Browsing by Subject "uterine leiomyosarcoma"

Uterine leiomyomas are common benign smooth muscle tumors. They are a major gynecological problem affecting women’s health and contribute to a significant burden on national health expenditure. They can be classified based on their histopathology into conventional, and histopathological variants. Most of the conventional tumors exclusively harbor one of the three drivers (MED12 mutations, HMGA2 overexpression, and biallelic FH inactivation). Based on the genetic background, histopathological subtypes differ from each other and from conventional leiomyomas. Although histopathological variants are considered benign, they share some resemblance to malignant uterine leiomyosarcomas. The overall aim of the thesis was to characterize the mutational landscape of histopathological leiomyoma variants using exome sequencing. The specific aims were, to identify new causative mutations in the histopathological variants and within subtypes, and to analyze pathogenic cancer census gene mutations within the variants. Exome sequencing was performed on 35 tumors representing variant histopathology (14 highly cellular, 12 bizarre nuclei, and 9 mitotically active tumors). The sequences were analyzed using BasePlayer software. Mutations were filtered through the designed pipeline using gnomAD, and COSMIC controls. Interesting findings were validated using Sanger sequencing. Exome data analysis of the highly cellular and bizarre nuclei tumors separately resulted in 10 and 17 different mutations in each subtype, respectively. They were found to be pathogenic by in silico predictions. Analysis of all histopathological variants including mitotically active tumors did not reveal any frequently mutated candidate genes. The tumors harbored somatic mutations in 98 genes related to cancer. A mutation in TP53 was found in one bizarre nuclei sample. Specific tumors harbored multiple cancer-related mutations indicating their malignant potential. The highly cellular tumors had the least frequent amount of causative mutations, indicating that the tumorigenesis mechanisms are probably other than missense mutations or small indels in exomes. Tumors with bizarre nuclei displayed a noticeably larger amount of possible pathogenic mutations, in both cancer census and exome analysis, suggesting possible cancerous tendency. This was also supported by the TP53 finding, a gene associated with uterine leiomyosarcomas. The histopathological subtypes pathogenesis is conceivably caused by larger genomic alterations, epigenetic variations or intronic mutations that remain to be found. Tumors with frequent cancer census mutations might harbor malignant potential. Understanding the etiology of these tumors is needed for better diagnostics and possible targeted treatments