Details of Disease

General Information of Disease (ID: DIS6COXM)

• Disease Name: Leiomyosarcoma
• Synonyms: leiomyosarcoma; leiomyosarcoma (excluding uterine leiomyosarcoma); Leiomyosarcomas; leiomyosarcoma, malignant; leiomyosarcoma - not uterine
• Disease Class: 2B58: Leiomyosarcoma
• Definition: An uncommon, aggressive malignant smooth muscle neoplasm, usually occurring in post-menopausal women. It is characterized by a proliferation of neoplastic spindle cells. Morphologic variants include epithelioid, granular cell, inflammatory and myxoid leimyosarcomas.
• Disease Hierarchy:
  DISSN8XB: Soft tissue sarcoma
  DIS79FY5: Smooth muscle cancer
  DIS1JTDO: Epstein-Barr virus-associated mesenchymal tumor
  DIS6COXM: Leiomyosarcoma
• ICD Code: ICD-11: ICD-11: 2B58
• Disease Identifiers:
  MONDO ID: MONDO_0005058
  UMLS CUI: C0023269
  MedGen ID: 9711
  HPO ID: HP:0100243
  Orphanet ID: 64720
  SNOMED CT ID: 1163022006

Drug-Interaction Atlas (DIA) of This Disease

This Disease is Treated as An Indication in 3 Approved Drug(s)

Drug Name	Drug ID	Highest Status	Drug Type	REF
Docetaxel	DMDI269	Approved	Small molecular drug	[1]
Gemcitabine	DMSE3I7	Approved	Small molecular drug	[2]
Trabectedin	DMG3Y89	Approved	Small molecular drug	[3]

This Disease is Treated as An Indication in 2 Clinical Trial Drug(s)

Drug Name	Drug ID	Highest Status	Drug Type	REF
AL3818	DM3WP0N	Phase 3	NA	[4]
Unesbulin	DM4M2MO	Phase 2/3	Small molecule	[5]

Molecular Interaction Atlas (MIA) of This Disease

This Disease Is Related to 19 DTT Molecule(s)

Gene Name	DTT ID	Evidence Level	Mode of Inheritance	REF
AMHR2	TTZDCPK	Limited	Altered Expression	[6]
CDK8	TTBJR4L	Limited	Altered Expression	[7]
CR2	TT0HUN7	Limited	Biomarker	[8]
DFFA	TTYVQ9C	Limited	Altered Expression	[9]
DFFB	TT2SRE0	Limited	Biomarker	[10]
DMD	TTWLFXU	Limited	Biomarker	[11]
DPEP1	TTYUENF	Limited	Biomarker	[12]
MYLK2	TTHLGB2	Limited	Biomarker	[13]
RICTOR	TT143WL	Limited	Altered Expression	[14]
SLC29A1	TTLXAKE	Limited	Altered Expression	[15]
TYRO3	TTIEMFN	Limited	Biomarker	[16]
VIPR2	TT4O5P0	Limited	Altered Expression	[17]
CSF3	TT5TQ2W	moderate	Therapeutic	[18]
HHAT	TT1VNCG	moderate	Biomarker	[19]
NACC1	TT4AQ5F	moderate	Biomarker	[19]
PTEN	TTEUQ4M	Moderate	Autosomal recessive	[20]
CHEK2	TT9ABMF	Strong	CausalMutation	[21]
GADD45B	TTMDW9L	Strong	Altered Expression	[22]
HMGA1	TTBA219	Strong	Biomarker	[23]

This Disease Is Related to 1 DTP Molecule(s)

Gene Name	DTP ID	Evidence Level	Mode of Inheritance	REF
SLC25A11	DT0YAUQ	Limited	Biomarker	[24]

This Disease Is Related to 37 DOT Molecule(s)

