Biography

Dr. Amundadottir received her Ph.D. in Cell Biology in 1995 from Georgetown University in Washington, D.C. Her postdoctoral training was at the Department of Genetics at Harvard Medical School in Boston, MA. In 1998, she joined deCODE genetics in Iceland as the Head of the Division of Cancer Genetics. Dr. Amundadottir joined the NCI in 2007 as a Senior Scientist and became an Investigator in the Laboratory of Translational Genomics in 2008.

Research Interests

Major advances have occurred in the last few years in our understanding of the genetics of common diseases, including cancer. Genome wide association studies (GWAS), which assess hundreds of thousands of single nucleotide polymorphisms (SNPs) in large cohort or case-control studies have provided new insights into the genomic regions that alter an individual’s risk of developing cancer. These efforts have led to the discovery of multiple common risk variants for several types of common cancer. However, the elucidation of functional roles for these variants with respect to disease is in the very early stages. This interface between genetics and the functional studies that follow suit is of special interest to the laboratory. Our approach focuses on the molecular phenotypes of association findings and functional characterization of plausible causal variants in order to understand how common sequence variation plays a role in the development of cancer. Work in the laboratory involves association analysis of large datasets, deep sequencing of candidate regions for fine mapping, genome wide and targeted expression profiling, gene regulation and epigenetics; and data analysis using current bioinformatics and statistical approaches.

Pancreatic Cancer

PanScan is a genome wide association study of pancreatic cancer within the framework of the NCI-sponsored Cohort Consortium. The aim of the study is to identify common susceptibility variants for pancreatic cancer. It involves an initial GWAS of 550,000 SNPs in 2,000 cases and 2,000 controls from 12 prospective cohort studies and one case control study. Replication of the most promising SNPs, as determined by rank p-values (i.e. the smallest p-values) as well as a genome wide scan of 610,000 SNPs in 8 independent case control studies will be performed after the initial scan. The combined dataset from both scans will include around 4,500 pancreatic cancer cases and 4,500 controls. My laboratory is investigating susceptibility variants that have been identified in PanScan. We are conducting fine mapping as well as functional studies with the aim of finding the underlying functional variants and understanding the mechanism by which they increase the risk of cancer. My work is thus aimed at unraveling the path from susceptibility loci to the functional pathways that initiate cancer with the goal of providing insight into how to better prevent and treat these devastating diseases.

Prostate Cancer

Genome wide association studies have successfully identified risk variants for prostate cancer at a number of loci and most of these have been unambiguously replicated in several populations. These studies have not implicated the Y chromosome in the risk of prostate cancer, possibly because very few ChrY markers are represented on the genotyping platforms currently used. Although gene poor, there is ample evidence that loci on the Y chromosome may play a role in altering risk of cancer. Loss of this chromosome is one of the most common genetic alterations seen in prostate cancer and overexpression of genes residing on the Y chromosome have also been reported in prostate cancer. Recent data from fruit flies indicate that the Y chromosome regulates the expression of a wide variety of genes on the autosomes and the X chromosome. Because most of the Y chromosome does not recombine, the Y chromosome is passed down unchanged from fathers to sons through generations. The only new changes introduced into the DNA sequence are from mutations. A set of biallelic markers can thus be used to identify Y chromosome haplogroups (or lineages) which can be organized along a phylogenetic tree and tested for association to disease. My laboratory is currently investigating the role of Y chromosome variation in prostate cancer risk using a set of SNPs that tag the most common European haplogroups. Prostate cancer cases and controls from five cohort studies are included in the study totaling about 5000 cases and 5000 controls.

Fine mapping and resequencing efforts of published prostate cancer loci are also being performed in the lab.

