Molecular pathology and novel clinical therapy for uterine leiomyosarcoma

Takuma Hayashi, Miki Kawano, Tomoyuki Ichimura, Koichi Ida, Hirofumi Ando, Dorit Zharhary, Yae Kanai, Hiroyuki Aburatani, Susumu Tonegawa, Tanri Shiozawa, Nobuo Yaegashi, Ikuo Konishi

Research output: Contribution to journalReview article

2 Citations (Scopus)

Abstract

Patients with uterine leiomyosarcoma (LMS) typically present with vaginal bleeding, pain, and a pelvic mass, with atypical presentations of hypercalcemia and eosinophilia also being reported. Radiographic evaluation with combined positron-emission tomography/computed tomography may assist in diagnosis and surveillance in women with uterine LMS; these are commonly used with stage and tumour grade as prognostic indicators and a recently developed risk-assessment index to predict disease-specific survival. Recent studies have shown that the addition of adjuvant therapy after surgical management does not seem to improve survival, and ovarian preservation does not appear to negatively impact outcome. Experimentally, it is noteworthy that proteasome subunit beta 9 (PSMB9)/1i-deficient mice exhibit spontaneous development of uterine LMS, with a disease prevalence of ~37% by 12 months of age. Furthermore, a recent report showed the loss of ability to induce PSMB9/1i expression, that is up-regulated by interferon-(IFN), in human uterine LMS tissues. Here, we reviewed human uterine LMS for genetic mutations in the IFN signal cascade, and found serious mutations in three genes, Janus activated kinase 1 (JAK1), signal transducer and activator of transcription 1 (STAT1) and PSMB9/1i promoter regions. Moreover, molecular experiments demonstrated differential expression of cyclin E and P27/KIP1, that regulate cell-cycle G1 arrest via PSMB9/1i expression. The discovery of this mutational activation of a key cell-signalling pathway may provide new targets for diagnostic approaches and therapeutic intervention.

Original languageEnglish
Pages (from-to)4997-5007
Number of pages11
JournalAnticancer research
Volume36
Issue number10
DOIs
Publication statusPublished - 2016 Oct

Keywords

  • Cyclin E
  • IFN
  • PSMB9/1i
  • Review
  • Uterine leiomyosarcoma

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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  • Cite this

    Hayashi, T., Kawano, M., Ichimura, T., Ida, K., Ando, H., Zharhary, D., Kanai, Y., Aburatani, H., Tonegawa, S., Shiozawa, T., Yaegashi, N., & Konishi, I. (2016). Molecular pathology and novel clinical therapy for uterine leiomyosarcoma. Anticancer research, 36(10), 4997-5007. https://doi.org/10.21873/anticanres.11068