# Conservation and functional-characterization of tumor methylation sites

> **NIH NIH R21** · UNIVERSITY OF SOUTHERN CALIFORNIA · 2020 · $179,438

## Abstract

We aim to develop statistical methods and software for analysis of DNA methylation data from human colorectal
cancer samples [CRCs] and matched normal tissue. We hypothesize that because epigenetics determines
mammalian cell phenotypes, it will be possible to reconstruct the phenotype of the tumor and its founder cell by
comparing epigenomes sampled from opposite sides of the same CRC. Therefore, we will rank genes or cell
pathways according to the degree of conservation of methylation status they exhibit, indicating which are likely
to be most important during tumor growth.
 We propose three innovations to accomplish these goals. First, we exploit a new Illumina microarray
which can measure methylation at ~850,000 CpG sites, allowing broad coverage of most human genes and
enhancers. We will develop methods to enable us to conduct an analysis of such data. We will demonstrate this
using a test dataset in which we have collected multi-regional sampling data (i.e., data in which we sample from
a number of different parts of the same tumor) for 26 human colorectal tumors, along with paired samples of
normal tissue for 6 of those patients and 9 other colons. Second, we propose a two-pronged attack designed to
assess whether each CpG site should be classified as ‘stable’ or ‘unstable’ with respect to the degree of CpG
variation permitted there. In Aim 1 we propose methods that are purely statistical in nature; In Aim 2 we propose
methods that will be built upon an explicit mathematical model for tumor evolution. We will compare and contrast
their results. An additional advantage of the second approach is that it will also allow us to reconstruct the
epigenome of the founder cell.
 Third, we will assess conservation of variation within genes or pathways to assess which are most
important during growth---pathways with smaller methylation differences between tumor sides are likely to be
more important and under selective pressures.
 The significance of the proposed studies is that we will develop new methods to extract epigenetic
information from multi-regional tumor sampling. Such data are rare at the moment, but will soon be routinely
collected. For that reason, in our fourth aim we propose to produce and freely distributed software and Shiny
applications.
 Our long-term goal is to facilitate more personalized and effective therapies that specifically target
pathways or genes most important to the growth of individual CRCs. The development of methods and software
to characterize variation in methylation patterns from multi-regional tumor sampling, and relate that to
genes/pathways will facilitate this process, and the relative ease of obtaining epigenetic information using
methylation arrays should allow widespread translation to other tumor types.

## Key facts

- **NIH application ID:** 9883761
- **Project number:** 5R21CA226106-02
- **Recipient organization:** UNIVERSITY OF SOUTHERN CALIFORNIA
- **Principal Investigator:** Paul Marjoram
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $179,438
- **Award type:** 5
- **Project period:** 2019-03-01 → 2022-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9883761

## Citation

> US National Institutes of Health, RePORTER application 9883761, Conservation and functional-characterization of tumor methylation sites (5R21CA226106-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9883761. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*