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Some leiomyomas have chromosomal rearrangements implicating chromothripsis, a process involving the formation of complex chromosomal rearrangements. In three instances, tumors obtained from the same woman were documented to be clonally related. Uterine leiomyomas are benign smooth-muscle tumors with an estimated prevalence of 77% among women of reproductive age in the United States 1 and can cause a range of health problems. 2 According to a nationwide analysis of 518,828 hysterectomies performed in 2005 in the United States, 282,291 of the patients who underwent the procedure (54%) had leiomyomas. 3 Hormonal factors, family history, African ancestry, and obesity increase the risk of leiomyomas. 4 Presentation with multiple tumors is typical (an estimated average is six to seven 1 ). Whether leiomyosarcomas develop from leiomyomas or arise independently is not known. Uterine leiomyosarcoma is very rare, 5 and it . . .

Uterine leiomyomas (ULs) are benign tumors that are a major burden to women’s health. A genome-wide association study on 15,453 UL cases and 392,628 controls was performed, followed by replication of the genomic risk in six cohorts. Effects of the risk alleles were evaluated in view of molecular and clinical characteristics. 22 loci displayed a genome-wide significant association. The likely predisposition genes could be grouped to two biological processes. Genes involved in genome stability were represented by TERT, TERC, OBFC1 - highlighting the role of telomere maintenance - TP53 and ATM. Genes involved in genitourinary development, WNT4, WT1, SALL1, MED12, ESR1, GREB1, FOXO1, DMRT1 and uterine stem cell marker antigen CD44, formed another strong subgroup. The combined risk contributed by the 22 loci was associated with MED12 mutation-positive tumors. The findings link genes for uterine development and genetic stability to leiomyomagenesis, and in part explain the more frequent occurrence of UL in women of African origin. Fibroids – also known as uterine leiomyomas, or myomas – are a very common form of benign tumor that grows in the muscle wall of the uterus. As many as 70% of women develop fibroids in their lifetime. About a fifth of women report symptoms including severe pain, heavy bleeding during periods and complications in pregnancy. In the United States, the cost of treating fibroids is estimated to be $34 billion each year. Despite the prevalence of fibroids in women, there are few treatments available. Drugs to target them have limited effect and often an invasive procedure such as surgery is needed to remove the tumors. However, a better understanding of the genetics of fibroids could lead to a way to develop better treatment options. Välimäki, Kuisma et al. used a genome-wide association study to seek out DNA variations that are more common in people with fibroids. Using data from the UK Biobank, the genomes of over 15,000 women with fibroids were analyzed against a control population of over 392,000 individuals. The analysis revealed 22 regions of the genome that were associated with fibroids. These regions included genes that may well contribute to fibroid development, such as the gene TP53, which influences the stability of the genome, and ESR1, which codes for a receptor for estrogen – a hormone known to play a role in the growth of fibroids. Variation in a set of genes known to control development of the female reproductive organs was also identified in women with fibroids. The findings are the result of the largest genome-wide association study on fibroids, revealing a set of genes that could influence the development of fibroids. Studying these genes could lead to more effective drug development to treat fibroids. Revealing this group of genes could also help to identify women at high risk of developing fibroids and help to prevent or manage the condition.

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.

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.

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.

Up to 86% of uterine leiomyomas harbour somatic mutations in mediator complex subunit 12 (MED12) . These mutations have been associated with conventional histology, smaller tumour size, and larger number of tumours within the uterus. Prior studies, with limited sample sizes, have failed to detect associations between other clinical features and MED12 mutations. Here, we prospectively collected 763 uterine leiomyomas and the corresponding normal myometrial tissue from 244 hysterectomy patients, recorded tumour characteristics, collected clinical data from medical records, and screened the tissue samples for MED12 mutations to assess potential associations between clinical variables and mutation status. Out of 763 leiomyomas, 599 (79%) harboured a MED12 mutation. In the analysis of tumour characteristics, positive MED12- mutation status was significantly associated with smaller tumour size, conventional histology, and subserous location, relative to intramural. In the analysis of clinical variables, the number of MED12- mutation-positive tumours showed an inverse association with parity, and the number of mutation-negative tumours showed a positive association with a history of pelvic inflammatory disease. This study confirmed the previously reported differences and discovered novel differentiating features for MED12- mutation-positive and -negative leiomyomas. These findings emphasise the relevance of specific driver mutations in genesis and presentation of uterine leiomyomas.

Uterine leiomyomas (ULs) are benign tumors that are a major burden to women's health. A genome-wide association study on 5,417 UL cases and 331,791 controls was performed, followed by replication of the genomic risk in two cohorts. Effects of the identified risk alleles were evaluated in view of molecular and clinical features. Five loci displayed a genome-wide significant association; the previously reported TNRC6B, and four novel loci ESR1 (ER ), WT1, WNT4, and ATM. The sixth hit TERT is also a conceivable target. The combined polygenic risk contributed by these loci was associated with MED12 mutation-positive tumors. The findings link genes for uterine development and genetic stability to leiomyomagenesis. While the fundamental role of sex hormones in UL aetiology has been clear, this work reveals a connection to estrogen receptor alpha on genetic level and suggests that determinants of UL growth associated with estrogen exposure have an inherited component.