Molecular Epidemiology
The molecular epidemiologic programmatic research focus is the study of gene-environment interactions in cancer etiology, emphasizing the study of genetically determined differences in response to environmental agents.
Susceptibility to Tobacco-Related Cancers
Although lung, upper aerodigestive tract and bladder cancers are paradigms of tobacco-related diseases, only a fraction of exposed individuals develop these cancers. The focus of this research component lies in studying this genetically determined susceptibility to tobacco carcinogenesis, an interest that crosses disciplines and departments. In a series of NCI-funded case-control studies, (Drs. Spitz, Wu and Wei) we are applying a panel of genotypic and phenotypic susceptibility markers. This includes functional assays of DNA repair capacity, and the prevalence of polymorphisms in a series of metabolic, DNA repair and cell cycle genes.
New assays are being tested and validated, including the single cell gel electrophoresis assay (COMET); levels of BPDE-induced DNA adducts in lymphocyte cultures; and assays evaluating apoptosis and cell cycle delay. The goal is to further the understanding of the molecular mechanisms underlying mutagen sensitivity and its implication for tobacco carcinogenesis. Diet/gene, gene/gene and gene/environment interactions, as well as genotype/phenotype correlations are being intensively investigated.
We also are studying susceptibility factors as predictors of risk of second primary tumors in patients who have been successfully treated for an initial upper aerodigestive tract cancer (Drs. Spitz and Wu). Collaborative studies of cervical cancer and Barrett’s esophagus incorporating a panel of markers are also underway (Dr. Wu).
Susceptibility to Ultraviolet Radiation-Induced Cancers
This component is aimed at identifying genetically determined susceptibility to UV radiation carcinogenesis (Drs. Wei and Strom) and to determine whether there is an association between DNA repair capacity and the risk of developing aggressive basal and squamous cell carcinoma of the skin. Drs. Wei and Strom are correlating the molecular and cytogenetic markers with gene mutations, epidemiologic and clinical information such as sunlight exposure, history, clinical stage of disease and treatment outcome.
The same techniques are being applied to the study of cutaneous malignant melanoma (CMM), (Dr. Wei) to construct detailed epidemiologic and clinical profiles of CMM cases and controls; to determine the association between cellular DNA repair capacity for UV damage and the risk of CMM by using a case-control study design; to study in vitro UV-induced sensitivity and expression of DNA repair genes in a subset of cases and controls expressing high- and low-repair capacity; and to evaluate the relationship of DNA repair capacity, UV-induced chromosome sensitivity and DNA repair gene expression to epidemiologic and clinical data on CMM.
Susceptibility to Hormonal Cancers
We have enrolled a cohort of 1,240 men with histologically confirmed prostate cancer (Drs. Strom, Spitz) and have identified risk factors associated with the development of clinically relevant prostate cancer, developed a unique phytoestrogen nutrient database and are applying a novel panel of genotypic predictors of prostate cancer risk. Recently, we have demonstrated that plasma leptin, an adiposity-related hormone, may modulate risk of clinically relevant prostate cancer through its effect on testosterone (Dr. Chang).
We have launched an innovative molecular cytogenetics research program (Dr. El-Zein) and are investigating the role of telomere dynamics as a predictor of clinically aggressive disease. Finally, the institution's Prostate Cancer Research Program funded two chemoprevention pilot projects for our collaborative efforts with the Department of Clinical Cancer Prevention: one is investigating the effects of selenium on NFkB activation and the other is using in situ hybridization methods to evaluate protein expression of 5-lipoxygenase.
In breast cancer, we are studying risk of lung cancer following irradiation for breast cancer and the role of genetic polymorphisms in breast cancer survival (Dr. Bondy). We are beginning to test hypotheses regarding the role of constitutional genetic polymorphisms in drug sensitivity as independent determinants of treatment response and toxicity in breast and ovarian cancers (Drs. Thompson and Bondy). The long-term goal is to initiate a prospective banking program (tumor, serum, lymphocyte and DNA) coupled with a comprehensive clinical database to support future studies of this kind.