Gene Name	DOT ID	Evidence Level	Mode of Inheritance	REF
ACSL4	OTI71MUJ	Limited	Altered Expression	[25]
ARL4C	OTQ3QNNU	Limited	Biomarker	[26]
CDO1	OTLG1P77	Limited	Posttranslational Modification	[27]
CHAMP1	OTBGWU86	Limited	Biomarker	[28]
EDIL3	OTDVVNS0	Limited	Genetic Variation	[29]
FERMT2	OTZNPWWX	Limited	Genetic Variation	[30]
FERMT3	OTFQOT3C	Limited	Genetic Variation	[30]
IFITM1	OTECO1G8	Limited	Biomarker	[31]
ITGA7	OTTBTAYW	Limited	Genetic Variation	[32]
LMOD1	OTZ2MEMG	Limited	Biomarker	[26]
MBD1	OTD19VO6	Limited	Biomarker	[33]
MEF2D	OT7CEIG0	Limited	Biomarker	[34]
MOV10L1	OTP978LK	Limited	Biomarker	[28]
MYLK3	OTC58V2Q	Limited	Biomarker	[13]
NDC80	OTS7D306	Limited	Altered Expression	[35]
NPAS2	OTMRT2TS	Limited	Genetic Variation	[36]
OBSCN	OTT14OVX	Limited	Altered Expression	[37]
PCP4	OTM1XXYX	Limited	Altered Expression	[38]
PEG10	OTWD2278	Limited	Genetic Variation	[39]
PPP1R12A	OT4AVU95	Limited	Posttranslational Modification	[40]
PRUNE1	OTQ3UHWQ	Limited	Biomarker	[41]
PRUNE2	OTGW2974	Limited	Biomarker	[42]
RFTN1	OT8875JE	Limited	Genetic Variation	[30]
RRAS2	OT83NCEB	Limited	Genetic Variation	[43]
SETMAR	OTE2MIMZ	Limited	Genetic Variation	[39]
SMARCAD1	OT90AZTX	Limited	Genetic Variation	[44]
SP3	OTYDQZ1T	Limited	Altered Expression	[45]
TNS1	OTZ8S1PL	Limited	Genetic Variation	[46]
TOPBP1	OT6UPZPD	Limited	Altered Expression	[47]
TRIM63	OTUSWA74	Limited	Altered Expression	[48]
CALD1	OTNJKJ6Q	moderate	Biomarker	[49]
FH	OTEQWU6Q	Moderate	Autosomal dominant	[50]
MYOCD	OTSJNHTH	moderate	Biomarker	[51]
PTEN	OTOWDUNT	Moderate	Autosomal recessive	[20]
COIL	OTP4I4DL	Strong	Biomarker	[52]
MED12	OTQZ4D2X	Strong	Altered Expression	[7]
SSX2	OT2Z6RLL	Strong	Genetic Variation	[53]

