The Endometrial Exome

In endometriosis, endometrial tissue grows outside of the uterus. More than half of those affected experience chronic pain, but the amount and location have little correspondence to the stage of disease. Staging is complex, and requires a survey of the lesions present. One international team of researchers decided to take a different approach, by sequencing the exomes of 24 women with benign endometriosis, with the eventual aim of developing a system for classifying endometriosis with a genetic basis. We asked Ie-Ming Shih, co-author of the associated paper (1) and Professor of Gynecology and Obstetrics at Johns Hopkins Medicine, about the implications of the findings.

What motivated this study?

Endometriosis is a highly intriguing lesion in terms of its originality and clonality, as well as its cancer-like behavior. Although it has been almost 90 years since the lesion was first described, very little is known about the etiology and molecular pathogenesis of this common condition. Interestingly, its molecular landscape has not been elucidated in the post-genomic era, even though the genomes in most human tumor types and lesions have been thoroughly sequenced. As a gynecologic pathologist and a cancer researcher, I think the time has come to apply cancer research tools to study benign diseases like endometriosis. We’ve also been inspired by our institution’s own history – John Sampson, a former student and resident, and Richard TeLinde, the founding Chair of the Department of Gynecology at the Johns Hopkins University, were pioneers in the study of endometriosis. We hope to continue this Hopkins legacy.

How do the mutations you found change our understanding of endometriosis?

The presence of somatic mutations, including driver mutations that are common in endometriosis-related neoplasms, such as ovarian clear cell and ovarian endometrioid carcinomas, really surprised us. At the moment, we don’t know whether normal endometrium in the uterus from endometriosis patients harbors any somatic mutations, and whether the mutations found in endometriosis are also present in the corresponding uterus.

In cancer, driver mutations are sufficient or even essential for tumor growth and progression – invasion, metastasis and acquisition of drug resistance, and so on. But those mutations in normal-appearing epithelium in an endometriotic lesion are puzzling. One can speculate that mutations such as KRAS and ARID1A may contribute to the survival of ectopic endometrial tissue outside the uterus. These mutations can also equip endometriosis with the invasive capacity to deeply infiltrate into peritoneal tissues (the tissues covering the organs in the abdominal cavity) and the bowel wall. But the main challenge is to develop an endometriosis animal model to start addressing these possibilities by manipulating specific gene mutations and expression in endometrial tissues.

Do you see potential in forecasting endometriosis patient outcomes?

This is what we are hoping for. The current classification and staging of endometriosis, although clinically useful to some extent, does not provide a correlation with clinical presentation or a prediction of disease behavior. Our next study will aim to answer this question.

We are going to study large cohorts to determine whether there is any association between certain mutation patterns and clinical presentation and outcome. With the advances in molecular pathology, we are in a good position to perform molecular tests for endometriosis if we are able to demonstrate a positive correlation.