Defining the molecular evolution of extrauterine high grade serous carcinoma

Beirne, James; McArt, Darragh G.; Roddy, Aideen C.; McDermott, Clara; Ferris, Jennifer S.; Buckley, Niamh E.; Coulter, Paula; McCabe, Nuala; Eddie, Sharon L.; Dunne, Philip D.; O’Reilly, Paul G.; Gilmore, Alan; Feeney, Laura; Ewing, David Lyons; Drapkin, Ronny; Salto-Tellez, Manuel; Kennedy, Richard D.; Harley, Ian; McCluggage, W. Glenn; Mullan, Paul B.

doi:10.1016/j.ygyno.2019.08.029

Cited by 18 publications

(18 citation statements)

References 33 publications

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“…Transcriptomic analysis demonstrates that HGSCs resemble fallopian tube epithelium at a molecular level as compared to ovarian surface epithelium or peritoneal mesothelium. 22,23 A recent study further applied singlecell transcriptome analysis on individual fallopian tube epithelial cells in women without cancer. 24 The investigators identified five major fallopian tube epithelial cell subtypes.…”

Section: Evidence Favoring the Tubal Paradigmmentioning

confidence: 99%

The Origin of Ovarian Cancer Species and Precancerous Landscape

Shih

Wang

2021

The American Journal of Pathology

156

103

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Unlike other human cancers, in which all primary tumors arise de novo, ovarian epithelial cancers are primarily imported from either endometrial or fallopian tube epithelium. The prevailing paradigm in the genesis of high-grade serous carcinoma (HGSC), the most common ovarian cancer, posits to its development in fallopian tubes through stepwise tumor progression. Recent progress has been made not only in gathering terabytes of omics data but also in detailing the histologicemolecular correlations required for looking into, and making sense of, the tissue origin of HGSC. This emerging paradigm is changing many facets of ovarian cancer research and routine gynecology practice. The precancerous landscape in fallopian tubes contains multiple concurrent precursor lesions, including serous tubal intraepithelial carcinoma (STIC), with genetic heterogeneity providing a platform for HGSC evolution. Mathematical models imply that a prolonged time (decades) elapses from the development of a TP53 mutation, the earliest known molecular alteration, to an STIC, followed by a shorter span (6 years) for progression to an HGSC. Genetic predisposition accelerates the trajectory. This timeline may allow for the early diagnosis of HGSC and STIC, followed by intent-to-cure surgery. This review discusses the recent advances in this tubal paradigm and its biological and clinical implications, alongside the promise and challenge of studying STIC and other precancerous lesions of HGSC.

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Section: Evidence Favoring the Tubal Paradigmmentioning

confidence: 99%

The Origin of Ovarian Cancer Species and Precancerous Landscape

Shih

Wang

2021

The American Journal of Pathology

156

103

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“…Tubo-ovarian high-grade serous carcinoma (HGSC) is the most frequent, aggressive, and lethal histotype among ovarian carcinomas (OC). HGSC originates most frequently from the fimbrial mucosa of the Fallopian tubes and rapidly disseminates throughout the peritoneal cavity [ 1 , 2 ]. HGSC standard management consists of cytoreductive surgery and platinum and taxol-based chemotherapy but most patients will relapse within five years [ 3 ].…”

Section: Introductionmentioning

confidence: 99%

A Keratin 7 and E-Cadherin Signature Is Highly Predictive of Tubo-Ovarian High-Grade Serous Carcinoma Prognosis

Communal

Roy

Cahuzac

et al. 2021

IJMS

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During tubo-ovarian high-grade serous carcinoma (HGSC) progression, tumoral cells undergo phenotypic changes in their epithelial marker profiles, which are essential for dissemination processes. Here, we set out to determine whether standard epithelial markers can predict HGSC patient prognosis. Levels of E-CADH, KRT7, KRT18, KRT19 were quantified in 18 HGSC cell lines by Western blot and in a Discovery cohort tissue microarray (TMA) (n = 101 patients) using immunofluorescence. E-CADH and KRT7 levels were subsequently analyzed in the TMA of the Canadian Ovarian Experimental Unified Resource cohort (COEUR, n = 1158 patients) and in public datasets. Epithelial marker expression was highly variable in HGSC cell lines and tissues. In the Discovery cohort, high levels of KRT7 and KRT19 were associated with an unfavorable prognosis, whereas high E-CADH expression indicated a better outcome. Expression of KRT7 and E-CADH gave a robust combination to predict overall survival (OS, p = 0.004) and progression free survival (PFS, p = 5.5 × 10−4) by Kaplan–Meier analysis. In the COEUR cohort, the E-CADH-KRT7 signature was a strong independent prognostic biomarker (OS, HR = 1.6, p = 2.9 × 10−4; PFS, HR = 1.3, p = 0.008) and predicted a poor patient response to chemotherapy (p = 1.3 × 10−4). Our results identify a combination of two epithelial markers as highly significant indicators of HGSC patient prognosis and treatment response.

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“…Recent molecular studies demonstrate that HGSOCs are derived from fallopian tube secretory cells [25-29]; thus, normal tissue controls included normal fallopian tubes and ovaries. IHC staining shows that normal fallopian tube contains TH (sympathetic) positive nerve bundles (Figure 2A, open arrowheads) that are negative for TRPV1 (sensory) and VIP (parasympathetic); scant single nerve fibers (Figure 2A, β-III tubulin positive, small filled arrowheads) are also evident.…”

Section: Resultsmentioning

confidence: 99%

Tumor-infiltrating nerves create an electro-physiologically active microenvironment and contribute to treatment resistance

Kovács

Vermeer

Madeo

et al. 2020

Preprint

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Patients with densely innervated tumors do poorly as compared to those with sparsely innervated disease. Why some tumors heavily recruit nerves while others do not, remains unknown as does the functional contribution of tumor-infiltrating nerves to cancer. Moreover, while patients receive chemotherapeutic treatment, whether these drugs affect nerve recruitment has not been tested. Using a murine model of ovarian cancer, we show that tumor-infiltrating sensory nerves potentiate tumor growth, decrease survival, and contribute to treatment resistance. Furthermore, matched patient samples show significantly increased tumor innervation following chemotherapy. In vitro analysis of tumor-released extracellular vesicles (sEVs) shows they harbor neurite outgrowth activity. These data suggest that chemotherapy may alter sEV cargo, endowing it with robust nerve recruiting capacity.

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Defining the molecular evolution of extrauterine high grade serous carcinoma

Cited by 18 publications

References 33 publications

The Origin of Ovarian Cancer Species and Precancerous Landscape

The Origin of Ovarian Cancer Species and Precancerous Landscape

A Keratin 7 and E-Cadherin Signature Is Highly Predictive of Tubo-Ovarian High-Grade Serous Carcinoma Prognosis

Tumor-infiltrating nerves create an electro-physiologically active microenvironment and contribute to treatment resistance

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