Research Abstract II – 2007

Characterizing Genetic Susceptibility to Breast and Prostate Cancer

This continuation of the Breast and Prostate Cancer and Hormone-Related Gene Variant Study provides for follow-up and activities of the NCI Breast and Prostate Cancer Cohort Consortium (BPC3). The study includes the following 6 large prospective cohorts: American Cancer Society Cancer Prevention Study-II (CPS-II); European Prospective Investigation of Cancer (EPIC): four Harvard Cohorts — Physician's Health Study (PHS), Nurses' Health Studies I and II (NHS and NHSII), Health Professionals Follow-up Study (HPFS), and Women's Health Study (WHS); Multiethnic Cohort (MEC); Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial, and Alpha-Tocopherol, Beta-Carotene (ATBC) Study.

This international consortium was first funded in 2003 and over its first four years assessed 55 candidate genes in the steroid hormone metabolism and IGF pathways in relation to risk for breast and prostate cancer, as well as single nucleotide polymorphisms (SNPs) in 22 additional genes in these and other important pathways that were not listed in the original grant application. In this phase of the research project, resequencing and genotyping data on these candidate genes were obtained, and tag-SNPs were selected in these genes. These data are available to the research community on a public Web site. Genotyping of these SNPs in more than 7,000 cases of breast cancer and more than 8,500 cases of prostate cancer has been completed or is near completion as of mid-2007. The investigators have established databases at two data coordinating centers for breast cancer and prostate cancer. With the accrual of additional cases by mid-2007, they expect that these databases can be expanded to 14,000 cases of breast cancer, and 16,000 cases of prostate cancer.

Starting in 2005, NCI’s Cancer Genetic Markers of Susceptibility (CGEMS) initiative, has been conducting genome-wide association studies (GWAS) in two of the BPC3 studies (prostate cancer in the PLCO study, and breast cancer in the NHS) with replication for SNPs highly ranked in the scan in the other studies of the BPC3. An admixture GWAS for prostate cancer was performed in the Multiethnic Cohort and identified an important susceptibility locus at chromosome 8q24. Other GWASs are ongoing, including a breast cancer scan using pooled DMAs in the Women's Health Initiative (WHI), and a breast cancer scan at the University of Cambridge, England. Infrastructure is now needed to rapidly verify findings in large independent data sets, to determine the role of genetic determinants in important clinical subtypes of these diseases, and to identify gene-environment interactions.

Specifically, this new study will expand the BPC3 to serve as a rapid verification test set for SNPs identified in the scans other than the CGEMS scan, and to examine gene-environment interactions in the SNPs identified in CGEMS and other studies as being associated with breast and prostate cancer.

With the completion of GWAS for breast cancer and prostate cancers in aggregate, important questions remain that the BPC3 is uniquely positioned to answer. Estrogen receptor negative (ER-) breast cancers have specific epidemiologic characteristics and greater lethality, but the current generation of scans is underpowered to discover gene variants associated with these tumors. Aggressive forms of prostate cancer, characterized by extraprostatic extension (Stage C/D) or high histologic grade (Gleason score 8+), differ epidemiologically from the vastly more common indolent forms of prostate cancer and are of the greatest clinical importance, but again the current scans are underpowered to discover associated genetic determinants. No single study is likely to have enough cases of these cancer subtypes to perform a GWAS. By pooling cases across the BPC3 studies, the investigators can achieve adequate power to discover genetic variation that gives rise to these important clinical subtypes.

Projects developed within the BPC3 are fostering continuing interactions between the genomic and epidemiologic research communities and are integrating the rapid advances in genomic research into large-scale epidemiologic studies. The ultimate goal is to provide the foundation for reducing t