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MED12 mutations and FH inactivation are mutually exclusive in uterine leiomyomas.
Br J Cancer. 2016 06 14; 114(12):1405-11.BJ

Abstract

BACKGROUND

Uterine leiomyomas from hereditary leiomyomatosis and renal cell cancer (HLRCC) patients are driven by fumarate hydratase (FH) inactivation or occasionally by mediator complex subunit 12 (MED12) mutations. The aim of this study was to analyse whether MED12 mutations and FH inactivation are mutually exclusive and to determine the contribution of MED12 mutations on HLRCC patients' myomagenesis.

METHODS

MED12 exons 1 and 2 mutation screening and 2SC immunohistochemistry indicative for FH deficiency was performed on a comprehensive series of HLRCC patients' (122 specimens) and sporadic (66 specimens) tumours. Gene expression analysis was performed using Affymetrix GeneChip Human Exon Arrays (Affymetrix, Santa Clara, CA, USA).

RESULTS

Nine tumours from HLRCC patients harboured a somatic MED12 mutation and were negative for 2SC immunohistochemistry. All remaining successfully analysed lesions (107/116) were deficient for FH. Of sporadic tumours, 35/64 were MED12 mutation positive and none displayed a FH defect. In global gene expression analysis FH-deficient tumours clustered together, whereas HLRCC patients' MED12 mutation-positive tumours clustered together with sporadic MED12 mutation-positive tumours.

CONCLUSIONS

Somatic MED12 mutations and biallelic FH inactivation are mutually exclusive in both HLRCC syndrome-associated and sporadic uterine leiomyomas. The great majority of HLRCC patients' uterine leiomyomas are caused by FH inactivation, but incidental tumours driven by somatic MED12 mutations also occur. These MED12 mutation-positive tumours display similar expressional profiles with their sporadic counterparts and are clearly separate from FH-deficient tumours.

Authors+Show Affiliations

Genome-Scale Biology Research Program, Research Programs Unit, University of Helsinki, FIN-00014 Helsinki, Finland. Department of Medical and Clinical Genetics, Medicum, University of Helsinki, FIN-00014 Helsinki, Finland.Genome-Scale Biology Research Program, Research Programs Unit, University of Helsinki, FIN-00014 Helsinki, Finland. Department of Medical and Clinical Genetics, Medicum, University of Helsinki, FIN-00014 Helsinki, Finland.Genome-Scale Biology Research Program, Research Programs Unit, University of Helsinki, FIN-00014 Helsinki, Finland. Department of Medical and Clinical Genetics, Medicum, University of Helsinki, FIN-00014 Helsinki, Finland.Genome-Scale Biology Research Program, Research Programs Unit, University of Helsinki, FIN-00014 Helsinki, Finland. Department of Medical and Clinical Genetics, Medicum, University of Helsinki, FIN-00014 Helsinki, Finland.Department of Obstetrics and Gynecology, Oulu University Hospital, PEDEGO Research Unit, University of Oulu, FIN-90220 Oulu, Finland. Medical Research Center Oulu, FIN-90220 Oulu, Finland.Genome-Scale Biology Research Program, Research Programs Unit, University of Helsinki, FIN-00014 Helsinki, Finland. Department of Medical and Clinical Genetics, Medicum, University of Helsinki, FIN-00014 Helsinki, Finland.Genome-Scale Biology Research Program, Research Programs Unit, University of Helsinki, FIN-00014 Helsinki, Finland. Department of Medical and Clinical Genetics, Medicum, University of Helsinki, FIN-00014 Helsinki, Finland.Genome-Scale Biology Research Program, Research Programs Unit, University of Helsinki, FIN-00014 Helsinki, Finland. Department of Medical and Clinical Genetics, Medicum, University of Helsinki, FIN-00014 Helsinki, Finland.Genome-Scale Biology Research Program, Research Programs Unit, University of Helsinki, FIN-00014 Helsinki, Finland. Department of Medical and Clinical Genetics, Medicum, University of Helsinki, FIN-00014 Helsinki, Finland.Medical Research Center Oulu, FIN-90220 Oulu, Finland. Department of Pathology, Oulu University Hospital, Cancer and Translational Medicine Research Unit, University of Oulu, FIN-90220 Oulu, Finland.Department of Pharmacology, Physiology and Neuroscience, School of Medicine, University of South Carolina, Columbia, SC 29209, USA.Genome-Scale Biology Research Program, Research Programs Unit, University of Helsinki, FIN-00014 Helsinki, Finland. Department of Obstetrics and Gynecology, Helsinki University Central Hospital, FIN-00029 Helsinki, Finland. Department of Biochemistry and Developmental Biology, Medicum, University of Helsinki, FIN-00014 Helsinki, Finland.Department of Obstetrics and Gynecology, Helsinki University Central Hospital, FIN-00029 Helsinki, Finland.Department of Pathology, The Laboratory of Helsinki University Central Hospital (HUSLAB), Helsinki University Central Hospital and Medicum, University of Helsinki, FIN-00014 Helsinki, Finland.Genome-Scale Biology Research Program, Research Programs Unit, University of Helsinki, FIN-00014 Helsinki, Finland. Department of Medical and Clinical Genetics, Medicum, University of Helsinki, FIN-00014 Helsinki, Finland. Department of Biosciences and Nutrition, Karolinska Institutet, SE-171 77 Stockholm, Sweden.Genome-Scale Biology Research Program, Research Programs Unit, University of Helsinki, FIN-00014 Helsinki, Finland. Department of Medical and Clinical Genetics, Medicum, University of Helsinki, FIN-00014 Helsinki, Finland.

