title: Molecular Pathology and Novel Clinical Therapy for Uterine Leiomyosarcoma.
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)/β1i-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/β1i expression, that is up-regulated by interferon-γ (IFNγ), in human uterine LMS tissues. Here, we reviewed human uterine LMS for genetic mutations in the IFNγ signal cascade, and found serious mutations in three genes, Janus activated kinase 1 (JAK1), signal transducer and activator of transcription 1 (STAT1) and PSMB9/β1i promoter regions. Moreover, molecular experiments demonstrated differential expression of cyclin E and P27/KIP1, that regulate cell-cycle G1arrest via PSMB9/β1i expression. The discovery of this mutational activation of a key cell-signalling pathway may provide new targets for diagnostic approaches and therapeutic intervention.
authors: Department of Obstetrics and Gynecology, Shinshu University School of Medicine, Nagano, Japan takumah@shinshu-u.ac.jp.|Department of Medical Technology, International University of Health and Welfare, Chiba, Japan.
authors: Takuma
authors: T
authors: Hayashi
authors: Department of Medical Technology, International University of Health and Welfare, Chiba, Japan.|Department of Health Science, Kyushu University Graduate School of Medicine, Fukuoka, Japan.
authors: Miki
authors: M
authors: Kawano
authors: Department of Obstetrics and Gynecology, Osaka City University Graduate School of Medicine, Osaka, Japan.
authors: Tomoyuki
authors: T
authors: Ichimura
authors: Department of Obstetrics and Gynecology, Shinshu University School of Medicine, Nagano, Japan.
authors: Koichi
authors: K
authors: Ida
authors: Department of Obstetrics and Gynecology, Shinshu University School of Medicine, Nagano, Japan.
authors: Hirofumi
authors: H
authors: Ando
authors: SIGMA-Aldrich Israel, Rehovot, Israel.
authors: Dorit
authors: D
authors: Zharhary
authors: Pathology Division, Keio University School of Medicine, Tokyo, Japan.
authors: Yae
authors: Y
authors: Kanai
authors: The Cancer System Laboratory, Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo, Japan.
authors: Hiroyuki
authors: H
authors: Aburatani
authors: Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, U.S.A.
authors: Susumu
authors: S
authors: Tonegawa
authors: Department of Obstetrics and Gynecology, Shinshu University School of Medicine, Nagano, Japan.
authors: Tanri
authors: T
authors: Shiozawa
authors: Department of Obstetrics and Gynecology, Tohoku University Graduate School of Medicine, Miyagi, Japan.
authors: Nobuo
authors: N
authors: Yaegashi
authors: National Hospital Organization Kyoto Medical Centre, Kyoto, Japan.
authors: Ikuo
authors: I
authors: Konishi
mesh_terms: D000818:Animals; D003546:Cysteine Endopeptidases / Q000235:genetics; D005260:Female; D006801:Humans; D007371:Interferon-gamma / Q000235:genetics; D007890:Leiomyosarcoma / Q000235:genetics* / Q000628:therapy; D009154:Mutation; D014594:Uterine Neoplasms / Q000235:genetics* / Q000628:therapy
chemical_list: C071313:LMP-2 protein; D007371:Interferon-gamma; D003546:Cysteine Endopeptidases
keywords: IFNγ; PSMB9/β1i; Uterine leiomyosarcoma; cyclin E; review