Molecular Landscape of Endometrial Stromal Tumors
PURPOSE
The molecular heterogeneity of endometrial stromal tumors (ESTs) is demonstrated by the presence of the same fusion gene in distinct pathologic entities, such as endometrial nodules and low-grade endometrial stromal sarcoma, both exhibiting the
JAZ1::SUZ12
chimeric transcript. Given the limited knowledge on these tumors, which is based on a small number of cases studied with a restricted range of techniques, we analyzed 47 ESTs to explore their methylation and transcriptomic landscapes.
MATERIALS AND METHODS
Tumor methylation and transcriptomes profiles were investigated.
RESULTS
The methylation profile showed distinct clusters, which correlated with established histopathologic and molecular subtypes. The highest methylation value was reported for nuclear factor of activated T cytoplasmic 1, and the lowest was detected for miR34C. Two different 5'—C—phosphate—G—3' (CpG) sites of
LMX1B
(
LMX1B-cg04996334
and
LMX1B
), along with
miR34C
, showed the same methylation pattern in both low-grade and high-grade endometrial stromal sarcoma (HG-ESS). Similarly,
CFAP45
,
HDAC4
,
ACY3
,
MOB3A
, and
XXYLT1
showed identical methylation patterns in HG-ESS and undifferentiated uterine sarcomas, highlighting the similarities between these tumors within the EST spectrum. We identified 13 novel fusion transcripts involving several genes that are active in transcriptional regulation.
CONCLUSION
In ESTs, the genes involved in chromosomal rearrangements function as transcription regulators, either directly through the formation of zinc finger motifs or indirectly through epigenetic regulation. The methylation signature is different for distinct subgroups of the EST spectrum, with more aggressive tumors, HG-ESS, and undifferentiated uterine sarcoma, clustering together. Some genes showed similar methylation levels in different entities, highlighting the presence of a continuum in the tumor profile. Methylation levels of CpG sites at specific gene loci may serve as valuable biomarkers for these tumors.
