome scans using 304 high-risk families,  (Janer et al., Hum Mol Genet 2003; Stanford et al., Hum Mol Genet 2009), resulting in the identification of multiple loci. Family-based association methods identified one locus on chromosome 22q12 which we mapped to a few kilobases (Johanneson et al., Hum Mol Genet 2010). They are also part of two international and highly successful consortia (e.g. Lu et al., Prostate 2011; Haiman et al., Nat Genet 2011) that have used GWAS to enumerate and now validate several new PC risk loci (e.g. Eeles et al., Nat Genet 2009; Kote-Jarai et al., Nat Genet 2011; Eeles et al., Nat Gen 2013).

Their second approach is a hypothesis-driven candidate gene analysis using a population-based cohort of 1,309 PC patients under long-term surveillance and upon which we have published extensively (e.g. Stanford et al., Cancer Res 1997; Kwon et al., CEBP 2011; Kwon et al., CEBP 2012). They have identified and validated five SNPs associated with PC specific mortality (PCSM) (Lin et al., CEBP2011). Patients with 4-5 (vs. 0-2) of the at-risk genotypes have a 50 percent higher risk of PCSM, and risk increases with number of at-risk genotypes. These results provide the first validation of a genetic predisposition for lethal PC and highlight genes of interest.

Recently, in a third approach, the group began sequencing high-grade prostate tumors to identify drivers of disease. Their goal is to find markers of prostate cancer specific mortality. They are also doing whole-exome sequencing of men from multiple high-risk PC families and aim to coordinate these and other data in men with long-term clinical follow-up to identify prognostic markers of disease.

Publications

Dunaway M, Ostrander EA. (1993). Local domains of supercoiling activate a eukaryotic promoter in vivo. Nature 361:746-8. 1993. [PubMed]

Langston AA, Malone KE, Thompson JD, Daling JR, Ostrander EA. (1996). BRCA1 mutations in a population-based sample of young women with breast cancer. N Engl J Med, 334:137-42. 1996. [PubMed]

Stanford JL, Just JJ, Gibbs M, Wicklund KG, Neal CL, Blumenstein BA, Ostrander EA. Polymorphic repeats in the androgen receptor gene: molecular marker of prostate cancer risk. Cancer Res, 57:1194-8. 1997. [PubMed]

Gibbs M, Stanford JL, McIndoe RA, Jarvik GP, Kolb S, Goode EL, Chakrabarti L, Schuster EF, Buckley VA, Miller EL, Brandzel S, Li S, Hood L, Ostrander EA. Evidence for a rare prostate cancer-susceptibility locus at chromosome 1p36. Am J Hum Genet, 64:776-87. 1999. [PubMed]

Guyon R, Lorentzen TD, Hitte C, Kim L, Cadieu E, Parker HG, Quignon P, Lowe JK, Renier C, Gelfenbeyn B, Vignaux F, DeFrance HB, Gloux S, Mahairas GG, André C, Galibert F, Ostrander EA. A 1-Mb resolution radiation hybrid map of the canine genome. Proc Natl Acad Sci U S A, 100:5296-301. 2003. [PubMed]

Lingaas F, Comstock KE, Kirkness EF, Sørensen A, Aarskaug T, Hitte C, Nickerson ML, Moe L, Schmidt LS, Thomas R, Breen M, Galibert F, Zbar B, Ostrander EA. A mutation in the canine BHD gene is associated with hereditary multifocal renal cystadenocarcinoma and nodular dermatofibrosis in the German Shepherd Dog. Hum Mol Genet, 12:3043-53. 2003. [PubMed]

Parker HG, Kim LV, Sutter NB, Carlson S, Lorentzen TD, Malek TB, Johnson GS, DeFrance HB, Ostrander EA, Kruglyak L. Genetic structure of the purebred domestic dog. Science, 304:1160-4. 2004. [PubMed]

Mosher DS, Quignon P, Bustamante CD, Sutter NB, Mellersh CS, Parker HG, Ostrander EA. A mutation in the myostatin gene increases muscle mass and enhances racing performance in heterozygote dogs. PLoS Genetics 5, 3(5):e79. 2007. [PubMed]

Sutter NB, Bustamante CD, Chase K, Gray MM, Zhao K, Zhu L, Padhukasahasram B, Karlins E, Davis S, Jones PG, Quignon P, Johnson GS, Parker HG, Fretwell N, Mosher DS, Lawler DF, Satyaraj E, Nordborg M, Lark KG, Wayne RK, Ostrander EA. A single IGF1allele is a major determinant of small size in dogs . Science, 316(5821):112-5. 2007. [PubMed]

Parker HG, vonHoldt BM, Quignon P, Margulies EH, Shao S, Mosher DS, Spady TC, Elkahloun A, Cargill M, Jones PG, Maslen CL, Acland GM, Sutter NB, Kuroki K, Bustamante CD, Wayne RK, Ostrander EA. An expressed Fgf4 retrogene is associated with breed-defining chondrodysplasia in domestic dogs. Science, 325:995-8. 2009. [PubMed]

