[Show abstract][Hide abstract] ABSTRACT: The objective of this study was to investigate the expression and clinical role of 14 genes previously shown to be associated with chemotherapy response and/or progression-free survival in a smaller series of ovarian serous carcinoma effusions.
Advanced-stage serous ovarian carcinoma effusions (n = 150) were analyzed for mRNA expression of AKR1C1, ABCA4, ABCA13, ABCB10, BIRC6, CASP9, CIAPIN1, FAS, MGMT, MUTYH, POLH, SRC, TBRKB and XPA using quantitative real-time PCR. mRNA expression was studied for association with clinicopathologic parameters, including chemotherapy response and survival.
ABCA4 mRNA expression was significantly related to better (complete) chemotherapy response at diagnosis in the entire cohort (p = 0.018), whereas higher POLH mRNA levels were significantly related to better chemoresponse at diagnosis in analysis to 58 patients with pre-chemotherapy effusions treated with standard chemotherapy (carboplatin + paclitaxel; p = 0.023). In univariate survival analysis for patients with pre-chemotherapy effusions (n = 77), CIAPIN1 mRNA expression was significantly related to shorter overall (p = 0.007) and progression-free (p = 0.038) survival, whereas ABCA13 mRNA expression was significantly related to shorter OS (p = 0.024). Higher CIAPIN1 mRNA expression was an independent marker of poor overall survival in Cox multivariate analysis (p = 0.044).
Our data identify ABCA4 and POLH as markers of better chemotherapy response in metastatic serous carcinoma. CIAPIN1 and ABCA13 may be novel markers of poor outcome in pre-chemotherapy serous carcinoma effusions.
Molecular Cancer 12/2015; 14(1). DOI:10.1186/s12943-015-0317-1 · 4.26 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background:
Understanding carboplatin resistance in ovarian cancer is critical for the improvement of patients' lives. Multipotent mesenchymal stem cells or an aggravated epithelial to mesenchymal transition phenotype of a cancer are integrally involved in pathways conferring chemo-resistance. Long non-coding RNA HOTAIR (HOX transcript antisense intergenic RNA) is involved in mesenchymal stem cell fate and cancer biology.
We analyzed HOTAIR expression and associated surrogate DNA methylation (DNAme) in 134 primary ovarian cancer cases (63 received carboplatin, 55 received cisplatin and 16 no chemotherapy). We validated our findings by HOTAIR expression and DNAme analysis in a multicentre setting of five additional sets, encompassing 946 ovarian cancers. Chemo-sensitivity has been assessed in cell culture experiments.
HOTAIR expression was significantly associated with poor survival in carboplatin-treated patients with adjusted hazard ratios for death of 3.64 (95 % confidence interval [CI] 1.78-7.42; P < 0.001) in the discovery and 1.63 (95 % CI 1.04-2.56; P = 0.032) in the validation set. This effect was not seen in patients who did not receive carboplatin (0.97 [95 % CI 0.52-1.80; P = 0.932]). HOTAIR expression or its surrogate DNAme signature predicted poor outcome in all additional sets of carboplatin-treated ovarian cancer patients while HOTAIR expressors responded preferentially to cisplatin (multivariate interaction P = 0.008).
Non-coding RNA HOTAIR or its more stable DNAme surrogate may indicate the presence of a subset of cells which confer resistance to carboplatin and can serve as (1) a marker to personalise treatment and (2) a novel target to overcome carboplatin resistance.
Genome Medicine 10/2015; 7(1):108. DOI:10.1186/s13073-015-0233-4 · 5.34 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The aim of this study was to analyze the diagnostic role of MMP-7 in effusion cytology. Effusions (n = 356), consisting of 307 carcinomas (184 ovarian, 55 breast, 32 lung, 36 carcinomas of other origin) and 49 malignant mesotheliomas, were analyzed for MMP-7 expression using immunohistochemistry. MMP-7 was expressed in 124/307 (40%) carcinomas and was uniformly absent in malignant mesotheliomas (0/49; 0%; P < .001). Reactive mesothelial cells were similarly MMP-7 negative in all carcinoma specimens. In carcinomas, expression was most frequent in tumors of ovarian and other female genital (cervical and endometrial) origin (P < .001). The sensitivity and specificity of this marker in the differential diagnosis between high-grade serous carcinoma and malignant mesothelioma were 46% and 100%, respectively. In conclusion, MMP-7 expression is highly specific, though only of moderate sensitivity, for the diagnosis of carcinoma in the differential diagnosis from both benign and malignant mesothelial cells.
