Anne-Claire Voegeli

Institut de biologie moléculaire des plantes, Strasbourg, Strasburg, Alsace, France

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Publications (10)31.52 Total impact

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    ABSTRACT: MET pathway is a promising target in non-small cell lung cancers (NSCLC) requiring companion tests. The aim of this study was to compare MET expression/gene copy number in a Caucasian population of NSCLC patients.We analysed 201 NSCLC, with 141 adenocarcinomas classified according to 2011 IASLC recommendations, for MET expression by immunohistochemistry (IHC) and gene copy number (GCN) by silver in situ hybridisation (SISH) on tissue microarrays. Mutations in EGFR, KRAS, BRAF, HER2, PIK3CA genes and ALK rearrangements were determined.MET overexpression was observed in 44% and a high MET GCN (≥5 copies) in 14%. MET CGN was correlated with MET expression, regardless of IHC scores (p < 0.001) but only 31% of MET overexpressed cases were SISH positive. MET overexpression/GCN number was more frequent in ADC than the other types (p < 0.001), the highest in high grade (74%/34%) and sarcomatoid ADC (86%/43%). Mutations of current genes or ALK rearrangements were identified in overexpressed or amplified MET cases. MET overexpression was an independent prognostic factor for overall survival in non-smoker NSCLC in univariate (p = 0.01) and multivariate (p = 0.01) analyses.MET overexpression is more frequent than MET high GCN, particularly in high grade ADC, regardless of EGFR, KRAS, BRAF, HER2, PIK3CA and ALK status in NSCLC.
    Pathology 05/2015; DOI:10.1097/PAT.0000000000000269 · 2.62 Impact Factor
  • European Respiratory Review 09/2014; 23(133):390-2. DOI:10.1183/09059180.00009313
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    ABSTRACT: Epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors have limited use as first-line treatment for mutated EGFR metastatic non-small cell lung cancer. The French National Cancer Institute has installed molecular genetics platforms implementing EGFR and KRAS testing. However, there is considerable uncertainty as to which detection methods should be applied for routine diagnosis. This study aimed to compare the EGFR and KRAS genotyping methods developed by the IFCT/ERMETIC2 network platforms in two blind panels: 25 samples of serial dilutions of cell line DNA (20 centers) and 74 FFPE lung tumor samples (10 centers). The best threshold of mutation detection on cell lines was obtained using allele-specific amplification-based technologies. Nonamplifiable tissue samples were significantly less common when using alternative testing versus direct sequencing [15%; 95% confidence interval (CI), 14%-16% versus 40%; 95% CI, 39%-42%; P < 0.001]. Mutated cases increased from 42% (95% CI, 31%-54%) to 53% (95% CI, 41%-64%), with three supplementary EGFR mutations (p.G179A at exon 18 and p.L858R and p.L861Q at exon 21) and five supplementary KRAS mutations, when using alternative testing instead of direct sequencing. False-positive results were observed when using a PCR-based sizing assay, high-resolution melting, or pyrosequencing. Concordance analysis returned good kappa test scores for EGFR exon 19 and KRAS analysis when comparing sequencing with alternative methods and revealed no difference between alternative techniques themselves.
    The Journal of molecular diagnostics: JMD 10/2013; 16(1). DOI:10.1016/j.jmoldx.2013.07.009 · 3.96 Impact Factor
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    ABSTRACT: Sarcomas represent a complex and heterogeneous group of rare malignant tumors and their correct diagnosis is often difficult. Recent molecular biological techniques have been of great diagnostic use and there is a need to assess the cost of these procedures in routine clinical practice. Using prospective and observational data from eight molecular biology laboratories in France, we used "microcosting" method to assess the cost of molecular biological techniques in the diagnosis of five types of sarcoma. The mean cost of fluorescence in situ hybridization (FISH) was 318 € (273-393) per sample; mean reverse transcription polymerase chain reaction (RT-PCR) cost ranged from 300 € (229-481) per formalin-fixed, paraffin-embedded specimen to 258 € (213-339) per frozen specimen; mean quantitative polymerase chain reaction (Q-PCR) cost was 184 € (112-229) and mean CGH-array cost was 332 € (329-335). The cost of these recently implemented techniques varied according to the type of sarcoma; the method of tissue collection and local organizational factors including the level of local expertise and investment. The cost of molecular diagnostic techniques needs to be balanced against their respective performance.
    Bulletin du cancer 10/2013; DOI:10.1684/bdc.2013.1822 · 0.64 Impact Factor
