MAL gene overexpression as a marker of high-grade serous ovarian carcinoma stem-like cells that predicts chemoresistance and poor prognosis

AbstractChromosomal instability (CIN), the continual gain and loss of chromosomes or parts of chromosomes, occurs in the majority of cancers and confers poor prognosis. Mechanisms driving CIN remain unknown in most cancer types due to a scarcity of functional studies. High-grade serous ovarian carcinoma (HGSC), the most common subtype of ovarian cancer, is the major cause of death due to gynaecological malignancy in the Western world with chemotherapy resistance developing in almost all patients. HGSC exhibits high rates of chromosome aberrations and knowledge of causative mechanisms is likely to represent an important step towards combating the poor prognosis of this disease. However, very little is known about the nature of chromosomal instability exhibited by this cancer type in particular due to a historical lack of appropriate cell line models. Here we perform the first in-depth functional characterisation of mechanisms driving CIN in HGSC by analysing eight cell lines that accurately recapitulate HGSC genetics as defined by recent studies. We show, using a range of established functional CIN assays combined with live cell imaging and single molecule DNA fibre analysis, that multiple mechanisms co-exist to drive CIN in HGSC. These include supernumerary centrosomes, elevated microtubule dynamics and DNA replication stress. By contrast, the spindle assembly checkpoint was intact. These findings are relevant for developing therapeutic approaches to manipulating CIN in ovarian cancer, and suggests that such approaches may need to be multimodal to combat multiple co-existing CIN drivers.

Download Full-text

Aldehyde dehydrogenase 1/epidermal growth factor receptor coexpression is characteristic of a highly aggressive, poor-prognosis subgroup of high-grade serous ovarian carcinoma

Human Pathology ◽

10.1016/j.humpath.2012.12.016 ◽

2013 ◽

Vol 44 (8) ◽

pp. 1465-1471 ◽

Cited By ~ 23

Author(s):

Catarina Alisa Liebscher ◽

Judith Prinzler ◽

Bruno Valentin Sinn ◽

Jan Budczies ◽

Carsten Denkert ◽

...

Keyword(s):

Epidermal Growth Factor Receptor ◽

Growth Factor ◽

Epidermal Growth Factor ◽

Ovarian Carcinoma ◽

Aldehyde Dehydrogenase ◽

Poor Prognosis ◽

Growth Factor Receptor ◽

High Grade ◽

Serous Ovarian Carcinoma ◽

Epidermal Growth

Download Full-text

Overexpression of ICAM-1 Predicts Poor Survival in High-Grade Serous Ovarian Carcinoma: A Study Based on TCGA and GEO Databases and Tissue Microarray

BioMed Research International ◽

10.1155/2019/2867372 ◽

2019 ◽

Vol 2019 ◽

pp. 1-9 ◽

Cited By ~ 1

Author(s):

Shasha Wang ◽

Can Yin ◽

Ying Zhang ◽

Lu Zhang ◽

Lin Tao ◽

...

Keyword(s):

Overall Survival ◽

Ovarian Carcinoma ◽

Mrna Expression ◽

Adhesion Molecule ◽

Poor Prognosis ◽

Prognostic Biomarker ◽

The Cancer Genome Atlas ◽

High Grade ◽

Poor Survival ◽

Serous Ovarian Carcinoma

Intercellular cell adhesion molecule-1 (ICAM-1), an important adhesion molecule in the immunoglobulin superfamily, is expressed on many cell types. Recent studies have identified ICAM-1 as a potential oncogene that promotes the development of epithelial ovarian cancer (EOC); it was also found to be associated with poor survival. However, the clinical significance of its expression in high-grade serous ovarian carcinoma (HGSOC) is unclear. Thus, this study aimed to investigate the significance of ICAM-1 expression in HGSOC. Data on ICAM1 expression and mutations in serous ovarian carcinoma (SOC) were obtained from the Cancer Genome Atlas (TCGA), and ICAM1 mRNA expression data in HGSOC were obtained from the Gene Expression Omnibus (GEO) database. ICAM-1 expression was evaluated by immunohistochemistry in HGSOC and normal fallopian tube tissues microarray. In TCGA data, amplification/mutation of ICAM1 was identified in 12% of serous ovarian carcinoma samples, and overexpression of ICAM1 mRNA predicted reduced overall survival in SOC. From TCGA and GEO data, SOC patients with ICAM1 mRNA overexpression treated with chemotherapeutic drugs that contained taxol or taxol and platin together had significantly reduced progression-free survival. According to GEO data, ICAM1 mRNA expression was found significantly higher in HGSOC than in control samples. In our study, ICAM-1 overexpression was observed in 63.1% (65/103) of HGSOCs. As a prognostic biomarker, overexpression of ICAM-1 predicted reduced recurrence-free and overall survival and is an independent risk factor for poor prognosis. These findings suggest that overexpression of ICAM-I is an independent indicator of poor prognosis for HGSOC and that it can serve as an effective clinical prognostic biomarker for this disease.

Download Full-text

Proteomic Discovery of Biomarkers to Predict Prognosis of High-Grade Serous Ovarian Carcinoma

Cancers ◽

10.3390/cancers12040790 ◽

2020 ◽

Vol 12 (4) ◽

pp. 790 ◽

Cited By ~ 1

Author(s):

Se Ik Kim ◽

Minsun Jung ◽

Kisoon Dan ◽

Sungyoung Lee ◽

Cheol Lee ◽

...

Keyword(s):

Ovarian Carcinoma ◽

Poor Prognosis ◽

Apolipoprotein A1 ◽

High Expression ◽

Ca 125 ◽

High Grade ◽

Platelet Factor ◽

Favorable Prognosis ◽

Serous Ovarian Carcinoma ◽

Prognosis Group

Initial identification of biomarkers predicting the exact prognosis of high-grade serous ovarian carcinoma (HGSOC) is important in precision cancer medicine. This study aimed to investigate prognostic biomarkers of HGSOC through proteomic analysis. We conducted label-free liquid chromatography-mass spectrometry using chemotherapy-naïve, fresh-frozen primary HGSOC specimens, and compared the results between a favorable prognosis group (progression-free survival (PFS) ≥ 18 months, n = 6) and a poor prognosis group (PFS < 18 months, n = 6). Among 658 differentially expressed proteins, 288 proteins were upregulated in the favorable prognosis group and 370 proteins were upregulated in the poor prognosis group. Using hierarchical clustering, we selected α1-antitrypsin (AAT), nuclear factor-κB (NFKB), phosphomevalonate kinase (PMVK), vascular adhesion protein 1 (VAP1), fatty acid-binding protein 4 (FABP4), platelet factor 4 (PF4), apolipoprotein A1 (APOA1), and α1-acid glycoprotein (AGP) for further validation via immunohistochemical (IHC) staining in an independent set of chemotherapy-naïve primary HGSOC samples (n = 107). Survival analyses revealed that high expression of AAT, NFKB, and PMVK were independent biomarkers for favorable PFS. Conversely, high expression of VAP1, FABP4, and PF4 were identified as independent biomarkers for poor PFS. Furthermore, we constructed models predicting the 18-month PFS by combining clinical variables and IHC results. Through leave-one-out cross-validation, the optimal model was based on initial serum CA-125, germline BRCA1/2 mutations, residual tumors after surgery, International Federation of Gynecology and Obstetrics (FIGO) stage, and expression levels of the six proteins. The present results elucidate the proteomic landscape of HGSOC and six protein biomarkers to predict the prognosis of HGSOC.

Download Full-text