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Mazouni C.,Laboratoire Of Transfert Doncologie Biologique | Mazouni C.,Institute Gustave Roussy | Fina F.,Laboratoire Of Transfert Doncologie Biologique | Romain S.,Laboratoire Of Transfert Doncologie Biologique | And 3 more authors.
British Journal of Cancer | Year: 2011

Purpose:Although a potential role of the Epstein-Barr virus (EBV) in the pathogenesis of breast cancer (BC) has been underlined, results remain conflicting. Particularly, the impact of EBV infection on biological markers of BC has received little investigation. Methods: In this study, we established the frequency of EBV-infected BC using real-time quantitative PCR (RT-PCR) in 196 BC specimens. Biological and pathological characteristics according to EBV status were evaluated. Results: EBV DNA was present in 65 of the 196 (33.2%) cases studied. EBV-positive BCs tended to be tumours with a more aggressive phenotype, more frequently oestrogen receptor negative (P = 0.05) and with high histological grade (P = 0.01). Overexpression of thymidine kinase activity was higher in EBV-infected BC (P = 0.007). The presence of EBV was weakly associated with HER2 gene amplification (P = 0.08). Conclusion: Our study provides evidence for EBV-associated BC undergoing distinct carcinogenic processes, with more aggressive features. © 2011 Cancer Research UK All rights reserved.

Coulibaly B.,Marseille University Hospital Center | Coulibaly B.,French Institute of Health and Medical Research | Nanni I.,Laboratoire Of Transfert Doncologie Biologique | Quilichini B.,French Institute of Health and Medical Research | And 8 more authors.
Human Pathology | Year: 2010

Epidermal growth factor receptor is a transmembrane receptor involved in oncogenesis, including the development of glioblastoma. We studied the prognostic significance of epidermal growth factor receptor amplification as determined by fluorescence in situ hybridization, quantitative polymerase chain reaction, and protein expression by immunohistochemistry. Ninety-nine patients exhibiting glioblastoma were included. Immunohistochemistry was performed on microarray blocks with clone 25, which recognizes both epidermal growth factor receptor wild type and vIII, and scored using a semiquantitative approach. Quantitative polymerase chain reaction and fluorescence in situ hybridization techniques were performed on frozen section: 29.3% of cases had a high epidermal growth factor receptor immunohistochemistry score (score ≥200); and of these cases, 96.5% had gene amplification by fluorescence in situ hybridization and quantitative polymerase chain reaction. Conversely, of cases with a low immunohistochemistry score, 72.9% had normal karyotype or polysomy 7 by fluorescence in situ hybridization technique; but around 25% had gene amplification by fluorescence in situ hybridization and quantitative polymerase chain reaction. In the case of protein overexpression, quantitative polymerase chain reaction and fluorescence in situ hybridization could be avoided in first intention because their positive predictive value for amplification is 97%. In multivariate analysis, there was a trend toward an association between shorter overall survival time and epidermal growth factor receptor amplification as determined by fluorescence in situ hybridization analysis. However, cases with an immunohistochemistry score less 200 require further testing by fluorescence in situ hybridization or quantitative polymerase chain reaction. © 2010 Elsevier Inc. All rights reserved.

Metellus P.,Service de Neurochirurgie | Metellus P.,Aix - Marseille University | Metellus P.,French Institute of Health and Medical Research | Nanni-Metellus I.,Laboratoire Of Transfert Doncologie Biologique | And 18 more authors.
Annals of Surgical Oncology | Year: 2011

Background: Cancer stem cells are thought to represent the population of tumorigenic cells responsible for tumor development. The CD133 antigen has been described as a putative stem cell marker in malignant brain tumor that could identify such a tumorigenic population in a subset of glioblastoma. To date, the correlation between CD133 expression in primary glioblastoma and patient prognosis is not clearly established. To address this question we investigated the relationship between CD133 mRNA expression and patient outcome in a glioblastoma patient cohort. Materials and Methods: The quantitative expression of CD133 stem cell antigen mRNA using real-time QRT-PCR was assessed in a cohort of 48 consecutive primary glioblastoma patients treated by chemoradiation with temozolomide. Results: On multivariate survival analysis, high CD133 mRNA expression was a significant (P = 0.007) prognostic factor for adverse progression-free and overall survival independent of extent of resection (P = 0.012) and MGMT methylation status (P = 0.002). Patient age was also an independent prognosticator of overall survival (P = 0.037). Furthermore, according to the conjoined expression of CD133 mRNA and MGMT status, the patients were categorized into 3 groups with homogenous prognosis. Conclusions: These findings constitute conclusive evidence that the measurement of the mRNA expression of CD133 stem cell antigen actually impacts the survival of GBM patients. © 2011 Society of Surgical Oncology.