References

• [1] Docetaxel FDA Label
• [2] Gemcitabine FDA Label
• [3] Trabectedin FDA Label
• [4] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [5] ClinicalTrials.gov (NCT05269355) A Phase 2/3 Study to Evaluate the Efficacy and Safety of Unesbulin in Unresectable or Metastatic, Relapsed or Refractory Leiomyosarcoma. U.S.National Institutes of Health.
• [6] Mllerian inhibiting substance type II receptor (MISIIR): a novel, tissue-specific target expressed by gynecologic cancers.Gynecol Oncol. 2008 Jan;108(1):141-8. doi: 10.1016/j.ygyno.2007.09.010. Epub 2007 Nov 7.
• [7] CDK8 Expression in Extrauterine Leiomyosarcoma Correlates With Tumor Stage and Progression.Appl Immunohistochem Mol Morphol. 2018 Mar;26(3):161-164. doi: 10.1097/PAI.0000000000000409.
• [8] Association of Epstein-Barr virus with leiomyosarcomas in young people with AIDS.N Engl J Med. 1995 Jan 5;332(1):12-8. doi: 10.1056/NEJM199501053320103.
• [9] DNA fragmentation factors 40 and 45 (DFF40/DFF45) and B-cell lymphoma 2 (Bcl-2) protein are underexpressed in uterine leiomyosarcomas and may predict survival.Onco Targets Ther. 2017 Sep 14;10:4579-4589. doi: 10.2147/OTT.S142979. eCollection 2017.
• [10] Non-endometrioid and high-grade endometrioid endometrial cancers show DNA fragmentation factor 40 (DFF40) and B-cell lymphoma 2 protein (BCL2) underexpression, which predicts disease-free and overall survival, but not DNA fragmentation factor 45 (DFF45) underexpression.BMC Cancer. 2018 Apr 13;18(1):418. doi: 10.1186/s12885-018-4333-6.
• [11] Dystrophin is a tumor suppressor in human cancers with myogenic programs.Nat Genet. 2014 Jun;46(6):601-6. doi: 10.1038/ng.2974. Epub 2014 May 4.
• [12] Recurrent Leiomyosarcoma of External Oblique Muscle Detected on 99mTc-MDP SPECT/CT.Clin Nucl Med. 2017 Oct;42(10):782-783. doi: 10.1097/RLU.0000000000001796.
• [13] Myosin regulatory light chain phosphorylation is associated with leiomyosarcoma development.Biomed Pharmacother. 2017 Aug;92:810-818. doi: 10.1016/j.biopha.2017.05.139. Epub 2017 Jun 10.
• [14] From PTEN loss of expression to RICTOR role in smooth muscle differentiation: complex involvement of the mTOR pathway in leiomyosarcomas and pleomorphic sarcomas.Mod Pathol. 2012 Feb;25(2):197-211. doi: 10.1038/modpathol.2011.163. Epub 2011 Nov 11.
• [15] Human equilibrative nucleoside transporter 1 gene expression is associated with gemcitabine efficacy in advanced leiomyosarcoma and angiosarcoma.Br J Cancer. 2017 Jul 25;117(3):340-346. doi: 10.1038/bjc.2017.187. Epub 2017 Jun 22.
• [16] Expression and role of TYRO3 and AXL as potential therapeutical targets in leiomyosarcoma.Br J Cancer. 2017 Dec 5;117(12):1787-1797. doi: 10.1038/bjc.2017.354. Epub 2017 Oct 12.
• [17] Integrated genome analysis of uterine leiomyosarcoma to identify novel driver genes and targetable pathways.Int J Cancer. 2018 Mar 15;142(6):1230-1243. doi: 10.1002/ijc.31129. Epub 2017 Nov 7.
• [18] Phase II trial of paclitaxel in patients with soft-tissue sarcoma.Cancer Invest. 1998;16(7):442-6. doi: 10.3109/07357909809011697.
• [19] NAC1, a BTB/POZ protein overexpressed in uterine sarcomas.Anticancer Res. 2012 Sep;32(9):3841-5.
• [20] Loss of PTEN Is Associated with Resistance to Anti-PD-1 Checkpoint Blockade Therapy in Metastatic Uterine Leiomyosarcoma. Immunity. 2017 Feb 21;46(2):197-204. doi: 10.1016/j.immuni.2017.02.001.
