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About DCEG

Sharon A. Savage, M.D.

Investigator

Location: Executive Plaza South, Room 7018
Phone: 301-496-5785
Fax: 301-496-1854
E-mail: savagesh@mail.nih.gov

 Sharon A. Savage, M.D.

Biography

Dr. Savage joined the Clinical Genetics Branch, DCEG, NCI in 2006 as a tenure-track investigator. She received her M.D. from the University of Vermont College of Medicine, completed residency training in Pediatrics at Children’s National Medical Center, in Washington DC, and a fellowship in Pediatric Hematology/Oncology at the NCI Pediatric Oncology Branch and Johns Hopkins University. She is board-certified in both Pediatrics and Pediatric Hematology-Oncology. Dr. Savage is the NCI Liaison to the American Academy of Pediatrics Committee on Environmental Health. Her current research is focused on the genetic and molecular epidemiology of telomere biology, pediatric cancer etiology, and inherited cancer predisposition syndromes.

Research Interests

Genetic and Molecular Epidemiology of Telomere Biology

This program area incorporates clinical, genetic, molecular, and epidemiologic approaches to advance understanding of telomere biology and its relationship to cancer, as well as the contribution of telomere length (TL) and variation in telomere biology genes to disease risk. Telomeres are the specialized nucleoprotein structures present at the ends of chromosomes which are essential for chromosomal stability. Telomeres shorten with each cell division because the DNA replication machinery is unable to replicate terminal DNA at chromosome ends. When telomeres reach a critical length cellular senescence or apoptosis are triggered. Telomere attrition is a normal consequence of aging. If cells bypass senescence or apoptosis and continue to divide despite the presence of genomic instability, cancer can develop. Approximately 90% of cancers somatically up-regulate telomerase to maintain TL. Cancer cells typically have shorter telomeres than normal cells, although there is great variability in cancer cell TL.

Patients with Dyskeratosis Congenita (DC) have extremely short TL and approximately 60% have a germline mutation in a telomere biology gene (DKC1, TERC, TERT, TINF2, WRAP53, NOP10, or NHP2). DC is an inherited bone marrow failure syndrome (IBMFS) characterized by the triad of nail dystrophy, lacy skin pigmentation, and oral leukoplakia. Patients are at very high risk of bone marrow failure, leukemia, squamous cell cancers, pulmonary fibrosis, liver disease, and many other medical problems. Our work in DC has led to the discovery of two genetic distinct causes of this disorder: germline mutations in TINF2 (protein: TIN2) and WRAP53 (protein: TCAB1). Each of these unique findings implicated new biologic pathways in disease etiology. TINF2 codes for one of the six proteins of the shelterin telomere protection complex. The finding that germline mutations in WRAP53 cause DC was the first time that mislocalization of telomerase was considered a potential disease mechanism. Our DC studies led to the development of TL as a diagnostic test and quantified the associated cancer risk. Detailed studies of the clinical consequences of DC are underway. Numerous collaborative studies are in progress to further characterize the molecular consequences of aberrations in DC-associated genes. We are using state-of-the art genomic technologies to discover the genetic cause of DC in mutation-negative individuals.

A subset of individuals with severe aplastic anemia (SAA) may also have short telomeres and mutations in telomere biology genes. We are evaluating the association of TL and outcomes after hematopoietic stem cell transplantation in a collaborative study with NMDP and CIBMTR. This study will lead to important insights into the incidence of telomere biology abnormalities in SAA which inform future clinical and molecular studies.

We have expanded our population genetic studies of telomere biology genes in order to better understand the world-wide genetic diversity and the extent of linkage disequilibrium of genes important in telomere biology. This includes are recent study of genetic variants in 37 genes from 53 worldwide populations which showed that telomere biology genes have low to moderate ancestral allele frequencies, and low differentiation. We have also evaluated the association of TL and common single nucleotide polymorphisms (SNPs) in an effort to better understand TL regulation. Additional, related population genetic studies are ongoing.

