Biography

Dr. Sinha received a B.S. with honors in biochemistry from the University of Stirling in Scotland, and a Ph.D. in nutritional sciences from the University of Maryland. She began work at the NCI in the Laboratory of Cellular Carcinogenesis and Tumor Promotion in 1987, and joined the DCEG Epidemiology and Biostatistics Program in 1992. Dr. Sinha received a fellowship from the Japanese Foundation for Cancer Research in 1997. She was a steering committee member of the Molecular Epidemiology Group of the American Association for Cancer Research from 1997-1998, and of the Nutritional Epidemiology Research Interaction Group of the American Society of Nutritional Sciences from 1998-2000. Dr. Sinha was promoted to tenure in 2001.

Research Interests

Diet, Nutrition and Genetic Susceptibility

Only a small number of dietary components has been linked causally to cancer, even though diet is thought to be important in the etiology of certain human cancers. Our research focuses on interdisciplinary studies aimed at improving dietary exposure assessment using questionnaires and biochemical measures, as well as elucidating dietary exposures and biological mechanisms associated with cancer risk, including the role of genetic susceptibility. We are particularly interested in examining potential carcinogens formed in meats during the cooking process.

Cooking-Related Carcinogens

Cooking meats at high temperatures produces heterocyclic amines (HCAs) and polycyclic aromatic hydrocarbons (PAHs), known mutagens and animal carcinogens. Epidemiologic studies examining the influence of meat doneness and cooking methods, however, have not consistently shown a relationship with cancer risk. To clarify the effects of cooking-related carcinogens, we developed a three?part research program: 1) to improve methods of diet assessment for cooked meat, HCAs, and PAHs, 2) to evaluate the role of genetic susceptibility factors in the metabolism of HCAs and PAHs, and 3) to test the hypothesis that HCAs and PAHs are etiologic factors in the risk of certain human cancers.

• Exposure assessment. A database and dietary food frequency questionnaire (FFQ) were developed to improve estimates of exposure. For the database, different types of meats were cooked by assorted methods to varying degrees of doneness. Measurements were made for five HCAs and twelve PAHs. Integrated into the database is a module on meat cooking practices in an FFQ format. The module collects information on usual intake of meat type, portion size, cooking method, internal doneness, and external browning. Photographs are used to standardize responses. The FFQ module has been validated among 150 people by 12-day dietary records and one 24-hour recall. To identify biological markers of internal exposure, we conducted a metabolic study to collect data on the metabolism and excretion of HCAs and their metabolites.
• Genetic susceptibility assessment. Carcinogenic HCAs are formed through enzyme-mediated activation. In humans, the major HCAs, 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQX) and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), are metabolized by cytochrome P4501A2 (CYP1A2) and N-acetyltransferase (NAT2). The results from our metabolism study on the interaction of these HCAs and polymorphic genes suggest that inter-individual variation in CYP1A2 activity is relevant to HCA-associated carcinogenesis. We are now investigating the genetic basis of the difference.
• Epidemiologic studies. Using methodologic tools that we developed, the role of meat intake and exposure to HCAs is being examined in the etiology of colorectal adenomas and cancers of the lung, breast, and prostate. In addition, using refined questionnaires and other information collection methods, high temperature cooking techniques and doneness levels of red meat are being evaluated in relation to colorectal, stomach, lung, and breast cancers. In the colorectal study, we found an elevated risk of 10% per 10g for red meat consumption. The increased risk was mainly associated with well done/very well done red meat, with an excess risk of 29% per 10g verses 10% per 10g for rare/medium red meat. We also found increased risks associated with high temperature cooking methods of 27% per 10g for grilled red meat and 15% per 10g for pan-fried red meat.
• Using the HCA database with the refined questionnaire, we estimated intake of PhIP, MeIQx, and DiMeIQx. We found increased risk of colorectal adenomas associated with all three HCAs. However, increased risk was observed only for MeIQx after adjusting each HCA for the other. Our analysis suggests that intake of MeIQx could explain the risk associated with well done and fried red meat, but not with grilled red meat. It is possible that this risk may be associated with intake of PAHs. For lung cancer, we found similar results for red meat doneness, fried meat, and estimated MeIQx intake. These exposure assessment approaches are being used in large prospective studies worldwide and should help to clarify the role of doneness, cooking practices, and pyrolysis products in the etiology of human cancer.