• [21] Genomic profiling of pelvic genital type leiomyosarcoma in a woman with a germline CHEK2:c.1100delC mutation and a concomitant diagnosis of metastatic invasive ductal breast carcinoma.Cold Spring Harb Mol Case Stud. 2017 Sep 1;3(5):a001628. doi: 10.1101/mcs.a001628. Print 2017 Sep.
• [22] Down-regulation of growth arrest DNA damage-inducible gene 45beta expression is associated with human hepatocellular carcinoma. Am J Pathol. 2003 Jun;162(6):1961-74.
• [23] Cyclooxygenase inhibitors block uterine tumorigenesis in HMGA1a transgenic mice and human xenografts.Mol Cancer Ther. 2008 Jul;7(7):2090-5. doi: 10.1158/1535-7163.MCT-07-2282.
• [24] Leiomyosarcoma with osteoclast-like (LMS-OGC) giant cells the breast: A report of a rare case.Thorac Cancer. 2019 Oct;10(10):2054-2056. doi: 10.1111/1759-7714.13190. Epub 2019 Sep 1.
• [25] The endogenous subcellular localisations of the long chain fatty acid-activating enzymes ACSL3 and ACSL4 in sarcoma and breast cancer cells.Mol Cell Biochem. 2018 Nov;448(1-2):275-286. doi: 10.1007/s11010-018-3332-x. Epub 2018 Feb 15.
• [26] Clinically Relevant Molecular Subtypes in Leiomyosarcoma.Clin Cancer Res. 2015 Aug 1;21(15):3501-11. doi: 10.1158/1078-0432.CCR-14-3141. Epub 2015 Apr 20.
• [27] Clinical significance of cancer specific methylation of the CDO1 gene in small bowel cancer.PLoS One. 2019 Jan 24;14(1):e0211108. doi: 10.1371/journal.pone.0211108. eCollection 2019.
• [28] Comparative cytogenetic study of spindle cell and pleomorphic leiomyosarcomas of soft tissues: a report from the CHAMP Study Group.Cancer Genet Cytogenet. 2000 Jan 1;116(1):66-73. doi: 10.1016/s0165-4608(99)00114-4.
• [29] Cytogenetic observations in a human gastric leiomyosarcoma.Cancer Genet Cytogenet. 1989 Feb;37(2):215-20. doi: 10.1016/0165-4608(89)90051-4.
• [30] Expression of the mitogen-inducible gene-2 (mig-2) is elevated in human uterine leiomyomas but not in leiomyosarcomas.Hum Pathol. 2004 Jan;35(1):55-60. doi: 10.1016/j.humpath.2003.08.019.
• [31] IFITM1 Outperforms CD10 in Differentiating Low-grade Endometrial Stromal Sarcomas From Smooth Muscle Neoplasms of the Uterus.Int J Gynecol Pathol. 2018 Jul;37(4):372-378. doi: 10.1097/PGP.0000000000000424.
• [32] Analysis of integrin alpha7 mutations in prostate cancer, liver cancer, glioblastoma multiforme, and leiomyosarcoma.J Natl Cancer Inst. 2007 Jun 6;99(11):868-80. doi: 10.1093/jnci/djk199.
• [33] Discovery and mechanisms of host defense to oncogenesis: targeting the -defensin-1 peptide as a natural tumor inhibitor.Cancer Biol Ther. 2019;20(6):774-786. doi: 10.1080/15384047.2018.1564564. Epub 2019 Mar 22.
• [34] Different class IIa HDACs repressive complexes regulate specific epigenetic responses related to cell survival in leiomyosarcoma cells.Nucleic Acids Res. 2020 Jan 24;48(2):646-664. doi: 10.1093/nar/gkz1120.
• [35] Elevated NDC80 expression is associated with poor prognosis in osteosarcoma patients.Eur Rev Med Pharmacol Sci. 2017 May;21(9):2045-2053.
• [36] Associations of clock genes polymorphisms with soft tissue sarcoma susceptibility and prognosis.J Transl Med. 2018 Dec 5;16(1):338. doi: 10.1186/s12967-018-1715-0.
• [37] Highly accurate two-gene classifier for differentiating gastrointestinal stromal tumors and leiomyosarcomas.Proc Natl Acad Sci U S A. 2007 Feb 27;104(9):3414-9. doi: 10.1073/pnas.0611373104. Epub 2007 Feb 21.