Several studies suggest that blood or buccal cell TL may be associated with cancer risk in the general population. We found that shorter telomeres were associated with ovarian cancer in a population-based, case-control study. However, our cohort study of prostate cancer did not find an association between TL and prostate cancer risk. We did find that healthy lifestyle parameters were associated with longer TL. Our meta-analysis of TL and overall cancer risk suggests that while short telomeres were associated with cancer this associated may be driven by specific cancers and/or reverse causation bias. We are collaborating with several investigators to further understand the association of TL and cancer risk in larger populations and in different cancers.

Understanding Cancer Etiology - Osteosarcoma

Osteosarcoma is the most common primary malignant bone tumor and typically occurs during the adolescent growth spurt. Patients with localized osteosarcoma at diagnosis have a 60 to 80% long-term survival rate; metastatic disease carries a much poorer prognosis. In order to better understand its etiology, we conducted detailed epidemiologic studies of osteosarcoma incidence in the U.S. and around the world. Prior association studies of the association between tall stature or high birth weight and osteosarcoma risk were conflicting. We conducted a large, pooled analysis which showed that individuals >90th percentile for height were at increased risk of osteosarcoma. High birth weight was also associated with increased osteosarcoma risk. These studies formed the foundation for analysis of genetic risk factors for osteosarcoma. In a case-control study, we have shown that numerous SNPs in genetic important in growth, development, and DNA repair are associated with osteosarcoma risk. Ongoing studies include fine-mapping of these putative risk loci.

We have initiated an international, multi-institutional collaboration in order to conduct the first genome-wide association study (GWAS) of osteosarcoma. The first phase of genotyping is underway. Fine-mapping of osteosarcoma-associated loci will be performed in order to understand the genetic contribution to this important cancer. It possible that genes associated with risk for OS may be important in other pediatric and adult cancers.

Li-Fraumeni Syndrome

Li-Fraumeni syndrome (LFS) is a highly-penetrant autosomal dominant cancer predisposition syndrome associated with a wide range of cancer types which occur at younger-than-expected ages. It was first described in 1969 and germline mutations in TP53 were recognized as the primary cause in 1990. We initiated a new clinical, genetic, and epidemiologic study of LFS in order to further characterize the clinical and molecular consequences of this disorder, and to develop a cancer screening program for TP53 mutation carriers (www.lfs.cancer.gov). We have also assisted in the creation of an international LFS research consortium. Our ongoing studies will further define the cumulative cancer risk in individuals, assess the role of environmental risk modifying factors, evaluate the psychological and social effects of LFS on the entire family, identify genotype-phenotype relationships and novel causes of LFS, and create an annotated biospecimen repository for future collaborative studies.

Selected Publications

    Dyskeratosis Congenita

    • Savage SA, Giri N, Baerlocher GM, Lansdorp PM, Alter BP: TINF2, a component of the shelterin telomere protection complex, is mutated in dyskeratosis congenita. Am J Hum Gen 2008; 82(2):501-509 PMC2427222
    • Savage SA: Dyskeratosis Congenita. In: Pagon RA, Bird TC, Dolan CR, Stephens K, editors. GeneReviews [Internet]. Seattle (WA): University of Washington, Seattle; 1993-. 2009 Nov 12. http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=gene&part=dkc
    • Alter BP, Baerlocher GM, Savage SA, Chanock SJ, Weksler BB, Willner JP, Peters JA, Giri N, Lansdorp PM: Very short telomere length by flow-FISH identifies patients with dyskeratosis congenita. Blood 2007: 110(5)1439-1447, PMC1975834
    • Alter BP, Giri N, Savage SA, Rosenberg PS: Cancer in dyskeratosis congenita. Blood 2009; 113(26):6549-6557 PMC2710915
    • Savage SA, Bertuch AA: The genetics and clinical manifestations of telomere biology disorders. Genetics in Medicine 2010; 12(12):753-76
    • *Zhong F, *Savage SA, Shkreli M, Giri N, Jessop L, Myers T, Chen R, Alter BP, Artandi SE: Mutations in TCAB1 cause dyskeratosis congenita by disrupting telomerase trafficking. Genes Devel 2011; 25(1): 11-16 PMC3012932 *co-first authors
    • Giri N, Lee R, Far A, Huddleston CB, White F, Alter BP, Savage SA: Lung transplantation for pulmonary fibrosis in dyskeratosis congenita: Case report and systematic literature review. BMC Blood Disord 2011;11(1):3
    • Gadalla S, Savage SA: Telomere biology in hematopoiesis and stem cell transplantation. Blood Rev 2011 Jul 15 [Epub ahead of print]