Suuriniemi, M, Aaliu I, Schaid DJ, Johanesson B, McDonell SK, Iwasaki L., Stanford JL, Ostrander EA. Confirmation of a positive association between prostate cancer risk and a locus at chromosome 8q24. Cancer Epi Biomarkers, 16(4):809-14. 2007. [PubMed]

Schaid DJ, Stanford JL, McDonnell, SK, Suuriniemi M, McIntosh L, Karyadi DM, Carlson E, Deutsch K., Janer M., Hood L. Ostrander E.A. Genome-wide linkage scan of prostate cancer Gleason score and confirmation of chromosome 19q. Hum. Genetics, 121:729-35. 2007. [PubMed]

Parker HG, Kukekova AV, Akey DT, Goldstein O, Kirkness E F, Baysac KC, Mosher DS, Aguirre GD, Acland GM, Ostrander EA Breed relationships facilitate fine mapping studies: A 7.8 Kb deletion cosegregates with collie eye anomaly across multiple dog breeds. Genome Res, 17:1562-1571. 2007. [PubMed]

Holt SK, Karyad DM, Kwon EM, Stanford JL, Nelson PS, Ostrander EA. Association of megalin genetic polymorphisms with prostate cancer risk and prognosis. Clinical Cancer Research, 15:3823-31. 2008. [PubMed]

FitzGerald LM, Kwon EM, Koopmeiners JS, Salinas CA, Stanford JL, Ostrander EA. Analysis of recently identified prostate cancer susceptibility loci in a population-based study: Associations with family history and clinical features. Clinical Cancer Research, 5:3231-7. 2009. [PubMed]

Parker HG, Von Holdt BM, Quignon P, Margulies EH, Shao S, Mosher DS, Spady TC, Elkahloun A, Cargill M, Jones PG, Maslen CL, Acland GM, Sutter NB, Kuroki K, Bustamante CD, Wayne RK, Ostrander EA. An expressed Fibroblast Growth Factor 4 (fgf4) retrogene is associated with breed-defining chondrodysplasia in the domestic dog. Science, 325:995-8. 2009. [PubMed]

Cadieu E, Neff MW, Quignon P, Walsh K, Chase K, Parker HG, vonHoldt BM, Rhue A, Boyko A, Byers A, Wong A, Mosher DS, Elkahloun AG, Spady TC, André C, Lark KG, Cargill M, Bustamante CD, Wayne RK, Ostrander EA. Coat variation in the domestic dog is governed by variants in three genes. Science, 326:150-3. 2009. [PubMed]

Boyko AR, Quignon P, Li L, Schoenebeck JJ, Degenhardt JD, Lohmueller KE, Zhao K, Brisbin A, Parker HG, vonHoldt BM, Cargill M, Auton A, Reynolds A, Elkahloun AG, Castelhano M, Mosher DS, Sutter NB, Johnson GS, Novembre J, Hubisz MJ, Siepel A, Wayne RK, Bustamante CD, Ostrander EA. A simple genetic architecture underlies morphologic variation in dogs. PLoS Biol, 8:e1000451. 2010. [PubMed]

vonHoldt BM, Pollinger JP, Lohmueller KE, Han E, Parker HG, Quignon P, Degenhardt JD, Boyko AR, Earl DA, Auton A, Reynolds A, Bryc K, Brisbin A, Knowles JC, Mosher DS, Spady TC, Elkahloun A, Geffen E, Pilot M, Jedrzejewski W, Greco C, Randi E, Bannasch D, Wilton A, Shearman J, Musiani M, Cargill M, Jones PG, Qian Z, Huang W, Ding ZL, Zhang YP, Bustamante CD, Ostrander EA, Novembre J, Wayne RK. Genome-wide SNP and haplotype analyses reveal a rich history underlying dog domestication. Nature, 464: 898-902. 2010. [PubMed]

Kwon EM, Salinas CA, Kolb S, Fu R, Feng Z, Stanford JL, Ostrander EA. Genetic polymorphisms in inflammation pathway genes and prostate cancer risk. Cancer Epidemiol Biomarkers Prev, 20:923-33. 2011. [PubMed]

Shearin AL, Hedan B, Cadieu E, Erich SA, Schmidt EV, Faden DL, Cullen J, Abadie J, Kwon EM, Gröne A, Devauchelle P, Rimbault M, Karyadi DM, Lynch M, Galibert F, Breen M, Rutteman GR, André C, Parker HG, Ostrander EA. The MTAP-CDKN2A locus confers susceptibility to a naturally occurring canine cancer. Cancer Epidemiol Biomarkers Prev, 21:1019-27. 2012. [PubMed]

