Expression Profiling of Primary and Metastatic Ovarian Tumors Reveals Differences Indicative of Aggressive Disease

Abstract

The behavior and genetics of serous epithelial ovarian cancer (EOC) metastasis, the form of the disease lethal to patients, is poorly understood. The unique properties of metastases are critical to understand to improve treatments of the disease that remains in patients after debulking surgery. We sought to identify the genetic and phenotypic landscape of metastatic progression of EOC to understand how metastases compare to primary tumors. DNA copy number and mRNA expression differences between matched primary human tumors and omental metastases, collected at the same time during debulking surgery before chemotherapy, were measured using microarrays. qPCR and immunohistochemistry validated findings. Pathway analysis of mRNA expression revealed metastatic cancer cells are more proliferative and less apoptotic than primary tumors, perhaps explaining the aggressive nature of these lesions. Most cases had copy number aberrations (CNAs) that differed between primary and metastatic tumors, but we did not detect CNAs that are recurrent across cases. A six gene expression signature distinguishes primary from metastatic tumors and predicts overall survival in independent datasets. The genetic differences between primary and metastatic tumors, yet common expression changes, suggest that the major clone in metastases is not the same as in primary tumors, but the cancer cells adapt to the omentum similarly. Together, these data highlight how ovarian tumors develop into a distinct, more aggressive metastatic state that should be considered for therapy development.

Identification of candidate biomarkers for epithelial ovarian cancer metastasis using microarray data

“…Of the dataset, 9 primary tissue samples (control samples) and 9 matched omental metastatic tumor samples (metastatic samples) from patients with serous EOC were used in the present study. The platform used for the detection of this microarray data in the study by Brodsky et al (4) was the GeneChip™ Human Gene 1.0 ST Array (Affymetrix; Thermo Fisher Scientific, Inc., Waltham, MA, USA).…”

“…EOC accounts for 90% of cases of ovarian cancer and is characterized by metastasis (3). Typically, primary EOC tumors disseminate within the peritoneal cavity, primarily into the omentum (4). Only once the tumor cells have spread into the peritoneal cavity may EOC be diagnosed, which often results in a poor prognosis (5).…”

Dynamic changes of tumor gene expression during repeated Pressurized Intraperitoneal Aerosol Chemotherapy (PIPAC) in women with peritoneal cancer

“…Specific genes were chosen based on previous literature associating these genes with ovarian cancer carcinogenesis and metastatic promotion [10][11][12][13]19]. A list of corresponding primers, primer sequences, product lengths, and GenBank accession numbers can be found in Additional file 2: Table S2.…”

Genome-wide analysis of microRNA and mRNA expression signatures in cancer

“…Since then, genome-wide microarray analysis has been widely utilized in identifying numerous diagnostic biomarkers in lung cancer [111] , gastric cancer [112] , prostate cancer [113] , and other types of cancer. Different types of cancer exhibit distinctive expression profiles; for example, in epithelial ovarian cancer (EOC) there is low expression of p53, BCL-2, BAX, EGFR and HER2,and overexpression of ASAP1 [114][115][116][117] . The expression of IKBKβ, CREBBP, WNT10B, PRDX6, ITGAV, and IFNAR1 was found to be associated with hepatic carcinogenesis [118] .…”