# Somatic MED12 Mutations in Myometrial Cells

## TL;DR

This study finds that non-cancerous myometrial cells often have MED12 mutations, suggesting these mutations may start early and contribute to uterine tumor development.

## Contribution

The study is the first to show non-random accumulation of MED12 mutations in non-neoplastic myometrial cells using duplex deep sequencing.

## Key findings

- Myometrial cells show high frequency of MED12 exon 2 mutations, especially at c.130-131.
- Baseline mutations in other MED12 regions and TP53 hotspot are low in myometrial cells.
- Early somatic MED12 mutations in myometrial cells may contribute to leiomyoma development.

## Abstract

Over 70% of leiomyoma (LM) harbor MED12 mutations, primarily in exon 2 at c.130-131 (GG). Myometrial cells are the cell origin of leiomyoma, but the MED12 mutation status in non-neoplastic myometrial cells is unknown. In this study, we investigated the mutation burden of MED12 in myometrium. As traditional Sanger or even NGS sequencing may not be able to detect MED12 mutations that are lower than 0.1% in the testing sample, we used duplex deep sequencing analysis (DDS) to overcome this limitation. Tumor-free myometria (confirmed by pathology evaluation) were dissected, and genomic DNA from MED12 exon 2 (test) and TP53 exon 5 (control) were captured by customer-designed probe sets, followed by DDS. Notably, DDS demonstrated that myometrial cells harbored a high frequency of mutations in MED12 exon 2 and predominantly in code c.130-131. In contrast, the baseline mutations in other coding sequences of MED12 exon 2 as well as in the TP53 mutation hotspot, c.477-488 were comparably low in myometrial cells. This is the first report demonstrating a non-random accumulation of MED12 mutations at c.130-131 sites in non-neoplastic myometrial cells which provide molecular evidence of early somatic mutation events in myometrial cells. This early mutation may contribute to the cell origin for uterine LM development in women of reproductive age.