Schoenebeck JJ, Hutchinson SA, Byers A, Beale HC, Carrington B, Faden DL, Rimbault M, Decker B, Kidd JM, Sood R, Boyko AR, Fondon JW 3rd, Wayne RK, Bustamante CD, Ciruna B, Ostrander EA. Variation of BMP3 contributes to dog breed skull diversity. PLoS Genet, 8:e1002849. 2012. [PubMed]

Ostrander EA. Franklin H. Epstein Lecture. Both ends of the leash--The human links to good dogs with bad genes. New Engl J Med,367:636-46. 2012. [PubMed]

Rimbault M, Beale HC, Schoenebeck JJ, Hoopes BC, Allen JJ, Gilroy-Glynn P, Wayne RK, Sutter NB, Ostrander EA. Derived variants at six genes explain nearly half of size reduction in domestic dogs. Genome Res., 23:1985-95. 2013. [PubMed Central]

Rebbeck TR, Devesa SS, Chang B-L, Bunker CH, Cheng I, Cooney KA, Eeles R, for The UKGPCS Coordinating Group and Collaborators, Fernandez P, Giri VN, Gueye SM, Haiman CA, Henderson BE, Heyns C, Hu JJ, Ingles SA, Isaacs W, Jalloh M, John, EM, Kibel AS, Kidd, LR, Layne P, Leach RJ, Neslund-Dudas C, Okobia MN, Ostrander EA, Park JY, Patrick AL, Phelan C, Ragin C, Roberts R, Rybicki B, Stanford JL, Strom S, Thompson IM, Witte J, Xu J, Yeboah E, Hsing, AW, Zeigler-Johnson C. Global patterns of prostate cancer incidence, aggressiveness and mortality in men of African descent. Prostate Cancer 2013:560857. 2013.

Karyadi DM, Karlins E, Decker B, vonHoldt BM, Carpintero-Ramirez G, Parker HG, Wayne RK, Ostrander EA. A copy number variant at the KITLG locus likely confers risk for canine squamous cell carcinoma of the digit. PLoS Genetics 9:e1003409; 2013. [PubMed]

Freedman A, Schweizer RM, Gronau I, Han Enujung, Vecchyo DOD, Silva P, Galaverni M, Zhenxin F, Marx P, Lorente-Galdos B, Beale H, Ramirez O, Hormozdiari F, Alkan C, Vilà C, Squire K, Geffern, E, Kusak J, Boyko AR, Parker H, Lee C, Tadigotla V, Siepel A, Bustamante C, Harkins T, Nelson SF, Ostrander EA, Marques-Bonet T, Wayne RK, Novembre J. Genome sequencing highlights the dynamic early history of dogs. PLoS Genetics, Jan:10(1):e1004016. 2014. [PubMed]

Decker B, Parker HG, Dhawan D, Kwon EM, Karlins E, Davis BW, Ramos-Vara JA, Bonney PL, McNiel EA, Knapp DW, Ostrander EA. Homologous mutation to human BRAF V600E is common in naturally occurring canine bladder cancer-evidence for a relevant model system and urine-based diagnostic test. Mol Canc Res 13(6):993-1002. 2015. [PubMed]

Bemdt SI, Wang Z, Yeager M, Alavanga, MC, Albanes, D, Amundadottir L, Andriole G, Freeman LB, Campa D, Cancel-Tassin G, Canzian F, Cornu J-N, Cussenot O, Diver WR, Gapstur SM, Grönberg H, Haiman CA, Henderson B, Hutchinson A, Hunter DJ, Key TJ, Kolb S, Koutros S, Kraft P, Le Marchand L, Lindström S, Machiela MJ, Ostrander EA, Riboli E, Schumacher F, Siddiq A, Stanford JL, Stevens VL, Travis RC, Tsilidis KK, Virtamo J, Weinstein S, Wilkund F, Xu J, Zheng SL, Yu K, Wheeler W, Zhang H, African Ancestry Prostate Cancer GWAS Consortium, Sampson J, Black A, Jacobs K, Hoover RN, Tucker M, Chanock SJ. Two susceptibility loci identified for prostate cancer aggressiveness. Nat Comm. May 5;6:6889. doi: 10.1038/ncomms7889. 2015. [PubMed]

Decker B, Davis BW, Rimbault M, Long AH, Karlins E., Jagannathan, V, Reiman, R, Parker HG, Drogemuller, C, Corneveaux, JJ, chapman, ES, Trent JM, Leeb, T, Huentelman JM, WayneRK, Karyadi DM, Ostrander EA. Comparison against 186 canid whole genome sequences reveals survival strategies of an ancient clonally transmissible canine tumor. Genome Res. pii: gr.190314.115. 2015. [PubMed]

Comparative Genetics Section Staff

Heidi Parker
Heidi Parker, Ph.D.
  • Staff Scientist
  • Comparative Genetics Section
Danielle Karyadi
Danielle Karyadi, Ph.D.
  • Staff Scientist
  • Comparative Genetics Section