Selected Publications

• Yeager M, Xiao N, Hayes RB, Bouffard P, Desany B, Burdett L, Orr N, Matthews C, Qi L, Crenshaw A, Markovic Z, Fredrikson KM, Jacobs KB, Amundadottir L, Jarvie TP, Hunter DJ, Hoover R, Thomas G, Harkins TT, Chanock SJ. Comprehensive resequence analysis of a 136 kb region of human chromosome 8q24 associated with prostate and colon cancers. Hum Genet. 2008; 124(2):161-70
• Gudmundsson J, Sulem P, Manolescu A, Amundadottir LT, Gudbjartsson D, Helgason A, Rafnar T, Bergthorsson JT, Agnarsson BA, Adam Baker A, Asgeir Sigurdsson A, Benediktsdottir KR, Jakobsdottir M, Xu J, Blondal T, Kostic J, Jielin Sun J, Ghosh S, Stacey S, Mouy M, Saemundsdottir J, Backman VM, Kristjansson K, Tres A, Partin AW, Albers M, Godino J, Walsh PC, Swinkels DW, Navarrete S, Isaacs SD, Aben KK, Cashy J, Ruiz-Echarri M, Wiley KE, Suarez BK, Frigge M, Ober C, Jonsson E, Einarsson GV, Mayordomo JI, Kiemeney LA, Isaacs WB, Catalona WJ, Barkardottir RB, Gulcher JR, Thorsteinsdottir U, Kong A, Stefansson K. A Second Prostate Cancer Susceptibility Variant at 8q24 identified through a Genome-Wide Association Study. Nat Genet. 2007; 39(5):631-7
• Amundadottir LT, Sulem P, Gudmundsson J, Helgason A, Baker A, Agnarsson BA, Sigurdsson A, Benediktsdottir KR, Cazier JB, Sainz J, Jakobsdottir M, Kostic J, Magnusdottir DN, Ghosh S, Agnarsson K, Birgisdottir B, Le Roux L, Olafsdottir A, Blondal T, Andresdottir M, Gretarsdottir OS, Bergthorsson JT, Gudbjartsson D, Gylfason A, Thorleifsson G, Manolescu A, Kristjansson K, Geirsson G, Isaksson H, Douglas J, Johansson JE, Balter K, Wiklund F, Montie JE, Yu X, Suarez BK, Ober C, Cooney KA, Gronberg H, Catalona WJ, Einarsson GV, Barkardottir RB, Gulcher JR, Kong A, Thorsteinsdottir U, Stefansson K. A common variant associated with prostate cancer in European and African populations. Nat. Genet. 2006; 38(6):652-8
• Bergthorsson JT, Agnarsson BA, Gudbjartsson T, Magnusson K, Thoroddsen A, Palsson B, Bjornsson J, Stefansson K, Gulcher J, Einarsson GV, Amundadottir LT, Barkardottir RB. A genome-wide study of allelic imbalance in human testicular germ cell tumors using microsatellite markers. Cancer Genet. Cytogenet. 2006; 164(1):1-9
• Amundadottir LT, Thorvaldsson S, Gudbjartsson DF, Sulem P, Kristjansson K, Arnason S, Gulcher JR, Bjornsson J, Kong A, Thorsteinsdottir U, Stefansson K. Cancer as a complex phenotype: pattern of cancer distribution within and beyond the nuclear family. PLoS Med. 2004; 1(3):e65
• Jonsson S, Thorsteinsdottir U, Gudbjartsson DF, Jonsson HH, Kristjansson K, Arnason S, Gudnason V, Isaksson HJ, Hallgrimsson J, Gulcher JR, Amundadottir LT, Kong A, Stefansson K. Familial risk of lung carcinoma in the Icelandic population. JAMA 2004; 22;292(24):2977-83
• Ghiglione C, Amundadottir L, Andresdottir M, Bilder D, Diamonti JA, Noselli S, Perrimon N, Carraway III KL. Mechanism of inhibition of the Drosophila and mammalian EGF receptors by the transmembrane protein Kekkon 1. Development 2003; 130:4483-4493
• Littlepage LE, Wu H, Andresson T, Deanehan JK, Amundadottir LT, Ruderman JV. Identification of phosphorylated residues that affect the activity of the mitotic kinase Aurora-A Proc Natl Acad Sci U S A 2002; 99:15440-5
• Ghiglione C, Carraway KL, Amundadottir LT, Boswell RE, Perrimon N, Duffy JB. The transmembrane molecule kekkon 1 acts in a feedback loop to negatively regulate the activity of the Drosophila EGF receptor during oogenesis. Cell 1999; 96:847-56
• Amundadottir LT and Leder P. Signal Transduction Pathways Activated and Required for Mammary Carcinogenesis in Response to Specific Oncogenes. Oncogene 1998; 16:737-746
• Amundadottir LT, Nass J, Berchem GJ, Johnson MD and Dickson RB. Cooperation of TGFa and c-Myc in mouse mammary tumorigenesis: Coordinated stimulation of growth and suppression of apoptosis. Oncogene 1996; 13:757-765
• Amundadottir LT, Johnson MD, Merlino G, Smith G and Dickson RB. Synergistic interaction of Transforming Growth Factor alpha and c-Myc in mouse mammary and salivary gland tumorigenesis. Cell Growth. Diff. 1995; 6:737-748