Integrative epidemiology: From risk assessment to outcome prediction.

ED08-01

We propose an integrative epidemiologic approach to studying the entire cancer spectrum from exposure, to predisposition, early diagnosis and ending with cancer outcome, by applying the principles and perspective of epidemiology to the notable advances in molecular biology. This approach begins with epidemiologic case-control studies in which biologically intensive studies can be carried out usually on surrogate tissues (lymphocytes, plasma or serum). Common genetic variants that modulate behavior (eg CYP2A6) may also modify predisposition through altered metabolism of carcinogenic exposures. Tumor DNA can be isolated from serum or plasma, as a useful source for screening specific transcripts or mutations in mitochondrial or nuclear-DNA sequences. Identification of protein patterns in serum using high throughput proteomics linked to novel bioinformatics approaches can be useful for early detection. As we move along the continuum from surrogate to intermediate and target tissues, the procedures become more invasive, the size of the study more restricted, and we apply the case series approach. Pharmacogenetic profiles can be used to individualize therapy and to understand the functional consequences of chemoprevention, chemotherapy, or radiotherapy response. Again, common genetic variants may affect both risk and outcome, eg, matrix metalloproteases. At this level we can also correlate the genetic and epigenetic spectrum of changes in tumor tissue with epidemiologic data, and with surrogate tissue phenotype and genotype data. The converse direction also applies in that genes demonstrated to contribute to tumorigenesis provide a rich source of candidates for analysis related to exposure, to predisposition, early diagnosis. For example, polymorphisms in the cyclin D1 protooncogene, which is frequently elevated in tumors, are predictors of risk of development of lung cancer (correct the sentence). This allows leveraging of the power of approaches arising from the completion of the human genome project that facilitate analysis of genetic changes in tumors on a global basis. This is a powerful new approach that cannot be successfully accomplished by any discipline independently. Integrating these new approaches requires a combination of the rigor of data and sample collection and validation inherent in epidemiologic research with the ability to perform global, unbiased analysis of genetic aberrations in tumors.