[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: 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
[Show abstract][Hide abstract] ABSTRACT: The involvement of VICKZ proteins has been implicated in a large number of cancers. The aim of the present study was to investigate the biological and clinical role of VICKZ proteins in ovarian carcinoma. VICKZ1-3 protein expression was analyzed in 82 serous ovarian carcinoma specimens (51 effusions, 14 primary carcinomas, 17 solid metastases) by immunoblotting. Protein localization was studied using immunohistochemistry in 101 tumors (40 effusions, 25 primary carcinomas, 36 solid metastases). The effect of VICKZ silencing using short hairpin RNA (shRNA) on collagenolytic activity and invasion was assessed in ES-2 ovarian carcinoma cells. VICKZ2 was the most frequently expressed family member in serous carcinomas. VICKZ levels measured by pan-VICKZ antibody were significantly higher in primary carcinomas and solid metastases compared to effusions (p<0.001). In contrast, VICKZ1 and VICKZ2 were overexpressed in effusions compared to primary carcinomas and solid metastases (p=0.016 and p=0.024, respectively), and higher VICKZ2 expression in effusions was associated with shorter overall survival in univariate analysis (p=0.01). All 3 proteins were localized to OC cells by immunohistochemistry, with tumor-specific expression observed for VICKZ1 and VICKZ2. VICKZ silencing in ES-2 cells led to reduced matrix metalloproteinase-9 activity and reduced invasion. In conclusion, VICKZ2 is the most frequently expressed VICKZ family member in serous ovarian carcinomas. VICKZ1 and VICKZ2 are overexpressed in effusions compared to primary carcinomas and solid metastases, suggesting a biological role at this anatomic site, and appear to have a role in proteolysis and invasion. VICKZ2 may be a prognostic marker in ovarian serous carcinoma effusions.
Human pathology 07/2014; 45(7). DOI:10.1016/j.humpath.2014.03.005 · 2.77 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Objectives:
We previously described the overexpression of APOA1 and GPX3 in ovarian/peritoneal serous carcinoma compared with breast carcinoma effusions using gene expression array analysis. The objective of the present study was to validate this finding and to analyze the association between these genes and clinicopathologic parameters, including survival, in advanced-stage ovarian serous carcinoma.
APOA1 and GPX3 mRNA expression using quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) was analyzed in 121 effusions (101 ovarian, 20 breast carcinomas) and 85 solid ovarian carcinoma specimens (43 primary carcinomas, 42 metastases).
APOA1 and GPX3 transcript levels were significantly higher in ovarian carcinoma at all anatomic sites compared with breast carcinoma effusions (P < .001). GPX3 mRNA levels were significantly higher in primary carcinomas and solid metastases from patients who received neoadjuvant chemotherapy compared with chemo-naïve tumors (P = .016). APOA1 and GPX3 mRNA levels in the entire effusion series were unrelated to clinicopathologic parameters. However, higher APOA1 mRNA levels in primary diagnosis pre-chemotherapy effusions were significantly related to better overall survival (P = .045), a finding that retained its significance in Cox multivariate analysis (P = .016).
APOA1 and GPX3 mRNA levels on qRT-PCR effectively differentiate ovarian from breast carcinoma. APOA1 may be a novel prognostic marker in metastatic serous carcinoma.
American Journal of Clinical Pathology 07/2014; 142(1):51-7. DOI:10.1309/AJCPD8NBSHXRXQL7 · 2.51 Impact Factor