Pub Type(s)

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

Language

eng

PubMed ID

27187686

Citation

Kämpjärvi, Kati, et al. "MED12 Mutations and FH Inactivation Are Mutually Exclusive in Uterine Leiomyomas." British Journal of Cancer, vol. 114, no. 12, 2016, pp. 1405-11.
Kämpjärvi K, Mäkinen N, Mehine M, et al. MED12 mutations and FH inactivation are mutually exclusive in uterine leiomyomas. Br J Cancer. 2016;114(12):1405-11.
Kämpjärvi, K., Mäkinen, N., Mehine, M., Välipakka, S., Uimari, O., Pitkänen, E., Heinonen, H. R., Heikkinen, T., Tolvanen, J., Ahtikoski, A., Frizzell, N., Sarvilinna, N., Sjöberg, J., Bützow, R., Aaltonen, L. A., & Vahteristo, P. (2016). MED12 mutations and FH inactivation are mutually exclusive in uterine leiomyomas. British Journal of Cancer, 114(12), 1405-11. https://doi.org/10.1038/bjc.2016.130
Kämpjärvi K, et al. MED12 Mutations and FH Inactivation Are Mutually Exclusive in Uterine Leiomyomas. Br J Cancer. 2016 06 14;114(12):1405-11. PubMed PMID: 27187686.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - MED12 mutations and FH inactivation are mutually exclusive in uterine leiomyomas. AU - Kämpjärvi,Kati, AU - Mäkinen,Netta, AU - Mehine,Miika, AU - Välipakka,Salla, AU - Uimari,Outi, AU - Pitkänen,Esa, AU - Heinonen,Hanna-Riikka, AU - Heikkinen,Tuomas, AU - Tolvanen,Jaana, AU - Ahtikoski,Anne, AU - Frizzell,Norma, AU - Sarvilinna,Nanna, AU - Sjöberg,Jari, AU - Bützow,Ralf, AU - Aaltonen,Lauri A, AU - Vahteristo,Pia, Y1 - 2016/05/17/ PY - 2016/02/09/received PY - 2016/04/18/revised PY - 2016/04/24/accepted PY - 2016/5/18/entrez PY - 2016/5/18/pubmed PY - 2017/6/15/medline SP - 1405 EP - 11 JF - British journal of cancer JO - Br. J. Cancer VL - 114 IS - 12 N2 - BACKGROUND: Uterine leiomyomas from hereditary leiomyomatosis and renal cell cancer (HLRCC) patients are driven by fumarate hydratase (FH) inactivation or occasionally by mediator complex subunit 12 (MED12) mutations. The aim of this study was to analyse whether MED12 mutations and FH inactivation are mutually exclusive and to determine the contribution of MED12 mutations on HLRCC patients' myomagenesis. METHODS: MED12 exons 1 and 2 mutation screening and 2SC immunohistochemistry indicative for FH deficiency was performed on a comprehensive series of HLRCC patients' (122 specimens) and sporadic (66 specimens) tumours. Gene expression analysis was performed using Affymetrix GeneChip Human Exon Arrays (Affymetrix, Santa Clara, CA, USA). RESULTS: Nine tumours from HLRCC patients harboured a somatic MED12 mutation and were negative for 2SC immunohistochemistry. All remaining successfully analysed lesions (107/116) were deficient for FH. Of sporadic tumours, 35/64 were MED12 mutation positive and none displayed a FH defect. In global gene expression analysis FH-deficient tumours clustered together, whereas HLRCC patients' MED12 mutation-positive tumours clustered together with sporadic MED12 mutation-positive tumours. CONCLUSIONS: Somatic MED12 mutations and biallelic FH inactivation are mutually exclusive in both HLRCC syndrome-associated and sporadic uterine leiomyomas. The great majority of HLRCC patients' uterine leiomyomas are caused by FH inactivation, but incidental tumours driven by somatic MED12 mutations also occur. These MED12 mutation-positive tumours display similar expressional profiles with their sporadic counterparts and are clearly separate from FH-deficient tumours. SN - 1532-1827 UR - https://www.unboundmedicine.com/medline/citation/27187686/MED12_mutations_and_FH_inactivation_are_mutually_exclusive_in_uterine_leiomyomas_ L2 - http://dx.doi.org/10.1038/bjc.2016.130 DB - PRIME DP - Unbound Medicine ER -