    Telomere Biology

    • Mirabello L, Huang W, Wong JYY, Chatterjee N, Reding D, Crawford ED, De Vivo I, Hayes RB, Savage SA: The association between telomere length and cigarette smoking, dietary and physical variables, and risk of prostate cancer. Aging Cell 2009; 8:405-413 PMC2742954
    • Mirabello L, Garcia-Closas M, Cawthon R, Lissowska J, Brinton LA, Peplonska B, Sherman ME, Savage SA: Leukocyte telomere length in a population-based case-control study of ovarian cancer: A pilot study. Cancer Causes & Control 2009; 21(1):77-82 PMC3130499
    • Mirabello L, Yu K, Kraft P, De Vivo I, Hunter DJ, Prescott J, Wong JYY, Chatterjee N, Hayes RB, Savage SA: The association of telomere length and genetic variation in telomere biology genes. Hum Mutat 2010; 31(9):1050-8 PMC2932868 Mirabello L, Yeager M, Chowdhury S, Qi L, Deng X, Wang Z, Hutchinson A, Savage SA: Worldwide genetic structure in 37 genes important in telomere biology. Heredity 2011 Jul 6: [Epub ahead of print]
    • Wentzensen IM, Pfeiffer R, Mirabello L, Savage SA: The association of telomere length and cancer: A meta-analysis. Cancer Epidemiol Biomarkers Prev 2011;20(6):1238-50

    Osteosarcoma

    • Mirabello L, Troisi R, Savage SA: Osteosarcoma incidence and survival rates from 1973 to 2004: Data from the Surveillance, Epidemiology, and End Results Program. Cancer 2009; 115(7):1531-43 PMC2813207
    • Mirabello L, Troisi R, Savage SA: International osteosarcoma incidence and survival patterns in children and adolescents, middle age, and elderly persons. International Journal of Cancer 2009; 125(1):229-34 PMC3048853
    • Mirabello L, Berndt SI, Seratti GF, Burdett L, Yeager M, Chowdhury S, Teshome K, Uzoka A, Douglass C, Hayes RB, Hoover RN, Savage SA: Genetic variation at chromosome 8q24 in osteosarcoma cases and controls. Carcinogenesis 2010; 31(8):1400-1404 PMC2915635
    • Mirabello L, Richards EG, Duong LM, Yu K, Cawthon R, Berndt SI, Burdett L, Chowdhury S, Teshome K, Douglass C, Savage SA: Telomere length and variation in telomere biology genes in individuals with osteosarcoma. Int J Mol Epidemiol Genet 2011;2(1):19-29 PMC3077235
    • Mirabello L, Pfeiffer R, Murphy G, Daw NC, Patiño-Garcia A, Troisi RJ, Hoover RN, Douglass C, Schuz J, Craft AW, Savage SA: Height at diagnosis and birth-weight as risk factors for osteosarcoma. Cancer Causes and Control 2011;22:899-908
    • Mirabello L, Yu K, Berndt SI, Burdett L, Wang Z, Chowdhury S, Teshome K, Uzoka A, Hutchinson A, Grotmol T, Douglass C, Hayes RB, Hoover RN, Savage SA: A comprehensive candidate gene approach identifies genetic variation associated with osteosarcoma. BMC Cancer 2011;11(1):209
    • Savage SA, Mirabello L: Using epidemiology and genomics to understand osteosarcoma etiology. Sarcoma 2011; Article ID 548151:1-13 PMC3061299