Jezequel P.,Institute Of Cancerologie Of Louest Rene Gauducheau | Campion L.,Institute Of Cancerologie Of Louest Rene Gauducheau | Spyratos F.,Institute Curie | Loussouarn D.,Service dAnatomie Pathologique B | And 12 more authors.
International Journal of Cancer | Year: 2012

Novel prognostic biomarkers are imperatively needed to help direct treatment decisions by typing subgroups of node-negative breast cancer patients. Large screening of different biological compartments, such as the proteome, by means of high throughput techniques may greatly help scientists to find such markers. The present retrospective multicentric study included 268 node-negative breast cancer patients. We used a proteomic approach of SELDI-TOF-MS screening to identify differentially expressed cytosolic proteins with prognostic impact. The screening cohort was composed of 198 patients. Seventy supplementary patients were included for validation. Immunohistochemistry (IHC) and immunoassay (IA) were run to confirm the prognostic role of the marker identified by SELDI-TOF-MS screening. IHC was also used to explore links between selected marker and epithelial-mesenchymal transition (EMT)-like, proliferation and macrophage markers. Ferritin light chain (FTL) was identified as an independent prognostic marker (HR = 1.30-95% CI: 1.10-1.50, p = 0.001). Validation step by means of IHC and IA confirmed the prognostic value of FTL level. CD68 IHC showed that FTL was stored in tumor-associated macrophages (TAM), which exhibit an M2-like phenotype. We report here, first, the validation of FTL as a breast tumor prognostic biomarker in node-negative patients, and second, the fact that FTL is stored in TAM. Copyright © 2011 UICC.

Descotes F.,Center Hospitalier Lyon Sud | Dessen P.,Institute Gustave Roussy | Bringuier P.P.,HCL Inc | Decaussin M.,Center Hospitalier Lyon Sud | And 13 more authors.
BJU International | Year: 2014

Objective To try and identify a molecular signature for pathological staging and/or grading. through microarray analysis. Patients and Methods We performed a prospective multicentre study between September 2007 and May 2008 that included 108 bladder tumours (45 pTa, 35 pT1 and 28>pT1). Microarray analysis was performed using Agilent Technologies Human Whole Genome 4 × 44K oligonucleotide microarrays (Agilent, Santa Clara, CA, USA). A 'dual colour' method was used vs a reference pool of tumours. From the lists of genes provided by the Biometric Research Branch class comparison analyses, we validated the microarray results of 38 selected differentially expressed genes using reverse transcriptase quantitative PCR in another bladder tumour cohort (n = 95). Results The cluster 'superficial vs invasive stage' correctly classified 92.9% of invasive stages and 66.3% of superficial stages. Among the superficial tumours, the cluster analysis showed that pT1b tumours were closer to invasive stages than pT1a tumours. We also found molecular differences between low and high grade superficial tumours, but these differences were less well defined than the difference observed for staging. Conclusions We confirmed that the histopathological classification into subgroups pTa, pT1a and pT1b can be translated into a molecular signature with a continuous progression of deregulation (overexpression or repression of these genes) from superficial (pTa) to more invasive (pT1a then b) stages. © 2013 The Authors. BJU International © 2013 BJU International.

Mazouni C.,Laboratoire Of Transfert Doncologie Biologique | Mazouni C.,Institute Gustave Roussy | Fina F.,Institute Gustave Roussy | Romain S.,Institute Gustave Roussy | And 3 more authors.
Journal of Cancer Research and Clinical Oncology | Year: 2015

Purpose: To develop a prognostic nomogram to predict freedom from recurrence for patients treated with adjuvant hormonal therapy (HT) for localised breast cancer (BC).Methods: We performed a retrospective analysis of 142 patients treated with adjuvant HT between 1996 and 2000. Clinical and pathological parameters were analysed.Results: A nomogram that predicts the probability of remaining free of recurrence for 5 years after surgery with adjuvant HT was developed using a Cox proportional hazards regression model. The progesterone receptor status (p < 0.001), nodal status (p = 0.008) and cathepsin-D (p < 0.001) were retained to construct the nomogram (C-index 0.734).Conclusions: The nomogram we developed may be useful for estimating the probability of successful treatment 5 years after surgery for localised BC. © 2014, Springer-Verlag Berlin Heidelberg.

