title: Clinically Relevant Molecular Subtypes in Leiomyosarcoma.
abstract: OBJECTIVE
  Leiomyosarcoma is a malignant neoplasm with smooth muscle differentiation. Little is known about its molecular heterogeneity and no targeted therapy currently exists for leiomyosarcoma. Recognition of different molecular subtypes is necessary to evaluate novel therapeutic options. In a previous study on 51 leiomyosarcomas, we identified three molecular subtypes in leiomyosarcoma. The current study was performed to determine whether the existence of these subtypes could be confirmed in independent cohorts.
  
  
  METHODS
  Ninety-nine cases of leiomyosarcoma were expression profiled with 3'end RNA-Sequencing (3SEQ). Consensus clustering was conducted to determine the optimal number of subtypes.
  
  
  RESULTS
  We identified 3 leiomyosarcoma molecular subtypes and confirmed this finding by analyzing publically available data on 82 leiomyosarcoma from The Cancer Genome Atlas (TCGA). We identified two new formalin-fixed, paraffin-embedded tissue-compatible diagnostic immunohistochemical markers; LMOD1 for subtype I leiomyosarcoma and ARL4C for subtype II leiomyosarcoma. A leiomyosarcoma tissue microarray with known clinical outcome was used to show that subtype I leiomyosarcoma is associated with good outcome in extrauterine leiomyosarcoma while subtype II leiomyosarcoma is associated with poor prognosis in both uterine and extrauterine leiomyosarcoma. The leiomyosarcoma subtypes showed significant differences in expression levels for genes for which novel targeted therapies are being developed, suggesting that leiomyosarcoma subtypes may respond differentially to these targeted therapies.
  
  
  CONCLUSIONS
  We confirm the existence of 3 molecular subtypes in leiomyosarcoma using two independent datasets and show that the different molecular subtypes are associated with distinct clinical outcomes. The findings offer an opportunity for treating leiomyosarcoma in a subtype-specific targeted approach.
authors.affiliation: Department of Pathology, Stanford University School of Medicine, Stanford, California.
authors.forename: Xiangqian
authors.initials: X
authors.lastname: Guo
authors.affiliation: Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
authors.forename: Vickie Y
authors.initials: VY
authors.lastname: Jo
authors.affiliation: Department of Pathology, University of Virginia, Charlottesville, Virginia.
authors.forename: Anne M
authors.initials: AM
authors.lastname: Mills
authors.affiliation: Department of Pathology, Stanford University School of Medicine, Stanford, California.
authors.forename: Shirley X
authors.initials: SX
authors.lastname: Zhu
authors.affiliation: Division of Anatomical Pathology, Royal Alexandra Hospital, Edmonton, Alberta, Canada.
authors.forename: Cheng-Han
authors.initials: CH
authors.lastname: Lee
authors.affiliation: Department of Pathology, Hospital de la Santa Creu i Sant Pau, Autonomous University of Barcelona, Barcelona, Spain.
authors.forename: Inigo
authors.initials: I
authors.lastname: Espinosa
authors.affiliation: Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
authors.forename: Marisa R
authors.initials: MR
authors.lastname: Nucci
authors.affiliation: Department of Pathology, Stanford University School of Medicine, Stanford, California.
authors.forename: Sushama
authors.initials: S
authors.lastname: Varma
authors.affiliation: Department of Pathology, Stanford University School of Medicine, Stanford, California.
authors.forename: Erna
authors.initials: E
authors.lastname: Forgó
authors.affiliation: Department of Statistics, Stanford University, Stanford, California.
authors.forename: Trevor
authors.initials: T
authors.lastname: Hastie
authors.affiliation: Department of Pathology, Stanford University School of Medicine, Stanford, California.
authors.forename: Sharon
authors.initials: S
authors.lastname: Anderson
authors.affiliation: Stanford Comprehensive Cancer Center, Stanford University, Stanford, California.
authors.forename: Kristen
authors.initials: K
authors.lastname: Ganjoo
authors.affiliation: Department of Pathology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts.
authors.forename: Andrew H
authors.initials: AH
authors.lastname: Beck
authors.affiliation: Department of Pathology, Stanford University School of Medicine, Stanford, California.
authors.forename: Robert B
authors.initials: RB
authors.lastname: West
authors.affiliation: Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Fletcher
authors.affiliation: Department of Pathology, Stanford University School of Medicine, Stanford, California. mrijn@stanford.edu.
authors.forename: Matt
authors.initials: M
authors.lastname: van de Rijn
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000096:biosynthesis* / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007890:Leiomyosarcoma / Q000145:classification / Q000235:genetics* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000096:biosynthesis* / Q000235:genetics; D020411:Oligonucleotide Array Sequence Analysis; D011379:Prognosis; D046888:Tissue Array Analysis
chemical_list: D014408:Biomarkers, Tumor; D009363:Neoplasm Proteins