Integrated mutational landscape analysis of endometrial stromal sarcoma
Abstract
Endometrial stromal sarcoma (ESS) is a rare uterine malignancy with limited treatment options. We performed integrated whole-genome, whole-exome, and transcriptome sequencing on 80 ESS tumors, comprising 32 low-grade (LG) and 48 high-grade (HG) tumors, to characterize their genetic landscape. The overall mutation burden was modest, with no significant difference between grades; however, we identified six hypermutated cases (7.5%) harboring POLE or mismatch repair mutations, genomic features predictive of immunotherapy response. We identified focal RAD54B amplifications in 15 tumors (18.8%), leading to elevated RAD54B expression and significantly shorter survival. This establishes RAD54B as an oncogenic driver in ESS. Known tumor suppressors (PTEN, TP53) were frequently mutated in HG-ESS but rare in LG-ESS, highlighting distinct grade-specific drivers of malignancy. HG-ESS exhibited widespread chromosomal gains, frequent loss of cell-cycle regulators (RB1, CDKN2A), and numerous private gene fusions arising from complex DNA rearrangements. In contrast, LG-ESS were defined by canonical fusions (e.g., JAZF1–SUZ12 ) and co-occurring deletions in metabolic regulator genes (TSC2, STK11). Finally, in an activating NRAS-mutant (p.Q61R) HG-ESS xenograft, the combination of MEK and FAK inhibition dramatically suppressed tumor growth and prolonged survival, highlighting a promising targeted treatment strategy. Overall, our comprehensive analysis defines the molecular basis of ESS and provides a strong preclinical rationale for precision therapies in this aggressive cancer.
Article Details
Journal Info
Proceedings of the National Academy of Sciences
National Academy of Sciences
Authors (39)
Tobias M. P. Hartwich
Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine
Seungji Choi
Department of Biomedical Sciences, Korea University College of Medicine
Ayoung Hwang
Department of Biomedical Sciences, Korea University College of Medicine
Stefania Bellone
Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine
Luca Palmieri
Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine
Hae Seo
Department of Biomedical Sciences, Korea University College of Medicine
Taekeun Kim
Department of Biomedical Sciences, Korea University College of Medicine
Juhyeon Hong
Department of Biomedical Sciences, Korea University College of Medicine
Camilla Krakstad
Centre for Cancer Biomarkers, Department of Clinical Science, University of Bergen
Jone Trovik
Centre for Cancer Biomarkers, Department of Clinical Science, University of Bergen
Ingunn M. Stefansson
Centre for Cancer Biomarkers, Department of Clinical Science, University of Bergen
Hans Kristian Haugland
Department of Pathology, Haukeland University Hospital
Michelle Greenman
Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine
Victoria Ettorre
Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine
Sarah Ottum
Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine
Cem Demirkiran
Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine
Yang Yang-Hartwich
Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine
Natalia Buza
Department of Pathology, Yale University School of Medicine
Pei Hui
Department of Pathology, Yale University School of Medicine
Salvatore Lopez
Unit of Gynecologic Oncology, Istituto di Ricovero e Cura a Carattere Scientifico Istituto Tumori “Giovanni Paolo II”
Gennaro Cormio
Unit of Gynecologic Oncology, Istituto di Ricovero e Cura a Carattere Scientifico Istituto Tumori “Giovanni Paolo II”
Mariantonietta Ramunno
Unit of Pathology, Istituto di Ricovero e Cura a Carattere Scientifico Istituto Tumori “Giovanni Paolo II”
Alfredo Zito
Unit of Pathology, Istituto di Ricovero e Cura a Carattere Scientifico Istituto Tumori “Giovanni Paolo II”
Emanuele Perrone
Unit of Gynecologic Oncology, Department Woman and Child Health Sciences and Public Health, Fondazione Policlinico Universitario A. Gemelli Istituto di Ricovero e Cura a Carattere Scientifico
Anna Fagotti
Unit of Gynecologic Oncology, Department Woman and Child Health Sciences and Public Health, Fondazione Policlinico Universitario A. Gemelli Istituto di Ricovero e Cura a Carattere Scientifico
Francesco Fanfani
Unit of Gynecologic Oncology, Department Woman and Child Health Sciences and Public Health, Fondazione Policlinico Universitario A. Gemelli Istituto di Ricovero e Cura a Carattere Scientifico
Angela Santoro
Pathology Unit, Department of Woman and Child’s Health and Public Health Sciences, Fondazione Policlinico Universitario Agostino Gemelli Istituto di Ricovero e Cura a Carattere Scientifico
Antonella Ravaggi
Division of Obstetrics and Gynecology, Azienda Socio Sanitaria Territoriale Spedali Civili di Brescia
Eliana Bignotti
Division of Obstetrics and Gynecology, Azienda Socio Sanitaria Territoriale Spedali Civili di Brescia
Franco Odicino
Division of Obstetrics and Gynecology, Azienda Socio Sanitaria Territoriale Spedali Civili di Brescia
Laura Ardighieri
Unit of Pathology, Azienda Socio Sanitaria Territoriale Spedali Civili di Brescia
Elena Ratner
Roberto Angioli
Department of Gynecology, Fondazione Policlinico Universitario Campus Bio-Medico
Giuseppe Perrone
Operative Research Unit of Anatomical Pathology, Fondazione Policlinico Universitario Campus Bio-Medico
Daniela Luvero
Department of Gynecology, Fondazione Policlinico Universitario Campus Bio-Medico
Beatrice Conca
Department of Obstetrics and Gynecology, Fondazione Policlinico Universitario Campus Bio-Medico
Jungmin Choi
Department of Genetics, Yale School of Medicine
Joseph Schlessinger
Alessandro D. Santin
Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine