a)Determine how genetic, molecular and environmental exposures explain differences in susceptibility to skin and breast cancer
b) Understand more precisely the mechanistic role of free radicals in carcinogenesis in order to develop better chemopreventive and interventional therapies utilizing natural compounds.
PROJECTS
DNA repair and susceptibility to UV-induced basal cell carcinoma in Puerto Rican populations.
Funding source: NASA grant NAG-2-1385 (1999-2001), NIH-RCMI grant 2G12-RR03050-17 (2001-2003).
This project is the first molecular epidemiology study of non-melanoma skin cancer (NMSC) in Puerto Rico and the most comprehensive effort in the world. This is a collaborative study with Lawrence Grossman, PhD ( Johns Hopkins University), Jaime Villa, MD (dermatologist, Damas Hospital, Ponce), and Dr. Jorge Sanchez (Dept. of Dermatology, University of Puerto Rico. In the publication currently in press (Matta et al. 2003), we have validated the hypothesis that a reduced DNA repair capacity is a risk factor of sunlight-induced basal cell carcinoma (BBC) and squamous cell carcinoma (SCC) carcinoma. The experimental design involves the use of a clinically oriented case-control study. The peripheral lymphocytes of participants (n=280) with primary BCC and SCC and cancer-free controls (n=177) were used to measure their capacity to repair UV-induced DNA damage. A genetically engineered plasmid containing the luciferase reporter gene was irradiated with three doses of UVC light (254 nm) and transfected into human peripheral lymphocytes. This is a project in translational research encompassing both basic science (molecular biology, epidemiology) and clinical components. The clinical implications of this approach are expected to have a significant impact on the early detection and prevention of skin cancer in Puerto Rican populations that are frequently exposed to high levels of UV radiation. In addition to DNA repair, other significant risk factors were skin type, six or more lifetime severe burns, family history of cancer and/or skin cancer. Long-term goal this approach may be able to reduce mortality from other primary non-skin neoplasms in patients with NMSC.
Mutations in PTCH gene and early onset of basal cell carcinoma .(Pilot Project ) This project is being spearheaded by Juan Ramos,MD and Maria Carrero (undergraduate student).
In 1996, Hahn et al. (Cell 85:841-851) reported that mutations of the human homologue of Drosophila patched gene (PTCH) were responsible for the nevoid basal cell carcinoma syndrome. This is an autosomal dominant disorder characterized by multiple basal cell carcinomas (BCCs) and other developmental abnormalities. Ratner et al. 2001 (J. Am. Acad. Dermatol. 44: 293-297) reported that mutations in the PTCH tumor suppressor gene are also responsible for sporadic BCCs. As part of the ongoing skin cancer project in my laboratory funded by the RCMI Program, we have identified a subpopulation of 7 patients between 21 and 35 years of age with histopathologically confirmed basal cell carcinoma. These patients on an average have a comparable DNA repair capacity to the rest of the patients with BCC. However, they have an early onset basal cell carcinoma. Unpublished data using conformational gel electrophoresis, has shown that several of the participants with BCC have a genetic mutation in the PTCH. This mutation can partly explain the occurrence of non-melanoma skin cancer in this young Puerto Rican population.
Molecular epidemiology of breast cancer in Puerto Rican women
The overall objective is to examine the relationship between DNA repair and mutations in the TP53 and BRCA-1 genes in relation to breast cancer (BC) susceptibility. The hypothesis are: 1) Women with BC have a lower age-adjusted DRC than controls without BC, 2) Women with BC that have mutations in TP53 and BRCA-1 genes have a lower DRC than participants with BC without these mutations, 3) Women with BC and a low DRC have higher tumor grade and size and positive axillary lymph node metastasis when compared with women with BC and a high DRC. Specific Aims: 1) Determine the DNA repair capacity (DRC) in women with BC in PR using a host cell reactivation assay, 2) Compare the prevalence of mutations in TP53 and BRCA-1 mutations in women with and without BC, 3) Examine whether tumor grade and size and the presence of axillary lymph node metastasis are correlated with the level of DRC and types of mutations in TP53 and BRCA-1, 4) Obtain epidemiological data on participants with BC in order to determine familial, genetic, nutritional and occupational factors that can influence susceptibility to BC. Study Design: A case-control retrospective clinical study will be utilized. Molecular (DRC, TP53 and BRCA-1), epidemiological and pathological data will be analyzed to calculate statistical correlations in order to examine the potential relationship of these variables in terms of BC susceptibility. This study will represent the first research in PR to confirm and further elucidate many of the reported interactions between genetic, environmental and lifestyle factors as they relate to BC susceptibility.
Hyperspectral signatures and characterization of microorganisms and human health effects associated with Sahara dust: the use of NASA-developed technologies
(Pilot Project in collaboration with Roy A. Armstrong, PhD University of Puerto Rico, Mayaguez, Puerto Rico, Hector D’Antoni, PhD, NASA Ames Research Center, Ames, California)
Sahara dust (SD) plumes are generated annually by storm activity in northern Africa's Sahel region during the dry season. The dust, originating from fine particles in the dry topsoil, is transported into the atmosphere by winds and may be carried to an altitude of more than 10,000 feet. Each year millions of tons of dust are transported westward toward the Caribbean Sea and the eastern United States. The presence of minerals in SD such as iron can fertilize marine ecosystems and promote the growth of toxic phytoplankton. Microorganisms including pathogenic bacteria, viruses, fungi are also transported in SD, spreading thousands of miles with potentially worldwide implications for human health and the environment. The National Institute of Allergy and Infectious Diseases has concluded that airborne dust is a primary source of allergenic stress worldwide. The objectives of this pilot study are to: 1. Characterize the biological and mineral content of Sahara dust, 2. Obtain spectral signatures for microorganisms present in Sahara dust by means of the recently developed hyperspectral microscopy sensor (TIMS) under NASA SBIR Phase II Contract, 3. Develop new remote sensing methods using the spectral signatures developed with the TIMS, to determine the dust composition from space using the proposed micro satellite-based imaging interferometer (DASI), 4. Predict some of the most common health effects expected from acute and chronic exposure to Saharan dust.
EXTRAMURAL FUNDING Current Support:
Title: “DNA repair and susceptibility to UV-induced basal cell carcinoma in Puerto Rican populations”. Source: National Institutes of Health (NIH), National Center for Research Resources (NCRR), Research Center Minority Institutions (RCMI). 2001-2003. Budget: $227,002.25 (direct and F&A costs) 2001-2003.
Title: “Characterization of microorganisms and human health effects associated with Sahara dust”. Source: NASA (Pilot Project in collaboration with Roy A. Armstrong, PhD University of Puerto Rico, Mayaguez, Puerto Rico, Hector D’Antoni, PhD, NASA Ames Research Center, Ames, California. Budget: $16,878 (awarded to Dr. R. Armstrong).
Title: “Prevention of skin disease in Puerto Rican Fishermenand Farmers”. Source: North Carolina Agromedicine Institute, Budget: $17,600, March 1, 2003 to September 2003, (awarded to Dr. John Sabella). Pilot Project in collaboration with Susan Gustke, MD, FACP, Director, and John Sabella, EdD, Associate Director, North Carolina Agromedicine Institute, Greenville, North Carolina.
