Molecular Characterization of Mouse Models of High Grade Serous Carcinoma Based on Oviductal Epithelial Transformation
Year: 2018
Type: dissertation
Abstract: Based on recent studies, the most common and lethal type of "ovarian" cancer, high grade serous carcinoma (HGSC), is thought to originate in the fallopian tube epithelium rather than from the ovarian surface epithelium [1].To study the pathogenesis of HGSC in a mouse model, the Cho lab developed Ovgp1-iCreER T2 mice, in which the Ovgp1 promoter is used to control expression of tamoxifen (TAM)regulated Cre recombinase in the murine equivalent of human fallopian tube epithelium (oviductal epithelium).TAM-treated Ovgp1-iCreER T2 mice carrying various genetically engineered tumor suppressor gene alleles were used to study effects of inactivating different combinations of tumor suppressor genes in the oviductal epithelium.Specifically, Brca1, Trp53, Rb1, and Nf1 were selected because they are often inactivated in human HGSCs and lead to genetic instability and tumor development [2].In order to characterize oviductal tumors arising in our genetically engineered mouse models and verify how comparable they are to human HGSCs, targeted exome sequencing was used to analyze the 32 most commonly mutated genes in human HGSC.Our analysis employed the sequence data to assess DNA copy number alterations (CNAs) in the mouse tumors.Unsupervised hierarchical clustering was used to group tumors based on their CNA profiles.Like human HGSCs, the mouse tumors show a high level of genomic instability, with many widely distributed CNAs.In addition, the tumors acquire other genetic changes characteristic of human HGSCs, such as amplification of cMyc and deletion of Pten.
Author: Schulman, Stephanie
Institutions: University of Michigan, Michigan Medicine
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W3154621800