title: Integrated data analysis reveals uterine leiomyoma subtypes with distinct driver pathways and biomarkers.
abstract: Uterine leiomyomas are common benign smooth muscle tumors that impose a major burden on women's health. Recent sequencing studies have revealed recurrent and mutually exclusive mutations in leiomyomas, suggesting the involvement of molecularly distinct pathways. In this study, we explored transcriptional differences among leiomyomas harboring different genetic drivers, including high mobility group AT-hook 2 (HMGA2) rearrangements, mediator complex subunit 12 (MED12) mutations, biallelic inactivation of fumarate hydratase (FH), and collagen, type IV, alpha 5 and collagen, type IV, alpha 6 (COL4A5-COL4A6) deletions. We also explored the transcriptional consequences of 7q22, 22q, and 1p deletions, aiming to identify possible target genes. We investigated 94 leiomyomas and 60 corresponding myometrial tissues using exon arrays, whole genome sequencing, and SNP arrays. This integrative approach revealed subtype-specific expression changes in key driver pathways, including Wnt/β-catenin, Prolactin, and insulin-like growth factor (IGF)1 signaling. Leiomyomas with HMGA2 aberrations displayed highly significant up-regulation of the proto-oncogene pleomorphic adenoma gene 1 (PLAG1), suggesting that HMGA2 promotes tumorigenesis through PLAG1 activation. This was supported by the identification of genetic PLAG1 alterations resulting in expression signatures as seen in leiomyomas with HMGA2 aberrations. RAD51 paralog B (RAD51B), the preferential translocation partner of HMGA2, was up-regulated in MED12 mutant lesions, suggesting a role for this gene in the genesis of leiomyomas. FH-deficient leiomyomas were uniquely characterized by activation of nuclear factor erythroid 2-related factor 2 (NRF2) target genes, supporting the hypothesis that accumulation of fumarate leads to activation of the oncogenic transcription factor NRF2. This study emphasizes the need for molecular stratification in leiomyoma research and possibly in clinical practice as well. Further research is needed to determine whether the candidate biomarkers presented herein can provide guidance for managing the millions of patients affected by these lesions.
authors.affiliation: Medicum, Department of Medical and Clinical Genetics, University of Helsinki, Helsinki FIN-00014, Finland; Research Programs Unit, Genome-Scale Biology, University of Helsinki, Helsinki FIN-00014, Finland;
authors.forename: Miika
authors.initials: M
authors.lastname: Mehine
authors.affiliation: Medicum, Department of Medical and Clinical Genetics, University of Helsinki, Helsinki FIN-00014, Finland; Research Programs Unit, Genome-Scale Biology, University of Helsinki, Helsinki FIN-00014, Finland;
authors.forename: Eevi
authors.initials: E
authors.lastname: Kaasinen
authors.affiliation: Medicum, Department of Medical and Clinical Genetics, University of Helsinki, Helsinki FIN-00014, Finland; Research Programs Unit, Genome-Scale Biology, University of Helsinki, Helsinki FIN-00014, Finland;
authors.forename: Hanna-Riikka
authors.initials: HR
authors.lastname: Heinonen
authors.affiliation: Medicum, Department of Medical and Clinical Genetics, University of Helsinki, Helsinki FIN-00014, Finland; Research Programs Unit, Genome-Scale Biology, University of Helsinki, Helsinki FIN-00014, Finland;
authors.forename: Netta
authors.initials: N
authors.lastname: Mäkinen
authors.affiliation: Medicum, Department of Medical and Clinical Genetics, University of Helsinki, Helsinki FIN-00014, Finland; Research Programs Unit, Genome-Scale Biology, University of Helsinki, Helsinki FIN-00014, Finland;
authors.forename: Kati
authors.initials: K
authors.lastname: Kämpjärvi
authors.affiliation: Research Programs Unit, Genome-Scale Biology, University of Helsinki, Helsinki FIN-00014, Finland; Department of Obstetrics and Gynecology, Helsinki University Hospital, University of Helsinki, Helsinki FIN-00029, Finland;
authors.forename: Nanna
authors.initials: N
authors.lastname: Sarvilinna
authors.affiliation: Medicum, Department of Medical and Clinical Genetics, University of Helsinki, Helsinki FIN-00014, Finland; Research Programs Unit, Genome-Scale Biology, University of Helsinki, Helsinki FIN-00014, Finland;
authors.forename: Mervi
authors.initials: M
authors.lastname: Aavikko
authors.affiliation: Research Programs Unit, Genome-Scale Biology, University of Helsinki, Helsinki FIN-00014, Finland;
authors.forename: Anna
authors.initials: A
authors.lastname: Vähärautio
authors.affiliation: Department of Pathology and HUSLAB, Helsinki University Hospital, University of Helsinki, Helsinki FIN-00014, Finland;
authors.forename: Annukka
authors.initials: A
authors.lastname: Pasanen
authors.affiliation: Department of Pathology and HUSLAB, Helsinki University Hospital, University of Helsinki, Helsinki FIN-00014, Finland;
authors.forename: Ralf
authors.initials: R
authors.lastname: Bützow
authors.affiliation: Department of Obstetrics and Gynecology, Helsinki University Hospital, University of Helsinki, Helsinki FIN-00029, Finland;
authors.forename: Oskari
authors.initials: O
authors.lastname: Heikinheimo
authors.affiliation: Department of Obstetrics and Gynecology, Helsinki University Hospital, University of Helsinki, Helsinki FIN-00029, Finland;
authors.forename: Jari
authors.initials: J
authors.lastname: Sjöberg
authors.affiliation: Medicum, Department of Medical and Clinical Genetics, University of Helsinki, Helsinki FIN-00014, Finland; Research Programs Unit, Genome-Scale Biology, University of Helsinki, Helsinki FIN-00014, Finland;
authors.forename: Esa
authors.initials: E
authors.lastname: Pitkänen
authors.affiliation: Medicum, Department of Medical and Clinical Genetics, University of Helsinki, Helsinki FIN-00014, Finland; Research Programs Unit, Genome-Scale Biology, University of Helsinki, Helsinki FIN-00014, Finland;
authors.forename: Pia
authors.initials: P
authors.lastname: Vahteristo
authors.affiliation: Medicum, Department of Medical and Clinical Genetics, University of Helsinki, Helsinki FIN-00014, Finland; Research Programs Unit, Genome-Scale Biology, University of Helsinki, Helsinki FIN-00014, Finland; Department of Biosciences and Nutrition, Karolinska Institutet, SE-171 77, Stockholm, Sweden lauri.aaltonen@helsinki.fi.
authors.forename: Lauri A
authors.initials: LA
authors.lastname: Aaltonen
mesh_terms: D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D007889:Leiomyoma / Q000145:classification* / Q000235:genetics; D009154:Mutation; D000090063:Proto-Oncogene Mas; D014594:Uterine Neoplasms / Q000145:classification* / Q000235:genetics
chemical_list: D014408:Biomarkers, Tumor; C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas
keywords: HMGA2; MED12; transcriptional profiling; uterine leiomyoma