Relationships between highly recurrent tumor suppressor alterations in 489 leiomyosarcomas

Cancer. 2021 Aug 1;127(15):2666-2673. doi: 10.1002/cncr.33542. Epub 2021 Mar 31.


Background: Leiomyosarcoma (LMS) is the most common soft tissue and uterine sarcoma, but no standard therapy is available for recurrent or metastatic LMS. TP53, p16/RB1, and PI3K/mTOR pathway dysregulations are recurrent events, and some LMS express estrogen receptor (ER) and/or progesterone receptor (PR). To characterize relationships between these pathway perturbations, the authors evaluated protein expression in soft tissue and uterine nonprimary leiomyosarcoma (np-LMS), including local recurrences and distant metastases.

Methods: TP53, RB1, p16, and PTEN expression aberrations were determined by immunohistochemistry (IHC) in tissue microarrays (TMAs) from 227 np-LMS and a comparison group of 262 primary leiomyosarcomas (p-LMS). Thirty-five of the np-LMS had a matched p-LMS specimen in the TMAs. Correlative studies included differentiation scoring, ER and PR IHC, and CDKN2A/p16 fluorescence in situ hybridization.

Results: Dysregulation of TP53, p16/RB1, and PTEN was demonstrated in 90%, 95%, and 41% of np-LMS, respectively. PTEN inactivation was more common in soft tissue np-LMS than uterine np-LMS (55% vs 31%; P = .0005). Moderate-strong ER expression was more common in uterine np-LMS than soft tissue np-LMS (50% vs 7%; P < .0001). Co-inactivation of TP53 and RB1 was found in 81% of np-LMS and was common in both soft tissue and uterine np-LMS (90% and 74%, respectively). RB1, p16, and PTEN aberrations were nearly always conserved in p-LMS and np-LMS from the same patients.

Conclusions: These studies show that nearly all np-LMS have TP53 and/or RB1 aberrations. Therefore, therapies targeting cell cycle and DNA damage checkpoint vulnerabilities should be prioritized for evaluations in LMS.

Keywords: DNA damage repair; biomarker; cell cycle; immunohistochemistry; leiomyosarcoma (LMS); soft tissue; uterine; uterus.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Female
  • Genes, p16
  • Genes, p53*
  • Humans
  • Immunohistochemistry
  • In Situ Hybridization, Fluorescence
  • Leiomyosarcoma* / genetics
  • Leiomyosarcoma* / pathology
  • PTEN Phosphohydrolase / genetics
  • Receptors, Estrogen / genetics
  • Receptors, Estrogen / metabolism
  • Retinoblastoma Binding Proteins / genetics*
  • Ubiquitin-Protein Ligases / genetics*
  • Uterine Neoplasms* / genetics
  • Uterine Neoplasms* / pathology


  • RB1 protein, human
  • Receptors, Estrogen
  • Retinoblastoma Binding Proteins
  • Ubiquitin-Protein Ligases
  • PTEN Phosphohydrolase
  • PTEN protein, human