Mazouni C.,Laboratoire Of Transfert Doncologie Biologique | Mazouni C.,Institute Gustave Roussy | Spyratos F.,University Pierre and Marie Curie | Romain S.,Laboratoire Of Transfert Doncologie Biologique | And 4 more authors.
European Journal of Cancer | Year: 2012

Background: Currently, the benefit of chemotherapy (CT) in node-negative breast carcinoma (NNBC) is discussed. The evaluation of classical clinical and histological factors is limited to assess individual outcome. A statistical model was developed to improve the prognostic accuracy of NNBC. Methods: A total of 305 node-negative breast carcinomas who underwent surgery (+/- radiotherapy) but no adjuvant treatment were selected. Putative prognosis factors including age, tumour size, oestrogen receptor (ER), progesterone receptor (PgR), Scarff-Bloom-Richardon (SBR) grading, urokinase plasminogen activator (uPA), plasminogen activator inhibitor 1 (PAI-1) and thymidine kinase (TK) were evaluated. The developed model was internally validated using Harrell's concordance index. A prognosis index (PI) was proposed and compared with Adjuvant! Online program. Results: Age (p < 0.001), pathological tumour size (pT) (p < 0.001), PgR (p = 0.02), and PAI-1 (p ≤ 0.001) were included in the Cox regression model predicting Breast cancer specific survival (BCSS) at 5-years. Internal validation revealed a concordance index of 0.71. A PI score was derived from our nomogram. The PI score was significantly associated with BCSS (hazard ratio (HR): 4.1 for intermediate, p = 0.02, HR: 8.8, p < 0.001 for high group) as compared to Adjuvant! Online score (HR: 1.4, p = 0.14). Conclusion: A nomogram can be used to predict probability survival curves for individual breast cancer patients. © 2012 Elsevier Ltd. All rights reserved.

Metellus P.,Hopital de la Timone | Metellus P.,French Institute of Health and Medical Research | Metellus P.,Aix - Marseille University | Colin C.,French Institute of Health and Medical Research | And 16 more authors.
Journal of Neuro-Oncology | Year: 2011

Mutations in the gene encoding isocitrate dehydrogenase enzyme isoforms 1 (IDH1) and 2 (IDH2) have recently been identified in a large proportion of glial tumors of the CNS, but their mechanistic role in tumor development remains unclear. Here, we assessed the actual impact of IDH1 and IDH2 mutations in patients harboring WHO grade II and III gliomas. We sequenced IDH1 at codon 132 and IDH2 at codon 172 in 33 patients with WHO grade II and III gliomas who benefited from a preoperative 18F-FDG positron emission tomography (PET). Immunohistochemical expression of Hypoxia Inducible Factor-1alpha (HIF-1α), Carbonic Anhydrase IX (CAIX), Glucose Transporter 1 (GLUT1) and Caspase 3 active form (CASP3) along with the R132HIDH1 mutation was assessed in all cases as well as 1p/19q deletion status and p53 expression. HIF-1α expression was found in 15% of IDH-mutated compared to 7.7% of IDH-nonmutated tumors (P = 0.954). Also, GLUT-1 positive staining was found in 5% of IDH-mutated and in 7.1% of IDH-nonmutated tumors (P = 0.794). Finally, CA-IX expression was found in 15% of IDH-mutated and in 7.7% of IDH-nonmutated tumors (P = 0.484). The combined expression of these three hypoxic markers was found in two WHO grade III tumors, one of which was IDH-mutated whereas the other was IDH-nonmutated (P = 0.794). In IDH-mutated tumors, the median SUVmax ratio was 2.24 versus 2.15 in IDH-nonmutated tumors (P = 0.775). Together, these data question the actual relationship between IDH mutation status and in vivo hypoxic biomarkers expression in WHO grade II and III gliomas. © 2011 Springer Science+Business Media, LLC.

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