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. 2017 Dec 5;117(12):1855-1864.
doi: 10.1038/bjc.2017.361. Epub 2017 Oct 26.

Global metabolomic profiling of uterine leiomyomas

Hanna-Riikka Heinonen  1 , Miika Mehine  1 , Netta Mäkinen  1 , Annukka Pasanen  2 , Esa Pitkänen  1 , Auli Karhu  1 , Nanna S Sarvilinna  3 , Jari Sjöberg  3 , Oskari Heikinheimo  3 , Ralf Bützow  2 , Lauri A Aaltonen  1 , Eevi Kaasinen  4
Affiliations

Global metabolomic profiling of uterine leiomyomas

Hanna-Riikka Heinonen et al. Br J Cancer. .

Abstract

Background: Uterine leiomyomas can be classified into molecularly distinct subtypes according to their genetic triggers: MED12 mutations, HMGA2 upregulation, or inactivation of FH. The aim of this study was to identify metabolites and metabolic pathways that are dysregulated in different subtypes of leiomyomas.

Methods: We performed global metabolomic profiling of 25 uterine leiomyomas and 17 corresponding myometrium specimens using liquid chromatography-tandem mass spectroscopy.

Results: A total of 641 metabolites were detected. All leiomyomas displayed reduced homocarnosine and haeme metabolite levels. We identified a clearly distinct metabolomic profile for leiomyomas of the FH subtype, characterised by metabolic alterations in the tricarboxylic acid cycle and pentose phosphate pathways, and increased levels of multiple lipids and amino acids. Several metabolites were uniquely elevated in leiomyomas of the FH subtype, including N6-succinyladenosine and argininosuccinate, serving as potential biomarkers for FH deficiency. In contrast, leiomyomas of the MED12 subtype displayed reduced levels of vitamin A, multiple membrane lipids and amino acids, and dysregulation of vitamin C metabolism, a finding which was also compatible with gene expression data.

Conclusions: The study reveals the metabolomic heterogeneity of leiomyomas and provides the requisite framework for strategies designed to target metabolic alterations promoting the growth of these prevalent tumours.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Overview of the metabolomic data. (A) A total of 641 metabolites were identified in the study. (B) Principal component analysis revealed five outlier samples (circle) and grouping of leiomyomas of the FH subtype together, while the rest of the samples were intermixed. Venn diagrams illustrating the number of significantly (C) increased and (D) decreased metabolites (q-value <0.1) among leiomyomas of the FH, MED12, HMGA2, and triple wild-type subtypes.
Figure 2
Figure 2
Supervised hierarchical clustering analysis with 63 metabolites comprising the 20 most significant metabolites of each leiomyoma subtype.
Figure 3
Figure 3
Levels of the most significantly dysregulated metabolites. Homocarnosine was the most significantly dysregulated metabolite in all leiomyomas. Fumarate, N6-succinyladenosine (S-ado), and argininosuccinate were the most uniquely dysregulated metabolites in leiomyomas of the FH subtype. Histamine and phenylalanine were the most uniquely dysregulated metabolites in leiomyomas of the MED12 subtype.
Figure 4
Figure 4
Schematic of the highlighted metabolic alterations in leiomyomas of the FH and MED12 subtypes. All leiomyomas displayed reduced homocarnosine and haeme metabolite levels and subtype-specific alterations in lipids. (A) FH-deficient leiomyomas displayed dysregulation of TCA cycle, PPP, and the metabolism of amino acids and nucleotides. (B) MED12-mutated leiomyomas harboured alterations affecting retinol, ascorbate, amino acids, and dipeptides. ADSL=adenylosuccinate lyase; ASL=argininosuccinate lyase; BCAA=branched chain amino acid; BCKDC=branched-chain alpha-keto acid dehydrogenase complex; FH=fumarate hydratase; HMOX1=haeme oxygenase 1; MED12=mediator complex subunit 12; NRF2=nuclear factor (erythroid-derived 2)-like 2; PPP=pentose phosphate pathway; S-ado=N6-succinyladenosine; SAM=S-adenosylmethionine; TCA=tricaboxylic acid.
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