PMID- 26787895
OWN - NLM
STAT- MEDLINE
DCOM- 20160808
LR  - 20220410
IS  - 1091-6490 (Electronic)
IS  - 0027-8424 (Print)
IS  - 0027-8424 (Linking)
VI  - 113
IP  - 5
DP  - 2016 Feb 2
TI  - Integrated data analysis reveals uterine leiomyoma subtypes with distinct driver 
      pathways and biomarkers.
PG  - 1315-20
LID - 10.1073/pnas.1518752113 [doi]
AB  - 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/beta-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.
FAU - Mehine, Miika
AU  - Mehine M
AD  - 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;
FAU - Kaasinen, Eevi
AU  - Kaasinen E
AD  - 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;
FAU - Heinonen, Hanna-Riikka
AU  - Heinonen HR
AD  - 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;
FAU - Makinen, Netta
AU  - Makinen N
AD  - 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;
FAU - Kampjarvi, Kati
AU  - Kampjarvi K
AD  - 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;
FAU - Sarvilinna, Nanna
AU  - Sarvilinna N
AD  - 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;
FAU - Aavikko, Mervi
AU  - Aavikko M
AD  - 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;
FAU - Vaharautio, Anna
AU  - Vaharautio A
AD  - Research Programs Unit, Genome-Scale Biology, University of Helsinki, Helsinki 
      FIN-00014, Finland;
FAU - Pasanen, Annukka
AU  - Pasanen A
AD  - Department of Pathology and HUSLAB, Helsinki University Hospital, University of 
      Helsinki, Helsinki FIN-00014, Finland;
FAU - Butzow, Ralf
AU  - Butzow R
AD  - Department of Pathology and HUSLAB, Helsinki University Hospital, University of 
      Helsinki, Helsinki FIN-00014, Finland;
FAU - Heikinheimo, Oskari
AU  - Heikinheimo O
AD  - Department of Obstetrics and Gynecology, Helsinki University Hospital, University 
      of Helsinki, Helsinki FIN-00029, Finland;
FAU - Sjoberg, Jari
AU  - Sjoberg J
AD  - Department of Obstetrics and Gynecology, Helsinki University Hospital, University 
      of Helsinki, Helsinki FIN-00029, Finland;
FAU - Pitkanen, Esa
AU  - Pitkanen E
AD  - 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;
FAU - Vahteristo, Pia
AU  - Vahteristo P
AD  - 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;
FAU - Aaltonen, Lauri A
AU  - Aaltonen LA
AD  - 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.
LA  - eng
GR  - 695727/ERC_/European Research Council/International
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20160119
PL  - United States
TA  - Proc Natl Acad Sci U S A
JT  - Proceedings of the National Academy of Sciences of the United States of America
JID - 7505876
RN  - 0 (Biomarkers, Tumor)
RN  - 0 (MAS1 protein, human)
RN  - 0 (Proto-Oncogene Mas)
SB  - IM
MH  - Biomarkers, Tumor/genetics/*metabolism
MH  - Female
MH  - Gene Expression Profiling
MH  - Humans
MH  - Leiomyoma/*classification/genetics
MH  - Mutation
MH  - Proto-Oncogene Mas
MH  - Uterine Neoplasms/*classification/genetics
PMC - PMC4747776
OTO - NOTNLM
OT  - HMGA2
OT  - MED12
OT  - transcriptional profiling
OT  - uterine leiomyoma
COIS- The authors declare no conflict of interest.
EDAT- 2016/01/21 06:00
MHDA- 2016/08/09 06:00
PMCR- 2016/08/02
CRDT- 2016/01/21 06:00
PHST- 2016/01/21 06:00 [entrez]
PHST- 2016/01/21 06:00 [pubmed]
PHST- 2016/08/09 06:00 [medline]
PHST- 2016/08/02 00:00 [pmc-release]
AID - 1518752113 [pii]
AID - 201518752 [pii]
AID - 10.1073/pnas.1518752113 [doi]
PST - ppublish
SO  - Proc Natl Acad Sci U S A. 2016 Feb 2;113(5):1315-20. doi: 
      10.1073/pnas.1518752113. Epub 2016 Jan 19.