# Molecular Mechanisms Underlying Environmental Effects that Influence Penetrance in Lynch Syndrome-Associated Endometrial Cancer

> **NIH NIH R01** · UNIVERSITY OF TX MD ANDERSON CAN CTR · 2021 · $256,000

## Abstract

Abstract
 Lynch syndrome is an inherited cancer susceptibility syndrome caused by mutation in one of several
DNA mismatch repair (MMR) genes, including MSH2, MSH6, MLH1, PMS2, and EPCAM. Women with Lynch
syndrome are at high risk for endometrial (uterine) cancer, colon cancer, as well as other tumor types. While
there has been significant progress in the understanding of Lynch syndrome associated colon cancer in terms
of molecular pathogenesis and risk, Lynch syndrome associated endometrial cancer is less well understood.
The lifetime risk of endometrial cancer in women with Lynch syndrome has been estimated near 54%, and may
equal or exceed the risk of colorectal cancer. MSH2 is one of the most commonly mutated MMR genes (50-
66%) in Lynch syndrome associated endometrial cancer.
 In addressing provocative question #2, we will evaluate mechanisms underlying how endometrial
cancer penetrance associated with loss of MSH2 is influenced by patient natural history (exposure to natural or
synthetic hormones) and obesity. We have developed a novel, uterine-targeted, MSH2 knockout mouse model
of Lynch syndrome that closely mimics the progression to endometrial cancer observed in women. This model
enables us to probe molecular mechanisms underlying how these environmental factors change the risk of
endometrial cancer in women with Lynch syndrome.
 Obesity and exposure to estrogen are associated with increased sporadic (not inherited) endometrial
cancer risk and are known to alter endometrial cell growth, growth factor signaling, as well as the immune
response and inflammation. We hypothesize that in the absence of MSH2, behaviors/factors that amplify these
changes in the endometrium will increase the likelihood of acquiring oncogenic mutations. Conversely, we
expect that environmental factors or behaviors that decrease endometrial cell growth and normalize growth
factor signaling and immune response (by lowering exposure to detrimental hormones or by maintaining a lean
weight and low insulin), will reduce the overall incidence and accumulation of oncogenic mutations, and
decrease the penetrance of disease in women with Lynch syndrome.
 We will evaluate the molecular changes that occur in the endometrium of normal mice and MSH2
knockout mice in response to hormone exposure and obesity using state-of-the-art tools for molecular profiling.
We expect to identify a subset of genes that are targets for mutation in the absence of MSH2, which contribute
to the development of endometrial cancer in Lynch Syndrome. We will further examine how changes in the
local immune response is altered due to the loss of MSH2 and how this is impacted by hormones and obesity.
These findings will be critical to developing effective prevention strategies (both behavioral and
pharmaceutical), which can delay or prevent endometrial cancer in these women.

## Key facts

- **NIH application ID:** 10107784
- **Project number:** 5R01CA216103-05
- **Recipient organization:** UNIVERSITY OF TX MD ANDERSON CAN CTR
- **Principal Investigator:** Melinda S. Yates
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $256,000
- **Award type:** 5
- **Project period:** 2017-04-05 → 2024-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10107784

## Citation

> US National Institutes of Health, RePORTER application 10107784, Molecular Mechanisms Underlying Environmental Effects that Influence Penetrance in Lynch Syndrome-Associated Endometrial Cancer (5R01CA216103-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10107784. Licensed CC0.

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