Biography

Dr. Savage received her M.D. from the University of Vermont College of Medicine. While in medical school, she spent two years in the Howard Hughes Medical Institute/ National Institutes of Health Research Scholars Program. Dr. Savage completed residency training in Pediatrics (board-certified) at Children's National Medical Center, in Washington, D.C., and a fellowship in Pediatric Hematology/Oncology at the NCI Pediatric Oncology Branch and Johns Hopkins University. During her post-doctoral research fellowship at the NCI she studied genetic variation and population genetics in genes important in telomere biology, as well as genetic variation and cancer risk in osteosarcoma and gastric cancer. She joined the Clincial Genetics Branch in 2006.

Research Interests

Genetic Epidemiology and Population Genetics of Genes Important in Telomere Biology

Telomeres consist of long TTAGGG nucleotide repeats and associated proteins at the ends of chromosomes that are essential to maintaining chromosomal integrity. We have shown that nucleotide diversity in genes coding for critical proteins in the telomere maintenance pathway is limited when compared to other types of genes. They are also highly conserved between species. Because these genes appear to be under constraint, it is possible that germ-line genetic variation (i.e. single nucleotide polymorphisms, SNPs) in these genes could be a significant risk factor for cancer or other diseases.

Further investigation into the population genetics and genetic variation of twelve genes critical in telomere maintenance is underway. This will further define the world-wide genetic diversity and the extent of linkage disequilibrium of genes important in telomere biology. Methodologic studies are also underway to evaluate telomere length in target tissues. This will form the basis for studies of germ-line genetic variants in genes critical in telomere biology as potential genetic markers for telomere length in healthy individuals and in individuals with cancer. Case-control studies of telomere length and cancer risk are also underway.

Our understanding of normal genetic variation in these genes will be used to identify new genes important in dyskeratosis congenita, an inherited bone marrow failure syndrome (IBMFS) characterized by abnormal nails, lacey reticular pigmentation, oral leukoplakia, significant risk for aplastic anemia, and short telomeres. Through the NCI’s IBMFS study, families with DC are evaluated for mutations known genes (DKC1, TERC and TERT) and those without a known mutation are studied further.

Genetic Variants as Modifiers of Cancer Risk

Osteosarcoma (OS) is the most common primary maligant bone tumor and typically occurs during the adolescent growth spurt. While OS has been well-described as a cancer seen in the Li-Fraumeni cancer predisposition syndrome, genetic risk factors for the more common, sporadic form of OS have not been well-described. In a case-control study done in collaboration with the NCI and Harvard School of Dental Medicine, we are investigating germ-line genetic variation in biologically important pathways (i.e. genes involved in growth and development, chromosomal stability and tumor suppressor genes). It possible that genes associated with risk for OS may be important in other pediatric and adult cancers.

Selected Publications

• Savage SA, Stewart BJ, Kiley M, Eckert A, Liao JS, Chanock SJ. Genetic variation, nucleotide diversity and linkage disequilibrium in seven telomere stability genes suggests that these genes could be under constraint. Hum Mutat 2005; 26(4):343-350
• Savage SA, Burdett L, Troisi R, Douglass C, Hoover RN, Chanock SJ. Germ-Line genetic variation of TP53 in osteosarcoma. Pediatr Blood Cancer 2007; 49(1):28-33
• 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
• Savage SA, Woodson K, Walk E, Modi WS, Liao J, Douglass C, Hoover RN, Chanock SJ. The National Osteosarcoma Etiology Study Group: Analysis of genes critical for growth regulation identifies IGF2R variations with possible functional significance as risk factors for osteosarcoma. Cancer Epidemiol Biomarkers Prev 2007; 16(8): 1667-1674
• Savage SA, Chanock SJ, Lissowska J, Brinton LA, Richesson D, Peplonska B, Bardin-Mikolajczak A, Zatonski W, Szeszenia-Dabrowska N, Garcia-Closas M. Genetic variation in five genes important in telomere biology and risk for breast cancer. Br J Cancer 2007; 97: 832-836
• 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
• 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 in press . 2009
• Savage SA, Alter BP. The role of telomere biology in bone marrow failure and other disorders. Mech Ageing Dev 2008; 129(1-2):35-47
• Savage SA. Cancer association studies in the genome-wide age. Personalized Medicine 2008; 5(6):589-597
• Savage SA , Alter BP. Dyskeratosis Congenita. Hematology-Oncology Clinics in press . 2009; 5(6):589-597

Collaborators

DCEG Collaborators

• Robert Hoover, M.D., Sc.D., Richard Hayes, D.D.S., M.P.H., Ph.D., Montserrat García-Closas, M.D., Dr.P.H., Qing Lan, M.D., Ph.D., M.P.H., Nat Rothman, M.D., M.P.H., M.H.S., Nilanjan Chatterjee, Ph.D., Mark Sherman, M.D., Stephen Chanock, M.D., Blanche Alter, M.D., M.P.H., Mark Greene, M.D.

Other NIH Collaborators

• Rodrigo Calado, M.D. (National Heart, Lung, and Blood Institute)
• Karen Woodson, Ph.D., M.P.H. (National Cancer Institute)
• Neal Young, M.D. (National Heart, Lung, and Blood Institute)

Other ScientificCollaborators

• Peter Lansdorp, M.D., Ph.D. (University of British Columbia)
• Logan Spector, Ph.D. (University of Minnesota)