title: Characterization of uterine leiomyomas by whole-genome sequencing.
abstract: BACKGROUND
  Uterine leiomyomas are benign but affect the health of millions of women. A better understanding of the molecular mechanisms involved may provide clues to the prevention and treatment of these lesions.
  
  
  METHODS
  We performed whole-genome sequencing and gene-expression profiling of 38 uterine leiomyomas and the corresponding myometrium from 30 women.
  
  
  RESULTS
  Identical variants observed in some separate tumor nodules suggested that these nodules have a common origin. Complex chromosomal rearrangements resembling chromothripsis were a common feature of leiomyomas. These rearrangements are best explained by a single event of multiple chromosomal breaks and random reassembly. The rearrangements created tissue-specific changes consistent with a role in the initiation of leiomyoma, such as translocations of the HMGA2 and RAD51B loci and aberrations at the COL4A5-COL4A6 locus, and occurred in the presence of normal TP53 alleles. In some cases, separate events had occurred more than once in single tumor-cell lineages.
  
  
  CONCLUSIONS
  Chromosome shattering and reassembly resembling chromothripsis (a single genomic event that results in focal losses and rearrangements in multiple genomic regions) is a major cause of chromosomal abnormalities in uterine leiomyomas; we propose that tumorigenesis occurs when tissue-specific tumor-promoting changes are formed through these events. Chromothripsis has previously been associated with aggressive cancer; its common occurrence in leiomyomas suggests that it also has a role in the genesis and progression of benign tumors. We observed that multiple separate tumors could be seeded from a single lineage of uterine leiomyoma cells. (Funded by the Academy of Finland Center of Excellence program and others.).
authors.affiliation: Department of Medical Genetics, Genome-Scale Biology Research Program, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland.
authors.forename: Miika
authors.initials: M
authors.lastname: Mehine
authors.forename: Eevi
authors.initials: E
authors.lastname: Kaasinen
authors.forename: Netta
authors.initials: N
authors.lastname: Mäkinen
authors.forename: Riku
authors.initials: R
authors.lastname: Katainen
authors.forename: Kati
authors.initials: K
authors.lastname: Kämpjärvi
authors.forename: Esa
authors.initials: E
authors.lastname: Pitkänen
authors.forename: Hanna-Riikka
authors.initials: HR
authors.lastname: Heinonen
authors.forename: Ralf
authors.initials: R
authors.lastname: Bützow
authors.forename: Outi
authors.initials: O
authors.lastname: Kilpivaara
authors.forename: Anna
authors.initials: A
authors.lastname: Kuosmanen
authors.forename: Heikki
authors.initials: H
authors.lastname: Ristolainen
authors.forename: Massimiliano
authors.initials: M
authors.lastname: Gentile
authors.forename: Jari
authors.initials: J
authors.lastname: Sjöberg
authors.forename: Pia
authors.initials: P
authors.lastname: Vahteristo
authors.forename: Lauri A
authors.initials: LA
authors.lastname: Aaltonen
mesh_terms: D002869:Chromosome Aberrations; D019457:Chromosome Breakage; D002872:Chromosome Deletion; D024141:Collagen Type IV / Q000235:genetics; D005260:Female; D005649:Fumarate Hydratase / Q000172:deficiency* / Q000235:genetics; D020869:Gene Expression Profiling; D015321:Gene Rearrangement; D055106:Genome-Wide Association Study; D006801:Humans; D007889:Leiomyoma / Q000235:genetics*; D056892:Mediator Complex / Q000235:genetics*; D009154:Mutation; D009215:Myometrium / Q000737:chemistry; D015854:Up-Regulation; D014594:Uterine Neoplasms / Q000235:genetics*
chemical_list: C478159:COL4A5 protein, human; C559044:COL4A6 protein, human; D024141:Collagen Type IV; C460107:MED12 protein, human; D056892:Mediator Complex; D005649:Fumarate Hydratase