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Characterization of desmoglein 2 expression in ovarian serous tumors and its prognostic significance in high-grade serous carcinoma.

ABSTRACT: Desmogleins (Dsgs) are major members of the desmosomal cadherins that are critically involved in cell-cell adhesion and the maintenance of normal tissue architecture in epithelia. DSG2 is the most ubiquitous desmosomal cadherin; however, abnormal expression of DSG2 has been detected in several types of cancer with controversial results. So far, little is known about DSG2 expression in ovarian serous tumor (OST) and its associations with survival and clinicopathologic data. In this study, mRNA and protein expression of DSG2 was detected in 33 cases of nonfixed samples and 92 cases of paraffin-embedded OST specimens (including benign, borderline, low-grade, and high-grade) by using qRT-PCR and immunohistochemistry, respectively. DSG2 expression was then measured in 162 cases of high-grade serous carcinoma (HGSC) by immunohistochemistry, and the expression levels were correlated with clinicopathologic and prognostic data. As the results, DSG2 could be readily detected in benign tumor with relative weak expression at the mRNA level and showed weak but complete staining at the cell-cell borders. This was similar to the expression pattern in the normal fallopian epithelial tissue. However, the expression tendency of DSG2 at the mRNA and protein level was inconsistent in borderline and malignant OST. In addition, we found that a low DSG2 expression was associated with poor prognosis (P < 0.05) and high mitosis (P = 0.0042) of HGSC. Thus, DSG2 may be involved in the progression of ovarian cancer and plays a different role in different OST. Moreover, a low DSG2 expression was associated with poor prognosis of HGSC.

SUBMITTER: Chen L

PROVIDER: S-EPMC6962919 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Characterization of desmoglein 2 expression in ovarian serous tumors and its prognostic significance in high-grade serous carcinoma.

Chen Ling L Liu Xinxin X Zhang Jin J Liu Yanxia Y Gao Ang A Xu Yanning Y Lin Yang Y Du Qiuyue Q Zhu Zhengmao Z Hu Yuanjing Y Liu Yixin Y

International journal of clinical and experimental pathology 20181001 10

Desmogleins (Dsgs) are major members of the desmosomal cadherins that are critically involved in cell-cell adhesion and the maintenance of normal tissue architecture in epithelia. DSG2 is the most ubiquitous desmosomal cadherin; however, abnormal expression of DSG2 has been detected in several types of cancer with controversial results. So far, little is known about DSG2 expression in ovarian serous tumor (OST) and its associations with survival and clinicopathologic data. In this study, mRNA an ...[more]

PMID: 31949574

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Project description:BackgroundAdministration of poly (ADP-ribose) polymerase (PARP) inhibitors after achieving a response to platinum-containing drugs significantly prolonged relapse-free survival compared to placebo administration. PARP inhibitors have been used in clinical practice. However, patients with platinum-resistant relapsed ovarian cancer still have a poor prognosis and there is an unmet need. The purpose of this study was to examine the clinical significance of metabolic genes and focal adhesion kinase (FAK) activity in advanced ovarian high-grade serous carcinoma (HGSC).MethodsThe RNA sequencing (RNA-seq) data and clinical data of HGSC patients were obtained from the Genomic Data Commons (GDC) Data Portal and analysed ( https://portal.gdc.cancer.gov/ ). In addition, tumour tissue was sampled by laparotomy or screening laparoscopy prior to treatment initiation from patients diagnosed with stage IIIC ovarian cancer (International Federation of Gynecology and Obstetrics (FIGO) classification, 2014) at the Saitama Medical University International Medical Center, and among the patients diagnosed with HGSC, 16 cases of available cryopreserved specimens were included in this study. The present study was reviewed and approved by the Institutional Review Board of Saitama Medical University International Medical Center (Saitama, Japan). Among the 6307 variable genes detected in both The Cancer Genome Atlas-Ovarian (TCGA-OV) data and clinical specimen data, 35 genes related to metabolism and FAK activity were applied. RNA-seq data were analysed using the Subio Platform (Subio Inc, Japan). JMP 15 (SAS, USA) was used for statistical analysis and various types of machine learning. The Kaplan-Meier method was used for survival analysis, and the Wilcoxon test was used to analyse significant differences. P < 0.05 was considered significant.ResultsIn the TCGA-OV data, patients with stage IIIC with a residual tumour diameter of 1-10 mm were selected for K means clustering and classified into groups with significant prognostic correlations (p = 0.0444). These groups were significantly associated with platinum sensitivity/resistance in clinical cases (χ2 test, p = 0.0408) and showed significant relationships with progression-free survival (p = 0.0307).ConclusionIn the TCGA-OV data, 2 groups classified by clustering focusing on metabolism-related genes and FAK activity were shown to be associated with platinum resistance and a poor prognosis.

Project description:While TP53 mutation is widely considered to be a defining feature of tubo-ovarian high-grade serous carcinoma (HGSC), rare TP53-mutation-negative cases have been reported. To gain further insight into this rare subset, a retrospective review was conducted on 25 TP53-wildtype tubo-ovarian HGSCs, constituting 2.5% of 987 HGSCs profiled by the MSK-IMPACT sequencing platform. Consistent with serous differentiation, positive staining for Pax8 and WT1 was present in virtually all TP53-wildtype HGSCs. Other characteristic features of HGSC, such as serous tubal intraepithelial carcinoma, or genetic alterations of CCNE1 and BRCA1/2 were identified in these tumors, furthering supporting their classification as bona fide HGSC, despite lacking TP53 mutations. Overall, the level of chromosomal instability of TP53-wildtype HGSCs was intermediate between low-grade serous carcinoma (LGSC) and TP53-mutated HGSC. Morphologic assessment by observers blinded to mutation status revealed a significant subset of tumors with Grade 2 nuclear atypia (which exceeds the degree of atypia allowed for LGSC, but less than typically encountered for HGSC) combined with micropapillary features (6/19, 32%, chemotherapy-naive TP53-wildtype HGSCs compared to 0/21, 0%, TP53-mutated HGSCs; p = 0.007). Some TP53-wildtype HGSCs harbored driver mutations in KRAS (n = 3), BRAF (n = 1) or NRAS (n = 2). Overall, 10 (40%) cases had "LGSC-like" morphology (i.e., Grade 2 nuclear atypia and micropapillary features) and/or RAS/RAF mutation, and most of these showed a wildtype p53 pattern of expression by immunohistochemistry (7/9, 78%). The remaining TP53-wildtype HGSCs (n = 15, 60%) exhibited severe nuclear atypia (Grade 3) and were morphologically indistinguishable from conventional TP53-mutated HGSC. Despite lacking genetic alterations of TP53, these "usual HGSC-like" tumors often showed evidence of p53 dysfunction, including downregulation of expression ('null' or equivocal p53 staining in 9/14, 64%) or MDM2 amplification (n = 2). Our results support the existence of TP53-wildtype HGSCs, which comprise a heterogeneous group of tumors which may arise via distinct pathogenic mechanisms.

Dataset Information

Characterization of desmoglein 2 expression in ovarian serous tumors and its prognostic significance in high-grade serous carcinoma.

Publications

Characterization of desmoglein 2 expression in ovarian serous tumors and its prognostic significance in high-grade serous carcinoma.

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