Novel high-grade serous epithelial ovarian cancer cell lines that reflect the molecular diversity of both the sporadic and hereditary disease

Hubert Fleury,Suzanna L Arcand,Diane Provencher,Anne-Marie Mes-Masson,Euridice Carmona,Kurosh Rahimi,Lise Portelance,Laudine Communal,Patricia N Tonin

doi:10.18632/genesandcancer.76

Abstract

Few cell line models of epithelial ovarian cancer (EOC) have been developed for the high-grade serous (HGS) subtype, which is the most common and lethal form of gynaecological cancer. Here we describe the establishment of six new EOC cell lines spontaneously derived from HGS tumors (TOV2978G, TOV3041G and TOV3291G) or ascites (OV866(2), OV4453 and OV4485). Exome sequencing revealed somatic TP53 mutations in five of the cell lines. One cell line has a novel BRCA1 splice-site mutation, and another, a recurrent BRCA2 nonsense mutation, both of germline origin. The novel BRCA1 mutation induced abnormal splicing, mRNA instability, resulting in the absence of BRCA1 protein. None of the cell lines harbor mutations in KRAS or BRAF, which are characteristic of other EOC subtypes. SNP arrays showed that all of the cell lines exhibited structural chromosomal abnormalities, copy number alterations and regions of loss of heterozygosity, consistent with those described for HGS. Four cell lines were able to produce 3D-spheroids, two exhibited anchorage-independent growth, and three (including the BRCA1 and BRCA2 mutated cell lines) formed tumors in SCID mice. These novel HGS EOC cell lines and their detailed characterization provide new research tools for investigating the most common and lethal form of EOC.

Highlights

Ovarian cancer is the fifth cause of cancer-related deaths in the Western world, the second most common gynecological cancer and the leading cause of death from gynecological malignancies [1]
The recent study from the The Cancer Genome Atlas Research (TCGA) highlighted the high molecular genetic heterogeneity among high grade serous (HGS) tumors, specific genomic anomalies recurred at variable frequencies [12]
There were recognizable features such as high somatic copy number alterations, an overall high frequency (96%) of somatic TP53 mutations, BRCA1/ BRCA2 germline/somatic mutations or silencing of gene expression in approximately 33% of the tumors, and somatic mutations in CSDM3, NF1, CDK12, and RB1 that each occurred at low frequency [12]

Summary

Introduction

Ovarian cancer is the fifth cause of cancer-related deaths in the Western world, the second most common gynecological cancer and the leading cause of death from gynecological malignancies [1]. The most common form of cancer of the ovary is epithelial ovarian cancer (EOC) (reviewed in [2, 3]). Of EOC patients are diagnosed at an advanced stage of the disease. Initial response rates are high but probably due to innate or acquired chemoresistance the disease recurs in more than 70% of patients [5, 6]. There is an understanding that distinct molecular events contribute to two possibly non-contiguous diseases, which differentiate low (LGS) and high grade serous (HGS) cancers. It is becoming increasingly clear that distinct molecular events are associated with each particular EOC subtype (discussed in [2, 7,8,9])

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Conclusion