Highly heterogeneous genomic landscape of uterine leiomyomas by whole exome sequencing and genome-wide arrays

Fertil Steril. 2017 Feb;107(2):457-466.e9. doi: 10.1016/j.fertnstert.2016.10.035. Epub 2016 Nov 23.


Objective: To determine the genomic signatures of human uterine leiomyomas and prevalence of MED12 mutations in human uterine leiomyosarcomas.

Design: Retrospective cohort study.

Setting: Not applicable.

Patient(s): This study included a set of 16 fresh frozen leiomyoma and corresponding unaffected myometrium specimens as well as 153 leiomyosarcomas collected from women diagnosed with uterine leiomyomas or leiomyosarcomas who underwent clinically indicated abdominal hysterectomy.

Intervention(s): None.

Main outcome measure(s): Whole exome sequencing and high-resolution X-chromosome and whole genome single nucleotide polymorphism microarray analyses were performed on leiomyoma samples negative for the known MED12 mutations and compared with their corresponding myometrium. Leiomyosarcoma specimens were examined for exon 2 MED12 mutations to evaluate the frequency of MED12 mutated leiomyosarcomas.

Result(s): Our results indicate remarkable genomic heterogeneity of leiomyoma lesions. MED12-negative leiomyomas contain copy number alterations involving the Mediator complex subunits such as MED8, MED18, CDK8, and long intergenic nonprotein coding RNA340 (CASC15), which may affect the Mediator architecture and/or its transcriptional activity. We also identified mutations in a number of genes that were implicated in leiomyomagenesis such as COL4A6, DCN, and AHR, as well as novel genes: NRG1, ADAM18, HUWE1, FBXW4, FBXL13, and CAPRIN1.

Conclusion(s): Mutations in genes implicated in cell-to-cell interactions and remodeling of the extracellular matrix and genomic aberrations involving genes coding for the Mediator complex subunits were identified in uterine leiomyomas. Additionally, we discovered that ∼4.6% of leiomyosarcomas harbored MED12 exon 2 mutations, but the relevance of this association with molecular pathogenesis of leiomyosarcoma remains unknown.

Keywords: MED12 mutation negative; Uterine leiomyoma; uterine leiomyosarcoma; whole exome sequencing; whole genome copy number analysis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Biomarkers, Tumor / genetics*
  • Chromosomes, Human, X
  • DNA Mutational Analysis*
  • Exome*
  • Exons
  • Female
  • Gene Expression Profiling / methods*
  • Gene Frequency
  • Genetic Predisposition to Disease
  • Genome-Wide Association Study
  • Humans
  • Karyotype
  • Leiomyoma / ethnology
  • Leiomyoma / genetics*
  • Leiomyoma / pathology
  • Mediator Complex / genetics*
  • Mutation*
  • Oligonucleotide Array Sequence Analysis*
  • Pennsylvania
  • Phenotype
  • Retrospective Studies
  • Uterine Neoplasms / ethnology
  • Uterine Neoplasms / genetics*
  • Uterine Neoplasms / pathology


  • Biomarkers, Tumor
  • MED12 protein, human
  • Mediator Complex