• [38] PEP-19 overexpression in human uterine leiomyoma.Mol Hum Reprod. 2003 Nov;9(11):709-17. doi: 10.1093/molehr/gag088.
• [39] Cytogenetic analysis of a leiomyosarcoma of the kidney.Cancer Genet Cytogenet. 1994 Feb;72(2):126-9. doi: 10.1016/0165-4608(94)90127-9.
• [40] Reconstituted human myosin light chain phosphatase reveals distinct roles of two inhibitory phosphorylation sites of the regulatory subunit, MYPT1.Biochemistry. 2014 Apr 29;53(16):2701-9. doi: 10.1021/bi5001728. Epub 2014 Apr 18.
• [41] Amplification and overexpression of PRUNE in human sarcomas and breast carcinomas-a possible mechanism for altering the nm23-H1 activity.Oncogene. 2001 Oct 18;20(47):6881-90. doi: 10.1038/sj.onc.1204874.
• [42] Expression patterns of prune2 is regulated by Notch and retinoic acid signaling pathways in the zebrafish embryogenesis.Gene Expr Patterns. 2017 Jan;23-24:45-51. doi: 10.1016/j.gep.2017.03.002. Epub 2017 Mar 11.
• [43] Ras-related TC21 is activated by mutation in a breast cancer cell line, but infrequently in breast carcinomas in vivo.Br J Cancer. 1998 Aug;78(3):296-300. doi: 10.1038/bjc.1998.490.
• [44] SMARCAD1, a novel human helicase family-defining member associated with genetic instability: cloning, expression, and mapping to 4q22-q23, a band rich in breakpoints and deletion mutants involved in several human diseases.Genomics. 2000 Oct 15;69(2):162-73. doi: 10.1006/geno.2000.6281.
• [45] Biglycan gene expression in the human leiomyosarcoma cell line SK-UT-1. Basal and protein kinase A-induced transcription involves binding of Sp1-like/Sp3 proteins in the proximal promoter region.J Biol Chem. 1998 Oct 30;273(44):29230-40. doi: 10.1074/jbc.273.44.29230.
• [46] The differential diagnoses of uterine leiomyomas and leiomyosarcomas using DNA and RNA sequencing.Am J Obstet Gynecol. 2019 Oct;221(4):320.e1-320.e23. doi: 10.1016/j.ajog.2019.05.018. Epub 2019 May 20.
• [47] TopBP1 promotes malignant progression and correlates with poor prognosis in osteosarcoma.Eur Rev Med Pharmacol Sci. 2017 Sep;21(18):4022-4031.
• [48] A systems biological approach to identify key transcription factors and their genomic neighborhoods in human sarcomas.Chin J Cancer. 2011 Jan;30(1):27-40. doi: 10.5732/cjc.010.10541.
• [49] A tale of two clones: Caldesmon staining in the differentiation of cutaneous spindle cell neoplasms.J Cutan Pathol. 2018 Aug;45(8):581-587. doi: 10.1111/cup.13259. Epub 2018 May 22.
• [50] The Gene Curation Coalition: A global effort to harmonize gene-disease evidence resources. Genet Med. 2022 Aug;24(8):1732-1742. doi: 10.1016/j.gim.2022.04.017. Epub 2022 May 4.
• [51] Genome profiling is an efficient tool to avoid the STUMP classification of uterine smooth muscle lesions: a comprehensive array-genomic hybridization analysis of 77 tumors.Mod Pathol. 2018 May;31(5):816-828. doi: 10.1038/modpathol.2017.185. Epub 2018 Jan 12.
• [52] Expression of ALK1 and p80 in inflammatory myofibroblastic tumor and its mesenchymal mimics: a study of 135 cases.Mod Pathol. 2002 Sep;15(9):931-8. doi: 10.1097/01.MP.0000026615.04130.1F.
• [53] Expression of SSX genes in human tumors.Int J Cancer. 1998 Jul 3;77(1):19-23. doi: 10.1002/(sici)1097-0215(19980703)77:1<19::aid-ijc4>3.0.co;2-2.