3254

A universal 24-hour circadian rhythm is a fundamental biological phenomenon. Disruption of the circadian rhythm has been indicated as a risk factor for breast cancer in recent epidemiological studies. A novel finding in circadian biology is the discovery of several genes responsible for circadian rhythm, which are Clock, casein kinase I (CKI ), cryptochrome 1 (Cry1), chryptochrome 2 (Cry2), Period1 (Per1), Period2 (Per2), Period3 (Per3), Bmal1 and NPAS2. Emerging data have demonstrated that circadian genes are involved in regulating cell proliferation and apoptosis by controlling expression of tumor suppressor genes, cell cycle genes, and genes that encode the caspases and transcription factors. Therefore, as the molecular clockworks regulate many biological pathways in tumorigenesis, mutations in circadian genes could conceivably result in deregulation of these processes and subsequent tumor development. In our on-going studies, we are conducting a molecular epidemiological study to test the hypothesis that adverse genotypes in these circadian genes may influence an individual’s susceptibility to human breast cancer by incorporating approaches from computational biology, genetics and circadian physiology. First, we utilized bioinformatic tools to predict functional genetic polymorphisms based on their evolutionary conservation levels, and their possible impacts on protein structures and splicing sites. Out of 105 genetic polymorphisms identified in the databases, 31 variations were predicted to have functional significance. Second, we are screening frequencies of these 31 polymorphisms in the control population of a recently completed breast cancer case-control study in the state of Connecticut. Finally, polymorphisms with at least 10% of their rare alleles in the control population will be genotyped for all breast cancer cases and controls. Our pilot study investigated the association between an exonic length variation (54bp deletion/insertion) in the Per3 gene and breast cancer risk in 389 Caucasian cases and 432 Caucasian controls. We found that the variant Per3 genotypes (heterozygous + homozygous long-repeat alleles) was significantly associated with an increased risk of breast cancer among premenopausal women (OR=1.7, 95% CI 1.0-3.0). This result demonstrates that the structural variation in the Per3 gene may affect breast cancer risk especially among young women, suggesting a potential role of circadian genes in breast tumorigenesis. Given the recent identification of circadian genes and their role as tumor suppressors, unraveling the association between circadian genes and breast cancer will add to our understanding of a fundamental aspect of cellular processes in tumorigenesis and it will facilitate the development of novel risk and prognostic biomarkers for breast cancer. This study was supported by the funds from Yale University and the NIH grants CA62006, CA108369 and CA110937.

[Proc Amer Assoc Cancer Res, Volume 46, 2005]