Alessandro Santin, MD, on defining molecular basis of endometrial stromal sarcoma

Researchers of a comprehensive genomic analysis published in Proceedings of the National Academy of Sciences investigated the molecular basis of endometrial stromal sarcoma (ESS), a rare uterine malignancy characterized by significant heterogeneity. Alessandro Santin, MD, Professor of Obstetrics, Gynecology, and Reproductive Sciences at Yale School of Medicine, explained that while both low-grade (LG) and high-grade (HG) ESS originate in the uterine stroma, their molecular fingerprints are a "completely different entity from a genetic point of view,” he said in the video above.

Grade-specific genetic landscapes

According to Santin, a primary surprise of the integrated analysis—which included whole-genome, whole-exome, and RNA sequencing of 80 tumors—was the lack of genetic overlap between grades. LG-ESS is typically a "relatively indolent" and hormone-sensitive entity defined by canonical fusions like JAZF1–SUZ12. Conversely, HG-ESS is an aggressive, "completely different entity" characterized by frequent mutations in tumor suppressors like PTEN and TP53, as well as focal RAD54B amplifications found in 18.8% of the study’s tumors.

“The initial idea was that there could be a progression, right, from the low grade to the high grade, and in reality, the genetic profile that we have seen in these 2 group of patients is completely different,” Santin said.

Hypermutation and immunotherapy potential

One of the most clinically significant findings involves the identification of a hypermutated subset within HG-ESS. The study found that approximately 7.5% of these tumors harbor mutations in the DNA polymerase epsilon (POLE) gene or mismatch repair (MMR) genes. These alterations impair the cell's proofreading and repair capabilities, leading to a high tumor mutational burden.

Santin emphasized that identifying these hypermutated cases is critical because they may be "exquisitely sensitive" to immune checkpoint inhibitors such as pembrolizumab or dostarlimab. “Even if it's 1 out of 10, 1 out of 15 that have this specific characteristic, they could really respond very well clinically,” Santin explained.

The research also highlighted the potential for combined MEK and FAK inhibition in NRAS-mutant HG-ESS, providing a preclinical rationale for precision therapies. Santin concluded that comprehensive sequencing is essential for all ESS patients to identify those who could achieve durable responses through these targeted and immunological strategies.

Reference:

Hartwich T, Choi S, Hwang A. Integrated mutational landscape analysis of endometrial stromal sarcoma, Proc. Natl. Acad. Sci. U.S.A. (2026). 123 (5) e2531105123. doi:/10.1073/pnas.2531105123