Integrated Analysis Reveals Tubal- and Ovarian-Originated Serous Ovarian Cancer and Predicts Differential Therapeutic Responses

Abstract

The relative importance of fallopian tube (FT) compared with ovarian surface epithelium (OSE) in the genesis of serous type of ovarian cancer (SOC) is still unsettled. Here, we followed an integrated approach to study the tissue origin of SOC, as well as its association with clinical outcome and response to therapeutic drugs. A collection of transcriptome data of 80 FTs, 89 OSEs, and 2,668 SOCs was systematically analyzed to determine the characteristic of FT-like and OSE-like tumors. A molecular signature was developed for identifying tissue origin of SOC and then was used to reevaluate the prognostic genes and therapeutic biomarkers of SOC of different tissue origins. IHC staining of tissue array and functional experiments on a panel of ovarian cancer cell lines were used to further validate the key findings. The expression patterns of tissue-specific genes, prognostic genes, and molecular markers all support a dualistic tissue origin of SOC, from either FT or OSE. A molecular signature was established to identify the tissue identity of SOCs. Surprisingly, the signature showed a strong association with overall survival (OSE-like vs. FT-like, HR = 4.16; 95% CI, 2.67-6.48; < 10). The pharmacogenomic approach revealed AXL to be a therapeutic target of the aggressive OSE-derived SOC. SOC has two subtypes originated from either FT or OSE, which show different clinical and pathologic features. .

Immunogenomic Analyses of Advanced Serous Ovarian Cancer Reveal Immune Score is a Strong Prognostic Factor and an Indicator of Chemosensitivity

“…Sixteen public cohort datasets with transcriptome data of high-grade, late-stage serous ovarian cancer were obtained through database searches of PubMed, ArrayExpress, TCGA, and GEO (Table 1), and processed as described in our previous study (16). In this study, we further added a recently released cohort dataset of 80 primary ovarian cancers (17).…”

Screening and Prevention for High-Grade Serous Carcinoma of the Ovary Based on Carcinogenesis—Fallopian Tube- and Ovarian-Derived Tumors and Incessant Retrograde Bleeding

“…Ovarian cancer screening needs to detect both early fallopian tube and ovarian lesions, as FTE and OSE are cells-of-origin for HGSC of the ovary [34][35][36][37]. Although ovarian cancer screening using TV-US and CA-125 is not recommended in low-risk women and high-risk women with BRCA mutations, for BRCA mutation carriers who have not yet undergone RRSO ovarian cancer screening may be considered at age 30-35 years [113].…”

“…A genomic study reveals that a proportion of STICs represents intraepithelial metastases to the fallopian tube rather than the origin of HGSC [33]. In a mouse model, ovaries harboring a p53 mutation develop metastatic HGSCs [34], and transcriptome data from OSE, fallopian tube epithelium (FTE), and HGSC samples reveal that HGSC has two subtypes originated from either FTE or OSE [35]. Interestingly, OSE-derived HGSC may have a worse prognosis and long latent period compared to FTE-derived HGSC [36,37].…”

Genetically Defined, Syngeneic Organoid Platform for Developing Combination Therapies for Ovarian Cancer

“…The cell-of-origin for HGSOC remains controversial. Although transcriptomic (Ducie et al, 2017;Hao et al, 2017;Lawrenson et al, 2019), proteomic (Coscia et al, 2016), epigenomic (Lawrenson et al, 2019), and mouse modeling studies (Szabova et al, 2012;Zhang et al, 2019) suggest that at least some cases initiate in OSE, most HGSOC probably initiates in FTE (Ducie et al, 2017;Karnezis and Cho, 2017;Karnezis et al, 2017). For this reason, we engineered our initial models using FTE organoids.…”