Integrated epigenome, exome and transcriptome analyses reveal molecular subtypes and homeotic transformation in uterine fibroids

Abstract

ABSTRACTUterine fibroids are benign myometrial smooth muscle tumors of unknown etiology that when symptomatic are the most common indication for hysterectomy in the USA. We conducted an integrated analysis of fibroids and adjacent normal myometria by whole exome sequencing, Infinium MethylationEPIC array, and RNA-sequencing. Unsupervised clustering by DNA methylation segregated normal myometria from fibroids, and further separated the fibroids into subtypes marked byMED12mutation,HMGA2activation (HMGA2hi) andHMGA1activation (HMGA1hi). Upregulation ofHMGA2expression inHMGA2hi fibroids did not always appear to be dependent on translocation, as has been historically described, and was associated with hypomethylation in theHMGA2gene body. Furthermore, we found that expression ofHOXA13was highly upregulated in fibroids and that overexpression ofHOXA13in a myometrial cell line induced expression of genes classically associated with uterine fibroids. Transcriptome analyses of the most differentially expressed genes between cervix and myometrium also showed that uterine fibroids and normal cervix clustered together and apart from normal myometria. Together, our integrated analysis shows a role for epigenetic modification in fibroid biology and strongly suggests that homeotic transformation of myometrium cells to a more cervical phenotype is important for the etiology of the disease.