# Visualization and Epigenomic Characterization of Early Intestinal Tumorigenesis in Mice

> **NIH NIH R01** · VAN ANDEL RESEARCH INSTITUTE · 2020 · $434,625

## Abstract

PROJECT SUMMARY / ABSTRACT
 Cancer is thought to start with the loss of function of key gatekeeper genes, such as APC in intestinal
tumorigenesis. Sporadic cases of colorectal cancer in humans are thought to acquire somatic genetic hits for
both alleles, while cases of Familial Adenomatous Polyposis are thought to acquire the first hit through germline
inheritance of a defective allele, followed by somatic loss of heterozygosity of the remaining wildtype allele.
Although loss of Apc function is a powerful early oncogenic event in intestinal tumorigenesis, it does not by itself
appear to be sufficient to drive progression in all intestinal stem cells. The past three decades have witnessed
an accumulating body of evidence that epigenetic mechanisms play an instrumental role in human cancer.
Epigenetic alterations can serve as driver events in cancer by inactivating tumor-suppressor genes. The finding
that these silencing events are mutually exclusive with structural or mutational inactivation of the same gene
reinforces the functional significance of epigenetic silencing. Most epigenetic silencing events appear to be clonal,
suggesting that these alterations occur very early in tumorigenesis, possibly preceding clonal expansion. DNA
methylation silencing events in human and mouse tumors are enriched for gene targets of Polycomb repression
in stem cells that are normally required for differentiation. We hypothesize that stem cells with appropriate pre-
existing DNA methylation alterations, possibly resulting in impaired differentiation capability are primed for rapid
progression upon loss of Apc function. We propose to use an innovative visualization system in the ApcMin mouse
model of intestinal tumorigenesis to study the earliest events in cancer initiation, characterize the rates of
progression, and identify cooperating genetic and epigenetic events in early tumorigenesis. Specific Aim 1 will
be to determine the rate of Loss of Heterozygosity of Apc in intestinal epithelium. Our strategy to visualize loss
of the wildtype Apc allele is to incorporate a transcriptional repressor into the endogenous Apc locus through
gene targeting, without disrupting Apc function (Aim 1a). We will use this system to determine the rate of Apc
loss of heterozygosity in the intestinal epithelium and in early tumors (Aim 1b). Specific Aim 2 will be to define
genetic and epigenetic events in early progressing lesions. We will use fluorescence-based cell sorting and
Whole Genome Bisulfite Sequencing (WGBS) to identify DNA methylation alterations in early lesions, as well as
somatic mutation discovery and copy number alterations. Larger numbers of more advanced lesions will be
analyzed for recurrent DNA methylation abnormalities using a custom mouse DNA methylation Infinium array
that we have designed in collaboration with Illumina. Specific Aim 3 will be to identify early candidate driver
events that cooperate with Loss of Apc using human DNA methylation, mutation, copy ...

## Key facts

- **NIH application ID:** 9848515
- **Project number:** 5R01CA212374-04
- **Recipient organization:** VAN ANDEL RESEARCH INSTITUTE
- **Principal Investigator:** PETER W LAIRD
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $434,625
- **Award type:** 5
- **Project period:** 2017-01-05 → 2021-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9848515

## Citation

> US National Institutes of Health, RePORTER application 9848515, Visualization and Epigenomic Characterization of Early Intestinal Tumorigenesis in Mice (5R01CA212374-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9848515. Licensed CC0.

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