TSC2-mutant uterine sarcomas with JAZF1-SUZ12 fusions demonstrate hybrid features of endometrial stromal sarcoma and PEComa and are responsive to mTOR inhibition Journal Article


Authors: Chiang, S.; Vasudevaraja, V.; Serrano, J.; Stewart, C. J. R.; Oliva, E.; Momeni-Boroujeni, A.; Jungbluth, A. A.; Da Cruz Paula, A.; da Silva, E. M.; Weigelt, B.; Park, K. J.; Soslow, R. A.; Murali, R.; Ellenson, L. H.; Benayed, R.; Ladanyi, M.; Abu-Rustum, N. R.; Dickson, M. A.; Cohen, S.; Aghajanian, C.; Hensley, M. L.; Lee, C. H.; Snuderl, M.; Konner, J. A.
Article Title: TSC2-mutant uterine sarcomas with JAZF1-SUZ12 fusions demonstrate hybrid features of endometrial stromal sarcoma and PEComa and are responsive to mTOR inhibition
Abstract: Uterine perivascular epithelioid cell tumor (PEComa) is a rare mesenchymal neoplasm that occasionally shares morphologic and immunohistochemical overlap with low- and high-grade endometrial stromal sarcoma (LGESS and HGESS). In this study, we sought to characterize the clinical, morphologic, genetic, and epigenetic features of five uterine sarcomas that display histologic features of LGESS, HGESS, and PEComa. All tumors demonstrated epithelioid cells often associated with a low-grade spindled component resembling LGESS, with both regions expressing CD10, ER, PR, variable HMB45, and Melan-A immunoreactivity, and strong cathepsin K and pS6 expression. Targeted massively parallel sequencing analysis revealed the presence of somatic TSC2 mutations in all five cases, of which four harbored concurrent or consecutive JAZF1-SUZ12 gene fusions. Unsupervised hierarchical clustering analysis of methylation profiles of TSC2-mutant uterine sarcomas (n = 4), LGESS (n = 10), and HGESS (n = 12) demonstrated two clusters consisting of (1) all LGESS and TSC2-mutant uterine sarcomas and (2) all HGESS. KEGG pathway analysis detected methylation differences in genes involved in PI3K/AKT, calcium, and Rap1 signaling. TSC2-mutant uterine sarcomas were responsive to hormone suppression, and mTOR inhibition demonstrated clinical benefit in four patients with these neoplasms. Our results suggest that these tumors represent histologically distinctive LGESS with TSC2 mutations. TSC2 mutations and JAZF1-SUZ12 fusion may help diagnose these tumors and possibly direct effective treatment.
Keywords: morphology; molecular analysis; sirolimus; jazf1; hybridization; landscape; epithelioid cell tumor; package; jazf1-jjaz1 gene fusion; neoplasm pecoma
Journal Title: Modern Pathology
Volume: 35
Issue: 1
ISSN: 0893-3952
Publisher: Nature Research  
Date Published: 2022-01-01
Start Page: 117
End Page: 127
Language: English
ACCESSION: WOS:000700898700001
DOI: 10.1038/s41379-021-00922-7
PROVIDER: wos
PUBMED: 34561551
Notes: Article -- Source: Wos
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MSK Authors
  1. Jason Konner
    123 Konner
  2. Marc Ladanyi
    1175 Ladanyi
  3. Kay Jung Park
    259 Park
  4. Martee L Hensley
    257 Hensley
  5. Robert Soslow
    754 Soslow
  6. Rajmohan Murali
    195 Murali
  7. Mark Andrew Dickson
    127 Dickson
  8. Achim Jungbluth
    421 Jungbluth
  9. Britta Weigelt
    444 Weigelt
  10. Rym Benayed
    160 Benayed
  11. Sarah   Chiang
    99 Chiang
  12. Seth Matthew Cohen
    5 Cohen