Synapse - ESR1 hotspot mutations in endometrial stromal sarcoma with high-grade transformation and endocrine treatment

ESR1 hotspot mutations in endometrial stromal sarcoma with high-grade transformation and endocrine treatment Journal Article

Authors:	Dessources, K.; Miller, K. M.; Kertowidjojo, E.; Da Cruz Paula, A.; Zou, Y.; Selenica, P.; da Silva, E. M.; Benayed, R.; Ashley, C. W.; Abu-Rustum, N. R.; Dogan, S.; Soslow, R. A.; Hensley, M. L.; Weigelt, B.; Chiang, S.
Article Title:	ESR1 hotspot mutations in endometrial stromal sarcoma with high-grade transformation and endocrine treatment
Abstract:	High-grade endometrial stromal sarcomas (HGESSs) are more aggressive and have higher rates of resistance to endocrine therapy than low-grade endometrial stromal sarcomas (LGESSs). The pathogenesis of hormonal resistance in these lesions has yet to be defined. Here we sought to histologically and genetically characterize 3 LGESSs and their recurrences that underwent histologic high-grade transformation following endocrine therapy. For this, DNA from primary tumors and select subsequent recurrences were subject to massively parallel sequencing targeting 468 cancer-related genes. Somatic mutation analyses were performed using validated bioinformatics methods. In addition, RNA from each case was evaluated for the presence of gene fusions using targeted RNA-sequencing. All patients initially presented with LGESS, developed HGESS recurrences, and received at least 2 lines of hormonal suppressive therapy. Gene fusions classically described as associated with LGESS were identified in all 3 cases, including JAZF1-PHF1, EPC1-PHF1 and JAZF1-SUZ12 fusions for Cases 1, 2 and 3, respectively. Targeted sequencing analysis revealed that none of the primary LGESS, however the HGESS recurrences of Cases 1 and 3, and the LGESS and HGESS recurrences of Case 2 post endocrine treatment harbored ESR1 p.Y537S hotspot mutations. These ESR1 ligand-binding domain mutations have been found as a mechanism of acquired endocrine resistance in breast cancer. Also, a reduction in estrogen receptor (ER) expression was observed in recurrences. Our findings suggest that the ESR1 p.Y537S hotspot mutation in LGESS with histologic high-grade transformation may be associated with endocrine resistance in these lesions. Furthermore, our data suggest that genetic analyses may be performed in recurrent LGESS following hormonal therapy, development of high-grade morphology, and/or altered/diminished ER expression. © 2021, The Author(s), under exclusive licence to United States & Canadian Academy of Pathology.
Keywords:	adult; clinical article; controlled study; human tissue; middle aged; primary tumor; gene mutation; single nucleotide polymorphism; somatic mutation; frameshift mutation; genetics; mutation; splenectomy; case report; gemcitabine; endometrial neoplasms; metabolism; recurrence; pathology; histology; docetaxel; rna; tumor recurrence; gene fusion; recurrent disease; mitosis rate; hormonal therapy; letrozole; heterozygosity loss; abdominal mass; anastrozole; cyclin d1; bioinformatics; endometrium tumor; disease exacerbation; pathologist; genomic dna; small intestine obstruction; small intestine resection; fulvestrant; megestrol acetate; microdissection; mitosis index; retroperitoneal disease; endometrium sarcoma; estrogen receptor alpha; indel mutation; sarcoma, endometrial stromal; sanger sequencing; humans; human; female; article; rna sequencing; swi/snf related matrix associated actin dependent regulator of chromatin subfamily b member 1; high-grade endometrial stromal sarcoma; low-grade endometrial stromal sarcoma; tumor-related gene; treatment switching
Journal Title:	Modern Pathology
Volume:	35
Issue:	7
ISSN:	0893-3952
Publisher:	Nature Research
Date Published:	2022-07-01
Start Page:	972
End Page:	978
Language:	English
DOI:	10.1038/s41379-021-01003-5
PUBMED:	34961764
PROVIDER:	scopus
PMCID:	PMC9234101
DOI/URL:	https://www.scopus.com/inward/record.uri?eid=2-s2.0-85121677225&doi=10.1038%2fs41379-021-01003-5&partnerID=40&md5=7db5f6650bb5cd85553abcf597cbfbd0
Notes:	Article -- Export Date: 1 August 2022 -- Source: Scopus