July 22nd, 2008
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Chief, Laboratory of Human Carcinogenesis
Chief of Molecular Genetics & Carcinogenesis Section
Biography:Dr. Curtis C. Harris received his BA degree from Kansas University and his MD from Kansas University School of Medicine. His clinical training in Internal Medicine was completed at the University of California at Los Angeles and the National Cancer Institute. In 1981, he was appointed Chief of the Laboratory of Human Carcinogenesis and chief of its Molecular Genetics and Carcinogenesis Section. He also is Clinical Professor of Medicine and Oncology at Georgetown University School of Medicine.
The outstanding scientific contributions of Curtis C. Harris, M.D., to the fields of molecular carcinogenesis and molecular epidemiology of human cancer, has placed him at the international forefront. His research on environmental carcinogenesis, cancer risk factors and molecular genetics of human carcinogenesis has significantly impacted the field of cancer risk assessment and our understanding of the molecular pathogenesis of human cancer.
 Dr. Harris's Interview with Science Watch.
 Dr. Harris's article about MicroRNAs.
Extended Biography:
Dr. Harris' findings provided major elements of the scientific foundation for the molecular epidemiology of cancer. He pioneered the development of in vitro models using human tissues and cells to compare metabolic pathways of chemical carcinogen activation and detoxification in humans and laboratory animals. From his studies, quantitative and qualitative differences in carcinogen metabolism, carcinogen-DNA adduct formation and DNA repair were identified, found to have an inherited basis, and shown to play a critical role in cancer susceptibility to environmental carcinogens. Dr. Harris was the first to show that chemical carcinogens in tobacco smoke induce neoplastic transformation of human bronchial epithelial cells in the laboratory. Dr. Harris also is internationally recognized for his cellular and molecular studies of asbestos-induced human pleural mesothelioma and lung carcinogenesis.
Dr. Harris' research also significantly contributed to the discovery that mutation of the p53 tumor suppressor gene is the most common genetic lesion in human cancers. The characterization of mutational spectra of the p53 gene in human tumors provides unique and critical molecular links between environmental carcinogens and specific human cancers. Dietary exposure to the mycotoxin aflatoxin B1 is positively correlated with a specific codon 249 mutation in hepatocellular carcinoma, and a dose-response relationship exists between tobacco smoking and G to T transversions in lung cancer. Additionally, the p53 mutation spectra in lung cancer associated with environmental radon differs from that observed in tobacco smoke-induced lung cancer. Drs. Harris and Hollstein established the p53 mutation database in 1990 that has grown to be the world's largest mutation database with more than 15,000 entries of tumors with p53 mutations. In 1995 they transferred the electronically available p53 mutation database (http://www.iarc.fr/p53/homepage.htm) to the International Agency for Research on Cancer and they serve on its Advisory Board. This database continues to be useful to the scientific community for the purpose of generating hypotheses for laboratory, epidemiology and clinical investigations.
Administrative
Our productive collaborations with intramural scientists and extramural investigators worldwide have led to significant discoveries and productivity (H-factor of 100; ISI Web of Science). In the last few years, we have published 36 papers in peer-reviewed journals, 6 invited reports/reviews (mostly peer reviewed), 4 book chapters, edited one book, and filed 7 patent applications for the U.S. Government. Harris served on the NCI-CCR Advisory Board and currently serves on the Steering Committee of the Center of Excellence in Integrative Cancer Biology and Genomics, CCR. He is the elected Chairman of the Board of Directors of two nonprofit foundations, the Keystone Symposia of Molecular and Cellular Biology and the Aspen Cancer Conference. Harris holds the position of Clinical Professor of Medicine (Oncology) at the Georgetown University School of Medicine and serves as Editor-in-Chief of the journal Carcinogenesis. Harris presented 5 keynote addresses and other invited presentations at national and international conferences. He received the NCI Outstanding Mentor Award in 2007.
Current Research Projects
Project 1: Molecular Epidemiology of Human Cancer and Clinical Biomarkers of Cancer Diagnosis, Prognosis, and Therapeutic Outcome. Gene-environment interaction is a seminal concept in the molecular epidemiology of human cancer. Our case-control (using hospital- and population-based controls) studies focus on lung cancer, a tobacco-related cancer, and colon, a cancer type more associated with chronic inflammation. These studies require the integration of data from genetic association studies, analysis of carcinogen exposure, rapidly developing technologies, bioinformatics, social-ethical concerns, and epidemiological study-design methods and the hypothesis, aims, and demographic characteristics of study subjects of multiple investigations. We also validate our results with independent cohorts, e.g., The NCI Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial, Mayo Clinic Never Smoker Lung Cancer cohort (P. Yang), Black Women Health Study (J. Palmer and L. Adams-Campbell), and Hong Kong Colon Cancer cohort (S.Y. Leung), and contribute data to the large multi-institutional International Lung Cancer Consortium, e.g., replication of susceptibility loci identified in Genome-Wide Association Studies. For example, we discovered from 2 independent cohorts that childhood exposure to secondhand smoke and a hyperactive innate immune system is associated with an increased the lung cancer risk in never smokers. Our studies have also provided genetic and biological evidence of racial health disparity of lung and colon cancer in African Americans: common genetic variations in TP53 are associated with increased lung cancer risk and poor prognosis; a less efficient G2/M cell cycle checkpoint is associated with increased lung cancer risk; and an increased risk and/or poor survival of colon cancer are associated with either specific microRNA expression or SNPs in the MBL2 gene. Cancer cases were also utilized to develop clinical biomarkers. For example, microRNAs and selected inflammatory cytokines were found to be diagnostic and prognostic biomarkers of human lung, esophageal, and colon cancer in their early TNM stages. Some of these biomarkers are also associated with therapeutic outcome. We continue to focus on tobacco-related cancer, inflammation-associated cancer, and cancer-related health disparities.
Project 2: p53 and Cancer. The p53 pathway is an intrinsic monitor and response pathway of telomeric attrition involved in cellular aging and senescence. Cellular senescence is a tumor suppressive mechanism that can be activated by p53 in cancer cells. We are currently studying the molecular mechanisms of cellular senescence in normal human cells and the role of the telometric multiprotein complex, shelterin, that includes TRF2 and POT1 in aging and carcinogenesis.
Project 3: Inflammation and Cancer. Chronic inflammation can increase cancer risk. We are investigating the interaction between nitric oxide (NOo) and p53 as a crucial pathway in inflammatory-mediated carcinogenesis. We have shown that NOo induces ATM- and ATR-dependent p53 posttranslational modifications leading to a p53 stress response in human cells in vitro, in an admixture of activated macrophages and human cells in vitro, and in colon tissue from patients with ulcerative colitis or Crohn's, both of which are cancer prone, chronic inflammatory diseases. Furthermore, NOo can suppress or enhance tumorigenesis in an animal model of the Li- Fraumeni Syndrome, depending on NOo concentration.
Selected Recent References
( with PubMed hyperlinks )
1. Schetter, A. J., Leung, S. Y., Sohn, J. J., Zanetti, K. A., Bowman, E. D., Yanaihara, N., Yuen, S. T., Chan, T. L., Kwong, D.L.W., Au, G. K. H., Liu, C. G., Calin, G. A., Croce, C. M. and Harris, C. C.: MicroRNA expression profiles associated with prognosis and therapeutic outcome in colon adenocarcinoma. JAMA, 299: 425-436, 2008.
2. Martin RC, Barker DF, Doll MA, Pine SR, Mechanic L, Bowman ED, Harris CC, Hein DW.
Manganese superoxide dismutase gene coding region polymorphisms lack clinical incidence in general population.
DNA Cell Biol. 27: 321-3, 2008.
3. Kumamoto K, Spillare EA, Fujita K, Horikawa I, Yamashita T, Appella E, Nagashima M, Takenoshita S, Yokota J, Harris CC.
Nutlin-3a activates p53 to both down-regulate inhibitor of growth 2 and up-regulate mir-34a, mir-34b, and mir-34c expression, and induce senescence.
Cancer Res. 68: 3193-203, 2008.
4. Mechanic LE, Luke BT, Goodman JE, Chanock SJ, Harris CC.
Polymorphism Interaction Analysis (PIA): a method for investigating complex gene-gene interactions.
BMC Bioinformatics. 9: 146, 2008.
5. Sander M, Trump BF, Harris CC, Tennant RW.
The 20th Aspen Cancer Conference: Mechanisms of Toxicity, Carcinogenesis, Cancer Prevention, and Cancer Therapy 2005.
Mol. Carcinog. 2008.
6. Thomas DD, Ridnour LA, Isenberg JS, Flores-Santana W, Switzer CH, Donzelli S, Hussain P, Vecoli C, Paolocci N, Ambs S, Colton CA, Harris CC, Roberts DD, Wink DA.
The chemical biology of nitric oxide: Implications in cellular signaling.
Free Radic. Biol. Med. 45: 18-31, 2008.
7. Mechanic LE, Bowman ED, Welsh JA, Khan MA, Hagiwara N, Enewold L, Shields PG, Burdette L, Chanock S, Harris CC.
Common genetic variation in TP53 is associated with lung cancer risk and prognosis in African Americans and somatic mutations in lung tumors.
Cancer Epidemiol. Biomarkers Prev. 16: 214-22, 2007.
E-mail address: Curtis_Harris@nih.gov
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