title: Exploring chromosomal abnormalities and genetic changes in uterine smooth muscle tumors.
abstract: Smooth muscle tumors of the uterus are a diagnostically challenging group of tumors. Molecular surrogate markers reliably distinguishing between benign and malignant tumors are not available. Therefore, the diagnosis is based on morphologic criteria. The aim was to investigate a well-characterized group of challenging uterine smooth muscle tumors consisting of 20 leiomyomas, 13 leiomyomas with bizarre nuclei, and 14 leiomyosarcomas for copy number alterations, MED12 mutations and FH deletions to search for potential diagnostically useful surrogate markers. MED12 mutations were detected in 47, 15, and 25% of leiomyomas, leiomyomas with bizarre nuclei and leiomyosarcomas, respectively. MED12 mutations in leiomyomas with bizarre nuclei were detected outside the hotspot region. FH-deletions were seen in 27, 30.8, and 25% of leiomyomas, leiomyomas with bizarre nuclei and leiomyosarcomas, respectively. By using copy number alteration profiling a clear separation of leiomyomas, leiomyomas with bizarre nuclei and leiomyosarcomas could not be observed. Copy number alterations revealed clear genetic similarities between leiomyomas with bizarre nuclei and leiomyosarcomas. Leiomyosarcomas showed a similar pattern of gains and losses as leiomyomas with bizarre nuclei, with additional copy number alterations and more homozygous losses and high-level amplifications compared to leiomyomas with bizarre nuclei. In conclusion, this study demonstrates that known FH-deletions, a recurrent molecular change in leiomyomas, occur in morphologically challenging variants of leiomyomas, leiomyomas with bizarre nuclei and leiomyosarcomas. Although MED12 mutations are common in leiomyomas, they infrequently occur in leiomyomas with bizarre nuclei and leiomyosarcomas. The genetic similarities between leiomyomas with bizarre nuclei and leiomyosarcomas raise the intriguing possibility that uterine leiomyomas with bizarre nuclei and leiomyosarcomas are closely related and challenge the traditional concept that leiomyoma with bizarre nuclei is a tumor with just marked 'degenerative' cellular changes. These findings support the hypothesis that tumor progression within uterine smooth muscle tumors might occur.
authors.affiliation: Institute of Pathology, Medical University of Graz, Graz, Austria.
authors.forename: Bernadette
authors.initials: B
authors.lastname: Liegl-Atzwanger
authors.affiliation: Department of Human Genetics, Medical University of Graz, Graz, Austria.
authors.forename: Ellen
authors.initials: E
authors.lastname: Heitzer
authors.affiliation: Department of Human Genetics, Medical University of Graz, Graz, Austria.
authors.forename: Karin
authors.initials: K
authors.lastname: Flicker
authors.affiliation: Department of Human Genetics, Medical University of Graz, Graz, Austria.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Müller
authors.affiliation: Department of Human Genetics, Medical University of Graz, Graz, Austria.
authors.forename: Peter
authors.identifier: 0000-0001-5941-1160
authors.initials: P
authors.lastname: Ulz
authors.affiliation: Department of Pathology, Yale University School of Medicine, New Haven, CT, USA.
authors.forename: Ozlen
authors.initials: O
authors.lastname: Saglam
authors.affiliation: Department of Pathology, Yale University School of Medicine, New Haven, CT, USA.
authors.forename: Fattaneh
authors.initials: F
authors.lastname: Tavassoli
authors.affiliation: Department of Pathology, Hospices Civilis de Lyon, Lyon, France.
authors.forename: Mojgan
authors.initials: M
authors.lastname: Devouassoux-Shisheboran
authors.affiliation: Department of Human Genetics, Medical University of Graz, Graz, Austria.
authors.forename: Jochen
authors.initials: J
authors.lastname: Geigl
authors.affiliation: Department of Pathology, Hospital of the Sisters of Charity, Linz, Austria.
authors.forename: Farid
authors.initials: F
authors.lastname: Moinfar
mesh_terms: D000328:Adult; D000368:Aged; D002467:Cell Nucleus / Q000473:pathology; D002869:Chromosome Aberrations; D005260:Female; D006801:Humans; D007889:Leiomyoma / Q000235:genetics* / Q000473:pathology; D007890:Leiomyosarcoma / Q000235:genetics* / Q000473:pathology; D008875:Middle Aged; D014594:Uterine Neoplasms / Q000235:genetics* / Q000473:pathology