High-Throughput Polymorphism Detection
Collaboration of Harvard Investigators at the Brigham and Women’s Hospital (Jing Ma, Graham Colditz, David Hunter, Frank Spiezer), the School of Public Health (Ed Giovannucci), and Harvard Medical School (Sue Hankinson) in the NCI Breast and Prostate Cancer Cohort Consortium. This Consortium links the Nurses’ Health Study, Health Professionals Study, Physicians’ Health Study, and Womens’ Health Study cohorts with cohorts at USC, NCI, ACS, and IARC, and genomics groups at the Whitehead Institute and CEPH. Haplotypes in 53 candidate genes for breast and prostate cancer will be established, tested for association with these outcomes, and examined for gene-environment interactions. In all, over 100 SNPs will be assayed on 5,000 DNA samples.
Collaborating with DF/HCC investigators in genomics and utilizing the resources of the DF/HCC High-Throughput Polymorphism Detection Core (David Hunter, Director), DF/HCC Epidemiologists (Drs. Fuchs (DFCI), Chan (MGH), Giovannucci (HSPH), Colditz (BWH)) are examining whether pharmacogenomic profiles may influence the response to aspirin chemoprevention. Utilizing banked DNA specimens from 1062 women in the Nurses’ Health Study, we found that among women with variant genotypes of UDP-glucuronosylyltransferase 1A6 (UGT1A6), the major enzyme in glucuronidation of aspirin, (50% of the population) experienced a substantial reduction in adenoma risk when consuming aspirin, whereas women with wild-type genotypes did not experience any reduction in risk with regular aspirin use (Chan et al, J Natl Cancer Inst, 2004, in press). These findings are consistent with data that aspirin’s anti-neoplastic effect is dose-dependent and provides proof-of-principle that an individual’s pharmacogenomic profile may influence the response to drug therapy. We are now conducting larger studies to confirm these findings and to evaluate a possible role for genetic polymorphisms in tailoring an approach to colorectal cancer prevention. Furthermore, additional studies will address whether UGT1A6 genotype modifies the other potential benefits of aspirin or its potential hazards.
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