Abstract
Abstract Uterine leiomyomas, also known as fibroids, are benign smooth muscle tumors with an estimated prevalence of 77% among women of reproductive age. Although benign, they frequently cause a variety of health complications and are the leading cause of hysterectomy worldwide. Recent studies utilizing high-throughput sequencing have revealed recurrent and mutually exclusive mutations in a variety of genes, suggesting that distinct molecular pathways are involved in the initiation of leiomyoma tumorigenesis. The consequences of these mutations are poorly understood and expression signatures associated with these driver mutations may provide further insights. The aim of this study was to explore transcriptional differences between genetic subgroups of leiomyomas utilizing Affymetrix exon arrays and RNA-sequencing. We performed transcriptional profiling of ∼100 leiomyomas harboring different genetic drivers; these included leiomyomas harboring MED12 mutations, HMGA2/HMGA1 rearrangements, biallelic inactivation of FH and COL4A5-COL4A6 deletions. We identified a long non-coding transcript of RAD51B to be specifically upregulated in MED12 mutant leiomyomas. Genes involved in key metabolic pathways, including pentose phosphate pathway and glutathione biosynthesis, were specifically upregulated in FH-deficient leiomyomas. AKR1B10 was the most significantly upregulated gene in leiomyomas of the FH type. This gene was not expressed in other leiomyomas and may serve as a robust biomarker for FH-deficient leiomyomas. Overexpression of the proto-oncogene PLAG1 was specifically seen in leiomyomas harboring HMGA2 or HMGA1 aberrations, suggesting that these tumors exert their tumorigenic effect through dysregulation of PLAG1. This was supported by identification of one uterine leiomyoma harboring a translocation of PLAG1 resulting in a similar overexpression. While this study highlights the importance of stratifying each leiomyoma into a specific subgroup, it also shows that several genes are commonly dysregulated among all leiomyomas. Targeting these genes would be ideal in developing treatments for this disease. Citation Format: Miika Mehine, Eevi Kaasinen, Esa Pitkänen, Nanna Sarvilinna, Hanna-Riikka Heinonen, Netta Mäkinen, Jari Sjöberg, Lauri A. Aaltonen. Transcriptional profiling reveals uterine leiomyoma subtypes with distinct pathways and biomarkers of tumorigenesis. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1079. doi:10.1158/1538-7445.AM2015-1079
Published Version
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