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Principal Investigator
Name
Regina Ziegler
Degrees
-
Institution
NCI, DCEG, EBP
Position Title
-
Email
About this CDAS Project
Study
PLCO (Learn more about this study)
Project ID
2007-0261
Initial CDAS Request Approval
May 28, 2008
Title
Continuation of the Breast and Prostate Cancer Cohort Consortium (BPC3): Contributions of the PLCO Cohort to Breast Cancer Studies
Summary
We propose to continue the NCI Breast & Prostate Cancer Cohort Consortium (the BPC3). This submission focuses on the opportunities for breast cancer research. The BPC3 has been established over the last 4 years, and is nearing completion of the assessment of >70 candidate genes in the Steroid Hormone Metabolism and Insulin-like Growth Factor (IGF) pathways with respect to risk of breast and prostate cancer. Resequencing and genotyping data on these candidate genes were obtained, and tag-SNPs selected for genotyping; these data are available to the research community on a public website. Genotyping in over 7,000 cases of breast cancer has been completed or is nearing completion. With the accrual of additional cases by mid-2007, we expect that the database can be expanded to 14,000 cases and controls of breast cancer. Starting in 2005, the NCI Cancer - Genetic Markers of Susceptibility (CGEMS) project has been conducting genome-wide SNP scans for breast cancer in the Nurses' Health Study with replication for SNPs highly ranked in the scan in the other studies of the BPC3. Other genome-wide association studies are ongoing, including a breast cancer scan using pooled DNAs in the Womens' Health Initiative (WHI) and a breast cancer scan at the University of Cambridge (UK). We propose to expand the BPC3 to serve as a 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. We also propose to take advantage of the size of the BPC3 to conduct genome-wide association studies of estrogen receptor-negative (ER-) breast cancer. There is evidence that ER- breast cancer has a different etiology than estrogen receptor-positive (ER+) breast cancer. Single studies do not have power to address this important subtype. We will replicate findings for ER- breast cancer in 2500 cases from the Breast Cancer Association Consortium (BCAC). The alliance of the BPC3 with the BCAC will facilitate communications and pooled analyses between the two largest sets of studies examining inherited susceptibility to breast cancer.
Aims

We propose to continue follow-up and activities of the NCI Breast and Prostate Cancer Cohort Consortium (BPC3). The BPC3 includes the American Cancer Society Cancer Prevention Study-II (CPS-II), the Alpha-Tocopherol, Beta-Carotene Study (ATBC), the European Prospective Investigation of Cancer (EPIC), the Health Professionals Follow-up Study (HPFS), the Multiethnic Cohort (MEC), the Nurses' Health Studies I and II (NHS and NHSII), the Physician's Health Study (PHS), the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO), and the Women's Health Study (WHS). This international consortium has been established over the last 4 years, and is nearing completion of the assessment of the initial 51 candidate genes in the steroid hormone metabolism and IGF pathways with risk of breast and prostate cancer, as well as single nucleotide polymorphisms (SNPs) in 22 additional genes in these and other important pathways. In the first phase of the ongoing study, resequencing and genotyping data on these candidates were obtained, and tag-SNPs selected in these genes; these data are available to the research community on a public website. Genotyping of these SNPs in over 7,000 cases of breast cancer has been completed or is nearing completion. We have established a database at a breast cancer data coordinating center. With the accrual of additional cases by mid-2007, we expect that this database can be expanded to 14,000 cases of breast cancer. Starting in 2005, the NCI Cancer - Genetic Markers of Susceptibility (CGEMS) project has been conducting genome-wide association studies (GWAS) for breast cancer in the NHS, with replication for SNPs highly ranked in the scan in the other studies of the BPC3. Other GWAS are ongoing, including a breast cancer scan using pooled DNAs in the Women's Health Initiative (WHI) and a breast cancer scan at the University of Cambridge (UK). Infrastructure is now needed to rapidly verify findings in large independent data sets, to determine the role of genetic determinants in important clinical sub-types, and to identify gene-environment interactions. We propose to 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 cancer. With the completion of GWAS for breast cancer, there are important remaining questions 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. No single study is likely to have enough cases of this cancer subtype to perform a GWAS -- by pooling cases across the BPC3 studies we can achieve adequate power to discover genetic variation that gives rise to ER- breast cancer. HYPOTHESES: 1. The inherited germline predictors of clinically important cancer subtypes, such as ER- breast cancer, are different than for breast cancer overall. 2. SNPs identified as being robustly associated with total breast cancer, or its subtypes, have different effects within strata of defined environmental and lifestyle risk factors for breast cancer. SPECIFIC AIMS: To examine the above hypotheses we propose to: 1. Continue and expand our collaborative database to include over 14,000 cases of breast cancer with matched controls. 2. Genotype the existing and additional cases and controls added to the database for SNPs identified through the CGEMS and other genome-wide association studies as being likely to be causally associated with these cancers. 3. Assess whether the effects of the SNPs identified as likely to be causal vary according to established environmental and lifestyle risk factors. 4. Conduct a GWAS of ER- breast cancer in 1300 White cases and controls contributed by the NHS, CPS-II, WHS, EPIC, PLCO, and MEC studies. We will confirm highly associated SNPs in 2500 ER- cases and controls in the Breast Cancer Association Consortium (BCAC). 5. Assess the generalizability of these findings in non-White women from the MEC and, to the extent available, the other cohorts.

Collaborators

Christine Berg (NCI, DCP)
Stephen Chanock (NCI, DCEG)
Robert Hoover (NCI, DCEG)
Study center PI (TBD)
Meredith Yeager (NCI, CGF)
Regina Ziegler (NCI, DCEG)

Related Publications
  • The landscape of recombination in African Americans.
    Hinch AG, Tandon A, Patterson N, Song Y, Rohland N, Palmer CD, Chen GK, Wang K, Buxbaum SG, Akylbekova EL, Aldrich MC, Ambrosone CB, Amos C, Bandera EV, Berndt SI, Bernstein L, Blot WJ, Bock CH, Boerwinkle E, Cai Q, Caporaso N, Casey G, Cupples LA, Deming SL, Diver WR, Divers J, Fornage M, Gillanders EM, Glessner J, Harris CC, Hu JJ, Ingles SA, Isaacs W, John EM, Kao WH, Keating B, Kittles RA, Kolonel LN, Larkin E, Le Marchand L, McNeill LH, Millikan RC, Murphy A, Musani S, Neslund-Dudas C, Nyante S, Papanicolaou GJ, Press MF, Psaty BM, Reiner AP, Rich SS, Rodriguez-Gil JL, Rotter JI, Rybicki BA, Schwartz AG, Signorello LB, Spitz M, Strom SS, Thun MJ, Tucker MA, Wang Z, Wiencke JK, Witte JS, Wrensch M, Wu X, Yamamura Y, Zanetti KA, Zheng W, Ziegler RG, Zhu X, Redline S, Hirschhorn JN, Henderson BE, Taylor HA, Price AL, Hakonarson H, Chanock SJ, Haiman CA, Wilson JG, Reich D, Myers SR
    Nature. 2011 Aug; Volume 476 (Issue 7359): Pages 170-5 PUBMED
  • The potential for enhancing the power of genetic association studies in African Americans through the reuse of existing genotype data.
    Chen GK, Millikan RC, John EM, Ambrosone CB, Bernstein L, Zheng W, Hu JJ, Chanock SJ, Ziegler RG, Bandera EV, Henderson BE, Haiman CA, Stram DO
    PLoS Genet. 2010 Sep; Volume 6 (Issue 9): Pages e1001096 PUBMED