Novel near-diploid ovarian cancer cell line derived from a highly aneuploid metastatic ovarian tumor

Abstract

A new ovarian near-diploid cell line, OVDM1, was derived from a highly aneuploid serous ovarian metastatic adenocarcinoma. A metastatic tumor was obtained from a 47-year-old Ashkenazi Jewish patient three years after the first surgery removed the primary tumor, both ovaries, and the remaining reproductive organs. OVDM1 was characterized by cell morphology, genotyping, tumorigenic assay, mycoplasma testing, spectral karyotyping (SKY), and molecular profiling of the whole genome by aCGH and gene expression microarray. Targeted sequencing of a panel of cancer-related genes was also performed. Hierarchical clustering of gene expression data clearly confirmed the ovarian origin of the cell line. OVDM1 has a near-diploid karyotype with a low-level aneuploidy, but samples of the original metastatic tumor were grossly aneuploid. A number of single nucleotide variations (SNVs)/mutations were detected in OVDM1 and the metastatic tumor samples. Some of them were cancer-related according to COSMIC and HGMD databases (no founder mutations in BRCA1 and BRCA2 have been found). A large number of focal copy number alterations (FCNAs) were detected, including homozygous deletions (HDs) targeting WWOX and GATA4. Progression of OVDM1 from early to late passages was accompanied by preservation of the near-diploid status, acquisition of only few additional large chromosomal rearrangements and more than 100 new small FCNAs. Most of newly acquired FCNAs seem to be related to localized but massive DNA fragmentation (chromothripsis-like rearrangements). Newly developed near-diploid OVDM1 cell line offers an opportunity to evaluate tumorigenesis pathways/events in a minor clone of metastatic ovarian adenocarcinoma as well as mechanisms of chromothripsis.

Identification of Key Genes and Pathway for Ovarian Neoplasms Using the OVDM1 Cell Line Based on Bioinformatics Analysis

“…Ovarian neoplasms accounts for 2.5% of all malignancies in females, but 5% of female cancer deaths, due to low survival rates [1,2], which are mainly due to the late stage of diagnoses (stage III–IV) when tumors have metastasized to peritoneal and distant organs, at which point treatment is very difficult as the late-stage tumors become resistant to most cancer therapies [3–5]. According to the latest statistics from the World Health Organization, there were 65 538 new cases and 42 704 deaths caused by ovarian neoplasms in 2012 [6].…”

“…Therefore, research of many more well-characterized cell lines derived from ovarian neoplasms are necessary due to the high level of genomic heterogeneity among and within ovarian tumors. The new ovarian near-diploid cell line, OVDM1, was derived from a highly aneuploid serous ovarian metastatic adenocarcinoma [3]. Hence, further study of the different molecular mechanisms of OVDM1 and ovarian metastatic tumor tissue is necessary and will improve the understanding of the development of ovarian neoplasms.…”

Multicolor Fluorescence In Situ Hybridization (FISH) Approaches for Simultaneous Analysis of the Entire Human Genome

“…Currently both SKY and M‐FISH have commercial assay kits that support multiple species including human, rat, and mouse (for more information see the website links of the Applied Spectral Imaging and MetaSystems Imaging in the Internet resources). Since their introduction, SKY and M‐FISH have been widely used in a variety of research studies and clinical cytogenetics, especially for the delineation of chromosomal rearrangements in neoplastic cases (Conde et al., ; Guo, Han, Wu, Da, & Zhu, ; Minakata et al., ; Morishita et al., ; Pathak, Koturbash, & Hauer‐Jensen, ; Rozenblum et al., ; Yuan et al., ; Wafa et al., ; for a current bibliography, visit the Applied Spectral Imaging and MetaSystems websites, respectively).…”