Human pathology 09/2015; DOI:10.1016/j.humpath.2015.08.020 · 2.77 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: A comprehensive pathological report is essential for optimal patient management, cancer staging and prognostication. In many countries, proforma reports are used but these vary in their content. The International Collaboration on Cancer Reporting (ICCR) is an alliance formed by the Royal College of Pathologists of Australasia, the Royal College of Pathologists of the United Kingdom, the College of American Pathologists, the Canadian Partnership Against Cancer and the European Society of Pathology, with the aim of developing an evidence-based reporting data set for each cancer site. This will reduce the global burden of cancer data set development and reduplication of effort by different international institutions that commission, publish and maintain standardised cancer reporting data sets. The resultant standardisation of cancer reporting will benefit not only those countries directly involved in the collaboration but also others not in a position to develop their own data sets. We describe the development of a cancer data set by the ICCR expert panel for the reporting of primary ovarian, fallopian tube and peritoneal carcinoma and present the 'required' and 'recommended' elements to be included in the report with an explanatory commentary. This data set encompasses the recent International Federation of Obstetricians and Gynaecologists staging system for these neoplasms and the updated World Health Organisation Classification of Tumours of the Female Reproductive Organs. The data set also addresses issues about site assignment of the primary tumour in high-grade serous carcinomas and proposes a scoring system for the assessment of tumour response to neoadjuvant chemotherapy. The widespread implementation of this data set will facilitate consistent and accurate data collection, comparison of epidemiological and pathological parameters between different populations, facilitate research and hopefully will result in improved patient management.
Modern Pathology 06/2015; 28(8). DOI:10.1038/modpathol.2015.77 · 6.19 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Malignant tumors of the vulva account for only 5% of cancers of the female genital tract in the USA. The most frequent cancers of the vulva are squamous cell carcinoma (SCC) and malignant melanoma (MM). Little is known about the genetic aberrations carried by these tumors. We report a detailed study of 25 vulva tumors [22 SCC, 2 MM, 1 atypical squamous cell hyperplasia (AH)] analyzed for expression of the high-mobility group AT-hook family member genes HMGA2 and HMGA1, for mutations in the IDH1, IDH2 and TERT genes, and for methylation of the MGMT promoter. The RT-PCR and immunohistochemistry analyses showed that HMGA2 was expressed in the great majority of analyzed samples (20 out of 24; SCC as well as MM) but not in the normal controls. HMGA1, on the other hand, was expressed in both tumors and normal tissues. Five of the 24 tumors (all SCC) showed the C228T mutation in the TERT promoter. Our results showed that HMGA2 and TERT may be of importance in the genesis and/or the progression of tumors of the vulva.
[Show abstract][Hide abstract] ABSTRACT: We recently identified gene signatures which allow classification of ovarian carcinoma into 5 distinct clinically-relevant groups. In the present study, we investigated the clinical role of 10 protein products of the discriminating genes, with focus on epithelial-mesenchymal transition and stem cell markers. Expression of E-cadherin, N-cadherin, P-cadherin, Zeb1, HMGA2, Rab25, CD24, NCAM (CD56), Sox11 and vimentin was assessed in 100 advanced-stage (FIGO III-IV) serous ovarian carcinoma effusions using immunohistochemistry. Results were analyzed for association with clinicopathologic parameters, including chemotherapy response, and survival. All 10 proteins were frequently expressed in carcinoma cells. HMGA2 expression was related to older age (p = 0.015). HMGA2 and NCAM expression was related to stage III disease (p = 0.011 and p = 0.023, respectively) and NCAM was overexpressed in peritoneal compared to pleural effusions (p = 0.001). Vimentin and Zeb1 expression was significantly related to poor chemotherapy response at diagnosis (p = 0.005 and p = 0.017, respectively). The associations between NCAM and peritoneal localization and of vimentin and poor chemoresponse were retained after Bonferroni correction. NCAM expression was associated with a trend for shorter overall survival in univariate survival analysis (p = 0.187), but emerged as independent prognosticator in Cox multivariate analysis (p = 0.042). This study identifies Vimentin and Zeb1 as markers of poor chemoresponse in metastatic serous ovarian carcinoma effusions and suggests NCAM as potential prognostic marker in metastatic disease. The generally limited prognostic role of the studied markers emphasizes the difficulty in applying data obtained in studies of primary ovarian carcinomas to analyses of ovarian carcinoma effusions, reflecting the unique biology of the latter.
Human pathology 10/2014; 46(1). DOI:10.1016/j.humpath.2014.10.004 · 2.77 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Ovarian cancer remains the most lethal gynecologic malignancy, owing to late detection, intrinsic and acquired chemoresistance and remarkable heterogeneity. Despite optimization of surgical and chemotherapy protocols and initiation of clinical trials incorporating targeted therapy, only modest gains have been achieved in prolonging survival in this cancer. This review provides an update of recent developments in our understanding of the etiology, origin, diagnosis, progression and treatment of this malignancy, with emphasis on clinically relevant genetic classification approaches. In the authors' opinion, focused effort directed at understanding the molecular make-up of recurrent and metastatic ovarian cancer, while keeping in mind the unique molecular character of each of its histological types, is central to our effort to improve patient outcome in this cancer.