    Collaborators

    DCEG Collaborators

    • Michael Alavanja, Ph.D.
    • Demetrius Albanes, M.D.
    • Blanche Alter, M.D., M.P.H.
    • Stephen Chanock, M.D.
    • Nilanjan Chatterjee, Ph.D.
    • Mark H. Greene, M.D.
    • Wen-Yi Huang, Ph.D., M.S.P.H.
    • Hormuzd Katki, Ph.D.
    • Charles Matthews, Ph.D.
    • Lindsay Morton, Ph.D.
    • Ruth Pfeiffer, Ph.D.
    • Preetha Rajaraman, Ph.D.
    • Philip Rosenberg, Ph.D.
    • Mark Sherman, M.D., Ph.D.
    • Rashmi Sinha, Ph.D.
    • Nicolas Wentzensen, Ph.D.
    • Robert Hoover, M.D., Sc.D.
    • Sonja Berndt, Pharm.D., Ph.D.
    • Rebecca Troisi, Sc.D.
    • Sholom Wacholder, Ph.D.

    Other NIH Collaborators

    • Paul Hwang, M.D., Ph.D., Translational Medicine Branch, NHLBI
    • Paul Meltzer, M.D., CCR, NCI
    • Maryland Pao, M.D., Clinical Director, NIMH
    • Nan-ping Weng, M.D., Ph.D., Laboratory of Immunology, NIA
    • Neal Young, M.D., Hematology Branch, NHLBI

    Other ScientificCollaborators

    • Steven Artandi, M.D., Ph.D., Stanford University
    • Alison Bertuch, M.D., Ph.D., Baylor University
    • Gabriela Baerlocher, M.D., University Hospital Bern, Switzerland
    • Rodrigo Calado, M.D., Ph.D. Hematology Branch, University of São Paulo, Brazil
    • Richard Cawthon, M.D., University of Utah
    • Immaculata DeVivo, Ph.D., Harvard School of Public Health
    • Richard Hayes, D.D.S., Ph.D., New York University
    • Lifang Hou, Ph.D., Northwestern University
    • David Hunter, M.B.,B.S., Sc.D., Harvard School of Public Health
    • Peter Lansdorp, M.D., Ph.D., British Columbia Cancer Research Center
    • Alan Meeker, M.D., Johns Hopkins University
    • Davide Ruggero, Ph.D., University of California, San Francisco
    • Susan Smith, Ph.D., New York University
    • Stephen Spellman, M.S., National Marrow Donor Program
    • Jakub Tolar, M.D., Ph.D., University of Minnesota
    • Silvere van der Maarel, Ph.D., Leiden University Medical Center, The Netherlands
    • Judy Wong, Ph.D., University of British Columbia
    • Irene Andrulis, Ph.D., University of Toronto
    • Silvia Regina Caminada de Toledo, Ph.D., GRAACC/UNIFESP, Brazil
    • Chester Douglas, Ph.D., D.D.S., Harvard School of Public Health
    • Adreienne Flanagan, Ph.D., UCL Institute of Orthopeaedics and Musculoskeletal Science & Cancer Institute, UK
    • Ana Patino-Garcia, Ph.D., Universidad de Navarra, Spain
    • Claudia Hattinger, M.D., Orthopaedic Rizzoli Institute, Italy
    • Nilgun Kurucu, M.D., Ankara Oncology Research and Education Hospital, Turkey
    • Massimo Serra, M.D., Orthopaedic Rizzoli Institute, Italy
    • Logan Spector, Ph.D., University of Minnesota
    • Xijie Yu, M.D., Ph.D., Sichuan University, China
    • Maria Isabel Achatz, M.D., Ph.D., Hospital A. C. Carmargo-Fundação Antonio Prudente, São Paulo, Brazil
    • Pierre Hainaut, Ph.D., Molecular Carcinogenesis Group, IARC, Lyon, France
    • David Malkin, M.D., Ph.D., University of Toronto, Canada
    • Patricia Prolla, M.D. Federal University of Rio Grande do Sul and Hospital de Clinicas de Porto Alegre, Brazil