# Role of cancer-associated mutations in endometriosis

> **NIH NIH R01** · JOHNS HOPKINS UNIVERSITY · 2020 · $698,200

## Abstract

Millions of women in the US suffer from endometriosis, a poorly understood disease characterized
by the presence of lesions composed of endometrial glands and stroma located outside the
uterus. For women with deeply invasive endometriosis that does not respond to hormonal therapy,
surgical removal can be as extensive as cancer surgery, requiring segmental bowel excision and
extirpative resection of pelvic tissues. Progesterone-based therapy has become the mainstay in
treating endometriosis, but progesterone-resistance occurs in 40% of patients. Currently, the
molecular mechanisms underlying the disease phenotypes remain unclear and diagnostic and
predictive markers are urgently needed. There is a growing body of evidence that genetic
contributions play a pivotal role in the development of endometriosis and may explain the different
types and severity of endometriosis. Importantly, our preliminary studies of endometriotic lesions
showed that 26% of lesions harbored somatic, cancer-associated mutations (acquired mutations
in rogue cells) in genes known as “drivers” of cancer. Notably, the lesions containing the “driver”
mutations were associated with deeply invasive endometriosis, a particularly painful and disabling
form of endometriosis. These exciting results suggest a new research direction to understand the
pathogenesis of endometriosis; specifically, a biologically informed, molecular disease
classification to improve diagnosis and management. What is now needed is a comprehensive
catalogue of somatic variants of endometriosis lesions and correlation of molecular alterations
with disease phenotypes. Based on these results, we propose to establish a molecular
classification of endometriosis correlated with the clinical phenotype of disease. This study
includes key investigators with unique and complementary expertise including reproductive
biology, molecular genetics and genomics, pathology, and bioinformatics. First, we will use laser
capture microdissection to study 300 existing endometriosis specimens for changes in these
cancer-associated genes. Then, we will validate the findings in a prospective study of 100 women
with endometriosis, and 35 control subjects. Finally, we will rigorously test how these cancer-
driver mutations promote lesion development in endometriosis using three experimental models
used in endometriosis research. The expected results will enhance our understanding of the
pathophysiology of endometriosis and the mechanism of progesterone-resistance. The studies
will establish a biologically informed molecular classification of endometriosis and represent the
first step toward personalized medical treatment of endometriosis.

## Key facts

- **NIH application ID:** 9979935
- **Project number:** 5R01HD096147-02
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** IE-MING SHIH
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $698,200
- **Award type:** 5
- **Project period:** 2019-07-17 → 2024-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9979935

## Citation

> US National Institutes of Health, RePORTER application 9979935, Role of cancer-associated mutations in endometriosis (5R01HD096147-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9979935. Licensed CC0.

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