👤 Oskari Heikinheimo

Fibroblast growth factor 1-4 (FGFR1-4) are well-known oncogenic drivers in many cancer types. Here, we studied the role of FGFRs in uterine leiomyoma (UL) that is a benign neoplasm arising from the myometrium and the most common tumour in women. Although ULs can be classified to molecular subtypes based on genetic drivers, potential secondary drivers are not well characterised. We performed mutation analysis of RNA-sequencing data of ULs, followed by screening of FGFR alterations in our Finnish (n = 2677) and Swedish (n = 372) UL collections, utilising Sanger-, next-generation and Nanopore sequencing and SNP array data. The role of FGFR genes in UL predisposition was examined by GWAS. We identified FGFR activation in a subset of ULs on both genetic and epigenetic levels. In addition to single-nucleotide mutations in FGFR1/2, we detected an FGFR2-ERC1 fusion gene, FGFR1 gains and hypomethylation of regulatory regions of FGFR2/3. FGFR alterations were enriched in molecularly similar HMGA2, HMGA1 and PLAG1 UL subtypes. We also unveil a UL predisposing variant upstream of FGFR4 associated with increased expression in both normal myometrium and ULs. Our results establish the role of FGFR signalling in the genesis of UL. Show less

Endometriosis is a common condition associated with debilitating pelvic pain and infertility. A genome-wide association study meta-analysis, including 60,674 cases and 701,926 controls of European and East Asian descent, identified 42 genome-wide significant loci comprising 49 distinct association signals. Effect sizes were largest for stage 3/4 disease, driven by ovarian endometriosis. Identified signals explained up to 5.01% of disease variance and regulated expression or methylation of genes in endometrium and blood, many of which were associated with pain perception/maintenance (SRP14/BMF, GDAP1, MLLT10, BSN and NGF). We observed significant genetic correlations between endometriosis and 11 pain conditions, including migraine, back and multisite chronic pain (MCP), as well as inflammatory conditions, including asthma and osteoarthritis. Multitrait genetic analyses identified substantial sharing of variants associated with endometriosis and MCP/migraine. Targeted investigations of genetically regulated mechanisms shared between endometriosis and other pain conditions are needed to aid the development of new treatments and facilitate early symptomatic intervention. Show less