# Uncovering the Role of Colorectal Stem Cells on Disease Penetrance in Lynch Syndrome

> **NIH NIH R01** · UNIVERSITY OF TX MD ANDERSON CAN CTR · 2020 · $324,218

## Abstract

PROJECT SUMMARY
Lynch syndrome is an autosomal dominant hereditary condition predisposing patients to develop mainly colo-
rectal cancer with an estimated life-time risk as high as 80%, which is secondary to germline alterations in the
DNA mismatch repair genes. However, it has an incomplete disease penetrance that varies widely depending
on the genotype, age and gender of the patients. Penetrance studies looking into epidemiological factors as well
as single gene-to-gene interactions within the metabolism of xenobiotics have failed to refine risk estimations in
Lynch Syndrome, thus leading to boiler plate recommendations for colorectal cancer screening. Exposure to
non-steroidal anti-inflammatory agents, in particular Aspirin, has been the only factor that has been able to modify
disease penetrance (60% risk reduction). Our long-term goal is to explain the differences observed in colorectal
penetrance in this patient population by understanding the molecular events driving colorectal carcinogenesis in
Lynch Syndrome, so we can implement precision screening and chemoprevention. The objective of this appli-
cation is to characterize the cellular and molecular changes induced by chemoprevention with non-steroidal anti-
inflammatory agents and Statins on colorectal stem cells that lead to reduction of colorectal cancer penetrance.
Our central hypothesis is that variation of colorectal cancer penetrance among Lynch Syndrome patients is sec-
ondary to molecular changes directly involving the colorectal stem cell niche of the normal at-risk mucosa. The
rationale supporting this proposal is based on our observations that (1) at-risk mucosa and polyps from Lynch
Syndrome patients show transcriptional differences in intestinal stem cell signatures compared to normal mucosa
of healthy controls; (2) chemoprevention with Simvastatin induces a profound modulation of colorectal cancer
penetrance in an intestinal-specific mouse model of Lynch Syndrome; (3) chemoprevention with Simvastatin and
Naproxen decreases intestinal stem cell markers and simultaneously increases differentiation markers in at-risk
mucosa of Lynch Syndrome animal models. We propose to pursue the following three specific aims: (1) to define
a signature of mismatch repair-deficient intestinal stem cells in vivo; (2) to assess the modulatory effect of
Simvastatin and Naproxen as chemopreventive interventions on mismatch repair-deficient colorectal stem cells
using patient-derived organoids and 3) to assess changes in stem cell and epithelial differentiation markers in
normal colorectal mucosa biopsies of LS patients exposed to Naproxen in a Phase I chemoprevention trial. The
innovation of this study lies in the use of chemopreventive agents as modifying tools of cancer penetrance to
assess the role of colorectal stem cells and their related molecular pathways in the variation of colorectal cancer
penetrance in Lynch Syndrome. This contribution will be significant because it will lead to the di...

## Key facts

- **NIH application ID:** 10017673
- **Project number:** 5R01CA219463-04
- **Recipient organization:** UNIVERSITY OF TX MD ANDERSON CAN CTR
- **Principal Investigator:** Eduardo Vilar Sanchez
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $324,218
- **Award type:** 5
- **Project period:** 2017-09-12 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10017673

## Citation

> US National Institutes of Health, RePORTER application 10017673, Uncovering the Role of Colorectal Stem Cells on Disease Penetrance in Lynch Syndrome (5R01CA219463-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10017673. Licensed CC0.

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