Study
PLCO
(Learn more about this study)
Project ID
2006-0287
Initial CDAS Request Approval
Sep 22, 2006
Title
Loss of Imprinting and Risk of Colorectal Neoplasia
Summary
Genomic imprinting is an epigenetic modification in the gamete or zygote that leads to relative silencing of a specific parental allele in somatic cells of the offspring. Loss of imprinting (LOI) of the insulin-like growth factor II gene (IGF2) is defined as aberrant expression of the normally silent maternally inherited allele. We found that LOI in lymphocytes and colon is common in the population (prevalence of 5-10%), associated with a five-fold increased frequency of intestinal neoplasia in humans and a five-fold increased frequency of first degree relatives with colorectal cancer (CRC), suggesting that LOI of IGF2 contributes substantially to the population risk of CRC. We also developed a mouse model of LOI, showing that it increases the incidence of tumors when crossed with Min mice harboring a mutation in the adenomatous polyposis coli (Apc) gene. Thus, LOI might represent a common marker for CRC risk and an attractive target for chemoprevention. These findings now need to be confirmed in a large prospective setting with equal opportunity for detection of colorectal neoplasia and to assess whether LOI of IGF predicts another major epithelial cancer or is specific to the colon. The goal of the study is to determine the role of the loss of imprinting (LOI) of the insulin-like growth factor-II gene (IGF2) in the etiology of colorectal cancer and adenoma. We propose a series of nested case-control studies to investigate the association of LOI of IGF2 as assessed in peripheral blood lymphocytes with colorectal cancer and adenomas. Other tissue and serum-based analyses are proposed to uncover the mechanism underlying any such associations, to determine the stability over time of this epigenetic change, and to identify potential genetic variants that associate with LOI of IGF2 or its consequences. These studies should allow us to substitute a conventional genetic test for the epigenetic test of LOI, as well as identify additional potential targets of CRC risk, i.e. the genes responsible for maintaining IGF2 imprinting stringency or are associated with colorectal neoplasia in patients with LOI.
Aims
Aim 1. We will determine the stability of LOI of IGF2 in blood over several years. Hypothesis: LOI of IGF2in the peripheral blood lymphocytes of a given individual is stable over 6 years. Aim 2. We will perform a nested case-control study to determine whether LOI of IGF2 in blood is predictive of colorectal cancer and adenomas. Hypothesis: LOI of IGF2 is associated with a >= 2-fold higher risk of colorectal cancer and adenomas. Ancillary question 1: What is the histopathology of LOI-associated colorectal neoplasia in the PLCO cohort? Hypothesis: The extent of the expansion of the progenitor cell compartment is greater in those participants with LOI. Ancillary question 2: Does serum IGF2 concentration differ by LOI of IGF2 status in blood and in tissue? Hypothesis: Participants with LOI have higher serum IGF2 concentrations. Aim 3. We will search for variants in genes involved in two processes--genesis of methyl groups for DNA methylation and pathways involved in IGF2 signaling--that associate with LOI of IGF2 in blood in the population, or with colorectal neoplasia among subjects with LOI. Hypothesis: Variants in genes in the hypothesized processes are associated with LOI.
Collaborators
Andrew Feinberg (Johns Hopkins University)
M. Danielle Fallin (Johns Hopkins University)
Elizabeth Platz (Johns Hopkins University)
Richard Hayes (NCI, DCEG)
Wen-Yi Huang (NCI, DCEG)
Related Publications
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Temporal stability and age-related prevalence of loss of imprinting of the insulin-like growth factor-2 gene.
Cruz-Correa M, Zhao R, Oviedo M, Bernabe RD, Lacourt M, Cardona A, Lopez-Enriquez R, Wexner S, Cuffari C, Hylind L, Platz E, Cui H, Feinberg AP, Giardiello FM
Epigenetics. 2009 Feb 16; Volume 4 (Issue 2): Pages 114-8
PUBMED
