Tags

Type your tag names separated by a space and hit enter

Integrated data analysis reveals uterine leiomyoma subtypes with distinct driver pathways and biomarkers.
Proc Natl Acad Sci U S A. 2016 Feb 02; 113(5):1315-20.PN

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+Show Affiliations

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;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;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;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;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;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;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;Research Programs Unit, Genome-Scale Biology, University of Helsinki, Helsinki FIN-00014, Finland;Department of Pathology and HUSLAB, Helsinki University Hospital, University of Helsinki, Helsinki FIN-00014, Finland;Department of Pathology and HUSLAB, Helsinki University Hospital, University of Helsinki, Helsinki FIN-00014, Finland;Department of Obstetrics and Gynecology, Helsinki University Hospital, University of Helsinki, Helsinki FIN-00029, Finland;Department of Obstetrics and Gynecology, Helsinki University Hospital, University of Helsinki, Helsinki FIN-00029, Finland;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;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;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.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

26787895

Citation

Mehine, Miika, et al. "Integrated Data Analysis Reveals Uterine Leiomyoma Subtypes With Distinct Driver Pathways and Biomarkers." Proceedings of the National Academy of Sciences of the United States of America, vol. 113, no. 5, 2016, pp. 1315-20.
Mehine M, Kaasinen E, Heinonen HR, et al. Integrated data analysis reveals uterine leiomyoma subtypes with distinct driver pathways and biomarkers. Proc Natl Acad Sci USA. 2016;113(5):1315-20.
Mehine, M., Kaasinen, E., Heinonen, H. R., Mäkinen, N., Kämpjärvi, K., Sarvilinna, N., Aavikko, M., Vähärautio, A., Pasanen, A., Bützow, R., Heikinheimo, O., Sjöberg, J., Pitkänen, E., Vahteristo, P., & Aaltonen, L. A. (2016). Integrated data analysis reveals uterine leiomyoma subtypes with distinct driver pathways and biomarkers. Proceedings of the National Academy of Sciences of the United States of America, 113(5), 1315-20. https://doi.org/10.1073/pnas.1518752113
Mehine M, et al. Integrated Data Analysis Reveals Uterine Leiomyoma Subtypes With Distinct Driver Pathways and Biomarkers. Proc Natl Acad Sci USA. 2016 Feb 2;113(5):1315-20. PubMed PMID: 26787895.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Integrated data analysis reveals uterine leiomyoma subtypes with distinct driver pathways and biomarkers. AU - Mehine,Miika, AU - Kaasinen,Eevi, AU - Heinonen,Hanna-Riikka, AU - Mäkinen,Netta, AU - Kämpjärvi,Kati, AU - Sarvilinna,Nanna, AU - Aavikko,Mervi, AU - Vähärautio,Anna, AU - Pasanen,Annukka, AU - Bützow,Ralf, AU - Heikinheimo,Oskari, AU - Sjöberg,Jari, AU - Pitkänen,Esa, AU - Vahteristo,Pia, AU - Aaltonen,Lauri A, Y1 - 2016/01/19/ PY - 2016/1/21/entrez PY - 2016/1/21/pubmed PY - 2016/8/9/medline KW - HMGA2 KW - MED12 KW - transcriptional profiling KW - uterine leiomyoma SP - 1315 EP - 20 JF - Proceedings of the National Academy of Sciences of the United States of America JO - Proc. Natl. Acad. Sci. U.S.A. VL - 113 IS - 5 N2 - 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. SN - 1091-6490 UR - https://www.unboundmedicine.com/medline/citation/26787895/Integrated_data_analysis_reveals_uterine_leiomyoma_subtypes_with_distinct_driver_pathways_and_biomarkers_ L2 - http://www.pnas.org/cgi/pmidlookup?view=long&pmid=26787895 DB - PRIME DP - Unbound Medicine ER -