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Epigenotyping in Peripheral Blood Cell DNA and Risk of Breast Cancer

Principal Investigator
Name
Susan Sturgeon
Degrees
-
Institution
UMASS Amherst
Position Title
-
Email
About this CDAS Project
Study
PLCO (Learn more about this study)
Project ID
2009-0553
Initial CDAS Request Approval
Mar 3, 2010
Title
Epigenotyping in Peripheral Blood Cell DNA and Risk of Breast Cancer
Summary
Methylation is a type of epigenetic change: a non-sequence modification of DNA linked to overall changes in gene expression. Methylation within a cytosine guanine dinucleotide-rich area (CpG island) of the promoter region of a gene that is normally unmethylated is correlated with silencing of that gene. Silencing of genes involved in cell regulation is a common feature of breast cancer. Global DNA hypomethylation is another common aberrant feature of breast cancers. It is also well established that estrogens are centrally involved in breast cancer development. Laboratory studies suggest that higher levels of estrogen exposure over a lifetime result in decreased methylation in the promoter region of the estrogen receptor target (ERT) genes (i.e., downstream genes affected by activated estrogen receptor). Thus, the main goals of this study, based on strong preliminary data, are: 1) to evaluate whether low levels of methylation of specific ERT genes in peripheral white blood cells (WBC) are associated with an increased risk of breast cancer; and 2) to examine whether global DNA hypomethylation in WBC DNA is related to breast cancer risk. A secondary aim is to evaluate whether decreased methylation of ERT genes in WBC DNA is correlated with higher serum levels of estrogens and estrogen metabolites. We propose to conduct this work in the PLCO Etiology and Early Markers (EEMS) established study of postmenopausal women nested in the PLCO cohort. Because this is a prospective study with specimens collected up to twelve years before diagnosis, results from the combination of these goals could provide information on an individual's risk of developing breast cancer with sufficient accuracy to guide preventive measures.
Aims

1. We will investigate the association between baseline peripheral WBC DNA methylation patterns in a set of nine estrogen receptor alpha target genes (ERT) and risk of incident postmenopausal breast cancer [i.e., BRIP1, ESR1, SIRT3, NUP155, PITX2, DCC, ZNF217, FLI39739, PGR]. We hypothesize that absence of promoter methylation in NUP155 and ZNF217 will be associated with an increased risk of breast cancer; and 2. We will investigate the association between genomic DNA hypomethylation, as measured by repetitive DNA sequences (i.e., LINE-1 and Alu repeats) and 5-mdC levels in peripheral WBC DNA, and risk of incident postmenopausal breast cancer. We hypothesize that genomic DNA hypomethylation will be associated with an increased risk of breast cancer. Secondary Aim:1. We will investigate the association between serum levels of estrogens and markers in Aim 1. We hypothesize that absence of promoter methylation in ERT target genes, ZNF217 and NUP155, will be positively correlated with serum levels of unconjugated estradiol.

Collaborators

Adam Karpf (Rosweel Park Cancer Institute)
Gretchen Gierach (NCI, DCEG)
Jean-Pierre Issa (MD Anderson Cancer Center)
Kathleen Arcaro (Univ of Massachusetts Amherst)
Raji Balasubramanian (University of Massachusetts Amherst)
Richard Vachet (University of Massachusetts Amherst)
Catherine Schairer (NCI, DCEG)
Susan Sturgeon (University of Massachusetts Amherst)
Regina Ziegler (NCI, DCEG)

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