Montserrat Garcia-Closas

M.D., Dr.P.H.

National Cancer Institute

Principal Investigator

PLCO (Learn more about this study)

2011-0150

Aug 31, 2011

Genome-wide blood DNA methylation study of breast cancer risk

Environmental and genetic factors play an important role in cancer etiology and development, however the epigenetic component of cancer risk is largely unexplored. Recent published and unpublished data by our group and others indicate that epigenetic traits in white blood cells (WBC) are good candidate risk markers for cancer developing in solid tumors. We are proposing to conduct a multi-stage genome-wide WBCDNA methylation study to identify makers of breast cancer risk, on a total of 2,130 cases and 2,130 controls from four prospective cohort studies. In stage I, we will run the Illumina 450K Infinium array designed to cover both promoter and gene-body sequences, on 500 cases and 500 controls nested on the Breakthrough Generations Study (BGS). Potential risk markers will be followed up using a custom Illumina array with 384 probes on a stage II study of 1,500 cases and 1,500 controls from three prospective cohorts (BGS, PLCO and CPS-II). Candidate gene loci will be validated in stage III using bisulphite pyrosequencing. This stage will assess platform and cell-type variation, and provide further validation on 130 cases and 130 controls from a prospective study of breast cancer families (KConFab). We also plan to use this data to identify life-style, environmental and genetic determinants of DNA methylation, and to evaluate the impact of validated methylation markers on risk prediction models for breast cancer in the combined sample set of 2,000 cases and 2,000 controls in stages I+II. Replication studies are critical for the success of genome-wide studies and are integral to the aims of this proposal. For the stage II replication phase, we are requesting 650 invasive breast cancer cases and 650 controls from PLCO with consent, baseline questionnaire and blood DNA. To our knowledge, this will be the first large-scale, genome-wide methylation study of breast cancer risk. At the conclusion of the project, we expect to identify novel risk biomarkers that will improve our understanding of the epigenetic element in the etiology of breast cancer.