# GREB1 ‐rearranged uterine tumour shares a common DNA methylation signature with ESR1 ‐rearranged UTROSCT

## TL;DR

This study finds that GREB1-rearranged uterine tumors and UTROSCTs share similar DNA methylation patterns, suggesting they are closely related despite differences in appearance and genomic complexity.

## Contribution

The study demonstrates a shared DNA methylation signature between GREB1-rearranged uterine tumors and ESR1-rearranged UTROSCTs, supporting their classification within the same tumor spectrum.

## Key findings

- GREB1-rearranged uterine tumors and UTROSCTs form a distinct DNA methylation cluster separate from other uterine tumors.
- GREB1-rearranged tumors show more genomic complexity and fewer sex cord-like features compared to UTROSCTs.
- The epigenetic similarity supports the inclusion of GREB1-rearranged tumors in the UTROSCT spectrum despite morphological differences.

## Abstract

GREB1‐rearranged uterine tumours encompass a group of uterine mesenchymal tumours with varied histologic appearances. The fusion partners to GREB1 include NCOA1‐3, SS18 and NR4A3. Given that some GREB1‐rearranged uterine tumours exhibit histologic features of uterine tumours resembling ovarian sex cord tumour (UTROSCT), there is a general belief that GREB1‐rearranged uterine mesenchymal tumours are part of the UTROSCT family.

In this study, we applied global DNA methylation and copy number analyses to a series of 10 GREB1‐rearranged uterine tumours and 21 classic UTROSCTs (7 of which were molecularly confirmed to harbour ESR1::NCOA2/3 fusions).

We found that GREB1‐rearranged uterine tumors show an overlap in their global methylation profiles with UTROSCT, including ESR1::NCOA2/3 positive cases. Together, these tumours form a DNA methylation cluster separate from uterine smooth muscle tumours (leiomyomas and leiomyosarcomas), endometrial stromal sarcomas (low‐grade and high‐grade), embryonal rhabdomyosarcoma and SMARCA4‐deficient uterine sarcomas. However, despite their epigenetic similarity, there were two notable differences. First, GREB1‐rearranged uterine tumours as a group displayed a greater degree of genomic complexity with more extensive copy number alterations than conventional UTROSCTs, including those harbouring ESR1::NCOA2/3. Second, GREB1‐rearranged uterine tumours frequently lacked overt sex cord morphology: while all 7 ESR1::NCOA2/3 UTROSCTs demonstrated corded, nested, trabecular and/or tubular/sertoliform patterns, only 1 GREB1‐rearranged uterine tumour displayed a prominent trabecular pattern, with the remaining cases showing exclusively or predominantly diffuse/solid growth.

Overall, our findings confirm that GREB1‐rearranged uterine tumours are part of the UTROSCT spectrum, though they frequently exhibit a more diffuse growth pattern and a higher degree of genomic instability.

GREB1‐rearranged uterine tumours share DNA methylation profiles with UTROSCTs, supporting a close relationship. Despite differences in morphology and genomic complexity, their epigenetic similarity supports the inclusion of these tumours within the UTROSCT spectrum.