Women s Health 09/2014; 10(5):519-33. DOI:10.2217/whe.14.37
[Show abstract][Hide abstract] ABSTRACT: Objective:
Wee1-like kinase (Wee1) is a tyrosine kinase which negatively regulates entry into mitosis at the G2 to M-phase transition and has a role in inhibition of unscheduled DNA replication in S-phase. The present study investigated the clinical role of Wee1 in advanced-stage (FIGO III-IV) ovarian serous carcinoma.
Wee1 protein expression was analyzed in 287 effusions using immunohistochemistry. Expression was analyzed for association with clinicopathologic parameters, including survival. Forty-five effusions were additionally studied using Western blotting. Wee1 was further silenced in SKOV3 and OVCAR8 cells by siRNA knockdown and proliferation was assessed.
Nuclear expression of Wee1 in tumor cells was observed in 265/287 (92%) and 45/45 (100%) effusions by immunohistochemistry and Western blotting, respectively. Wee1 expression by immunohistochemistry was significantly higher in post-chemotherapy disease recurrence compared to pre-chemotherapy effusions obtained at diagnosis (p=0.002). Wee1 silencing in SKOV3 and OVCAR8 cells reduced proliferation. In univariate survival analysis of the entire cohort, a trend was observed between high (>25% of cells) Wee1 expression and poor overall survival (p=0.083). Survival analysis for 109 patients with post-chemotherapy effusions showed significant association between Wee1 expression and poor overall survival (p=0.004), a finding which retained its independent prognostic role in Cox multivariate analysis (p=0.003).
Wee1 is frequently expressed in ovarian serous carcinoma effusions, and its expression is significantly higher following exposure to chemotherapy. The present study is the first to report that Wee1 is an independent prognostic marker in serous ovarian carcinoma.
[Show abstract][Hide abstract] ABSTRACT: Background: Malignant peripheral nerve sheath tumour (MPNST) is a highly
aggressive cancer, only 20−50% survive the first five years after diagnosis,
and there is a lack of good prognostic markers and effective treatment options
MPNST generally have very complex karyotypes, often with a triploid or
tetraploid chromosome number. DNA copy number gain of chromosome
arm 17q harbouring the antiapoptotic gene BIRC5 (baculoviral IAP repeat
containing 5/survivin) and loss of 10q harbouring the tumour suppressor gene
PTEN (phosphatase and tensin homolog) have been found to be associated
with aggressive disease in MPNST in previous studies. In this study we have
investigated the copy number changes of these genes and the prognostic
impact of their encoded products in a large series of MPNST.
Material and Methods: Genome-Wide Human SNP Array 6.0 (Affymetrix)
was used to analyse genomic copy number in 91 fresh frozen MPNSTs, using
the PennCNV-Affy protocol for preprocessing and the Bioconductor package
‘Copynumber’ for segmentation.
mRNA expression was analysed in 29 MPNSTs and eight neurofibromas
(AB1700 microarray, Applied Biosystems), while protein expression was
analysed by immunohistochemistry on formalin-fixed paraffin-embedded tissue
material from 63 MPNST patients.
Results: The overall profile for copy number changes across all 91 tumour
samples was as expected from previous publications from us and others.
In the present series, we found that 56% of the cases showed gain of the
band on chromosome arm 17q harbouring BIRC5, and 40% had loss of
the 10q sequences harbouring PTEN. Furthermore, we found a significant
increase of BIRC5 mRNA expression in the malignant versus benign tumours
(P = 3×10−7, Mann–Whitney U test, fold change 21), and a significant
decrease in expression of PTEN (P = 3×10−5, Mann–Whitney U test, fold
change 0.4). In univariate Cox regression analyses we also found a significant
association between mRNA expression of BIRC5 and PTEN and 5-year
disease-specific survival (HR 1.91; 95% CI 1.13–3.21; P = 0.015, and HR 0.52;
95% CI 0.31–0.89; P = 0.02, respectively). Expression of BIRC5 was validated
on the protein level, and nuclear staining for BIRC5 showed significant
association to poor disease-specific survival (HR 2.27; 95% CI 1.06–4.87;
P = 0.03).
Conclusions: A high resolution genome wide copy number profile is
determined for the largest MPNSTs series to date, which can be used to
confirm previous findings in smaller series and to detect new changes of
importance to MPNST. Here we demonstrate that differential expression of
BIRC5 and PTEN is best explained by copy number changes and that the
product of these genes may serve as prognostic markers for MPNST patients.
23rd Biennial Congress of the EUROPEAN ASSOCIATION FOR CANCER RESEARCH 2014, Munich; 07/2014