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Systems analysis of uterine and tumor microenvironments

ABSTRACT: Systems analysis of uterine and tumor microenvironments

PROVIDER: PRJNA282759 | ENA |

REPOSITORIES: ENA

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Project description:Uterine fibroids are benign tumours affecting up to 80% of women of reproductive age, with 30% of patients suffering severe symptoms including abnormal uterine bleeding, pain and infertility. Several studies have identified mutations in MED12 or HMGA2 that account for the vast majority of genomic abnormalities in uterine fibroids, however, the processes by which these lead to UFs and HMB remain poorly understood. To systematically correlate genetic, transcriptional and proteomic phenotypes we collected fibroid, myometrium and endometrium tissues from 137 donors undergoing hysterectomy, myomectomy, or transcervical resection. Donors were profiled by genome-wide SNP arrays and their fibroids were genotyped for known mutations using a targeted sequencing approach. Tissues were analysed by RNA-sequencing and proteomics followed by a systems level approach using multiomics factor analysis. Whilst genotyping revealed 39.7% of common MED12 UF mutations, we observe multiple novel exonic and intronic variants of previously known mutated genes like COL4A5 and COL4A6. Systems level analysis of genotype, transcriptomic, and proteomic data between myometrium and fibroid donors identified multiple interrelated gene sets involved in UF pathophysiology, including extracellular matrix deposition and remodelling, protein glycosylation and sulphate biology. Equivalent analysis of endometrium stratified by donor HMB status revealed gene sets implicated in the condition, in particular RNA splicing in MED12 mutant fibroids. A paradigm is proposed, supported by a mouse model of HMB, whereby aberrant production of signalling molecules by MED12 mutant fibroids influences RNA transcript isoform expression in the endometrium, associated with abnormal bleeding. By merging clinical, genetic, transcriptomic, and proteomic information, we highlight multiple pathways which may underlie the pathomechanisms of UF biology and may facilitate the development of novel therapeutic strategies to treat heavy menstrual bleeding

Dataset Information

Systems analysis of uterine and tumor microenvironments

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