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 my Show more
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
Although the primary cause of lung cancer is smoking, a considerable proportion of all lung cancers occur in never smokers. Gender influences the risk and characteristics of lung cancer and women are Show more
Although the primary cause of lung cancer is smoking, a considerable proportion of all lung cancers occur in never smokers. Gender influences the risk and characteristics of lung cancer and women are overrepresented among never smokers with the disease. Young age at onset and lack of established environmental risk factors suggest genetic predisposition. In this study, we used population-based sampling of young patients to discover candidate predisposition variants for lung adenocarcinoma in never-smoking women. We employed archival normal tissue material from 21 never-smoker women who had been diagnosed with lung adenocarcinoma before the age of 45, and exome sequenced their germline DNA. Potentially pathogenic variants were found in eight Cancer Gene Census germline genes: BRCA1, BRCA2, ERCC4, EXT1, HNF1 A, PTCH1, SMARCB1 and TP53. The variants in TP53, BRCA1, and BRCA2 are likely to have contributed to the early onset lung cancer in the respective patients (3/21 or 14%). This supports the notion that lung adenocarcinoma can be a component of certain cancer predisposition syndromes. Fifteen genes displayed potentially pathogenic mutations in at least two patients: ABCC10, ATP7B, CACNA1S, CFTR, CLIP4, COL6A1, COL6A6, GCN1, GJB6, RYR1, SCN7A, SEC24A, SP100, TTN and USH2A. Four patients showed a mutation in COL6A1, three in CLIP4 and two in the rest of the genes. Some of these candidate genes may explain a subset of female lung adenocarcinoma. Show less