Keywords

cooking method, DiMeIQx, genetic susceptibility, heterocyclic amines, MeIQx, PhIP, meat, polycyclic aromatic hydrocarbons (PAHs)

Selected Publications

• Sinha R, et al. "PhIP, a carcinogen produced during high temperature meat cooking, is associated with increased risk of breast cancer." J Natl Cancer Inst 2000; 92:1352-1354.
• Sinha R, et al. "Heterocyclic amines and colorectal adenomas." Cancer Epidemiol Biomarkers Prev 2001; 10:559-562.
• Poirier, LA, et al. "Blood determination of S-adenosylmethionine, S-adenosylhomocysteine, and homocysteine:correlation with diet." Cancer Epidemiol Biomarkers Prev 2001; 10:649-655.
• Kazerouni N, et al. "Analysis of 200 food items for benzo[a]pyrene and estimation of its intake in an epidemiologic study." Food Chem Toxicol 2001; 39:423-436.

Collaborators

DCEG Collaborators

• Arthur Schatzkin, M.D., Dr. P.H.; Michael Alavanja, Dr.P.H.; Neil Caporaso, M.D.; Wong-Ho Chow, Ph.D.; Thomas Fears, Ph.D.; Montserrat García-Closas, M.D., Dr.P.H.; Richard Hayes, D.D.S., Ph.D.; Robert Hoover, M.D., Sc.D.; Maria-Teresa Landi, M.D., Ph.D.; Steven Mark, M.D., Sc.D.; Kathryn McGlynn, Ph.D.; Nathaniel Rothman, M.D., M.P.H.

Other NCI Collaborators

• Elaine Lanza, Ph.D.; Miriam Poirier, Ph.D.; Amy Subar, Ph.D.

Other NIH Collaborators

• Christine Swanson, Ph.D., Office of Dietary Supplements, OD, NIH

Other Scientific Collaborators

• Nicholas Becker, M.D., German Cancer Research Center, Heidelberg, Germany
• Rosalind Breslow, Ph.D.; Elaine Gunter Ph.D., Center for Disease Control, Atlanta, GA
• Celia Byrne, Ph.D., Harvard Medical School, Cambridge, MA
• Federico Canzian, Ph.D., International Agency for Cancer Research, France
• Brian C-. H. Chiu, Ph.D., University of Nebraska, Omaha, NE
• David DeMarini, Ph.D., Environmental Protection Agency, Research Triangle Park, NC
• James Felton, Ph.D.; Mark Knize, M.S., Lawrence Livermore National Laboratories, Livermore, CA
• David W. Hein, Ph.D., University of Louisville School of Medicine, Louisville, KY
• Fred Kadlubar, Ph.D.; Lionel Poirier, Ph.D.; Christine Ambrosone, Ph.D., National Center for Toxicological Research, Jefferson, AR
• Garrett Keatings, Ph.D., Department of Energy, Livermore, CA
• Martin Kulldorff, Ph.D., University of Connecticut, Farmington, CT
• Nicholas Lang, M.D., FACS University of Arkansas, Little Rock, AR
• Emmanuel Petricoin, Ph.D., Food and Drug Administration, Bethesda, MD
• Sheila Prindiville, M.D., M.P.H., University of Colorado Health Science Center, Denver, CO
• Paul Strickland, Ph.D., The Johns Hopkins Bloomberg School of Public Health, Baltimore, MD
• Sarah Stillwell, Ph.D.; Steven Tannenbaum, Ph.D., Massachusetts Institute of Technology, Cambridge, MA
• Susan Sturgeon, Ph.D., University of Massachusetts, Amherst, MA
• Shoichiro Tsugane, M.D., M.P.H.; Kenji Wakabayashi, Ph.D., National Cancer Research Institute, Japan
• Lucille Adams-Campbell, Ph.D., Howard University, Washington, D.C.
• Kristin Anderson, Ph.D. University of Minnesota, Minneapolis, MN
• Hoda Anton-Culver, Ph.D.; Ralph Delfino, M.D., M.P.H., University of California, Irvine, CA
• Edward Giovannucci, M.D., Harvard Medical School, Cambridge, MA
• Robert Haile, Ph.D., University of Southern California, Los Angeles, CA
• Loic LeMarchand, M.D., Ph.D., University of Hawaii, Honolulu, HI
• Elena Martinez, Ph.D., Arizona Cancer Center, Tucson, AZ
• Robert Sandler, M.D., University of North Carolina, Chapel Hill, NC
• Peter Shields, M.D., Georgetown University, Washington, D.C.
• Wei Zheng, M.D., Ph.D., Vanderbilt University, Nashville, TN