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    ABSTRACT: Aggressive fibromatosis (AF) or desmoid tumor is a rare condition, characterized by deep tissue invasion by a monoclonal fibroblastic neoplasm, developed from musculoaponeurotic structures. Surgery is the treatment of choice, but negative margins can hardly been achieved in large tumors, and can lead to major functional disability. AF medical therapy includes nonsteroids anti-inflammatory drugs, tamoxifen, with inconsistent results. Several reports of imatinib efficacy in AF appear in the literature. Here, we describe for the first time a V530I KIT exon 10 mutant that was associated to a dramatic imatinib response in an extraabdominal aggressive fibromatosis. The previously discovered V530I substitution was characterized in the core binding factor AML, but had never been reported in any other condition, so far. In this paper, we discuss the KIT exon 10 mutations or polymorphisms that have been described in a variety of KIT-related conditions, including acute myelogenous leukemia, mastocytosis, and aggressive fibromatosis.
    Sarcoma 03/2010; 2010:458156. DOI:10.1155/2010/458156
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    ABSTRACT: Despite recent progress, colon cancer is often resistant to combination chemotherapy, highlighting the need for development of novel therapeutic approaches. An attractive target is hypoxia-inducible factor-1alpha (HIF-1alpha), a key transcription factor with a pivotal role in tumor cell metabolism. One potential class of therapeutic agents targeting HIF-1alpha are mammalian target of rapamycin inhibitors such as rapamycin. A second class are topoisomerase I inhibitors, such as irinotecan, which are able to inhibit the accumulation of HIF-1alpha. We here investigated whether combination of rapamycin and irinotecan was active in human colon cancer models. Human metastatic tumors were xenografted in nude mice and treated with low doses of irinotecan alone, rapamycin alone, or combination of both drugs. The cellular effects of irinotecan and rapamycin were further characterized for HT-29 and HCT-116 colon cancer cells in vitro. In contrast to single-agent therapy, xenografted tumors treated with combination of irinotecan and rapamycin showed potent inhibition of the mammalian target of rapamycin/HIF-1alpha axis, which was accompanied by a dramatic reduction in tumor volume. In vitro experiments showed that exposure to low concentrations of the two drugs resulted in massive HT-29 cell death under hypoxic, but not normoxic, conditions, in full agreement with a cytotoxic effect mediated through HIF-1alpha rather than through induction of genotoxic lesions. HCT-116 cells were less sensitive to the combined treatment due to constitutive activation of phosphatidylinositol 3-kinase/Akt and Ras/mitogen-activated protein kinase pathways. These results identify HIF-1alpha as a promising target and provide a rationale for clinical trials of low-dose irinotecan and rapamycin combination toward metastatic colon cancer.
    Clinical Cancer Research 03/2009; 15(4):1297-307. DOI:10.1158/1078-0432.CCR-08-0889 · 8.19 Impact Factor
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    ABSTRACT: Crohn’s disease is considered to be caused either by an excess of T-cell effector functions and/or by a defective regulatory T-cell compartment. The aim of this study was to assess in Crohn’s disease the frequency of circulating CD4+CD25high T cells that possess regulatory T-cell functions and CD4+CD25low T cells that contain activated T cells. Flow cytometry of peripheral blood was used to assess CD4+CD25high and CD4+CD25low T-cell frequencies in a cohort of 66 patients with Crohn’s disease in comparison to 19 patients with ulcerative colitis and 31 healthy individuals enrolled as controls. The CD4+CD25high T-cell frequency was significantly lowered in naïve Crohn’s disease (P=0.013) and in ulcerative colitis (P=0.001). CD4+CD25low T-cell frequency was increased in Crohn’s disease (P=0.0001) and in ulcerative colitis (P=0.0002). Both CD4+CD25high and CD4+CD25low T-cell frequencies are altered in naïve Crohn’s disease resulting in an imbalance between both populations and a relative contraction of the CD4+CD25high T-cell population.
    Digestive Diseases and Sciences 10/2008; 54(10):2084-2093. DOI:10.1007/s10620-008-0590-6 · 2.55 Impact Factor
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    ABSTRACT: Risk assessments of patients should be based on objective variables, such as biological markers that can be measured routinely. The acute response to stress causes the release of catecholamines from the adrenal medulla accompanied by chromogranin A (CGA). To date, no study has evaluated the prognostic value of CGA in critically ill intensive care unit patients. We conducted a prospective study of intensive care unit patients by measuring serum procalcitonin (PCT), C-reactive protein (CRP), and CGA at the time of admission. Univariate and multivariate analyses were performed to evaluate the ability of these biomarkers to predict mortality. In 120 consecutive patients, we found positive correlations between CGA and the following: CRP (r(2) = 0.216; P = 0.02), PCT (r(2) = 0.396; P < 0.001), Simplified Acute Physiologic Score II (SAPS II) (r(2) = 0.438; P < 0.001), and the Logistic Organ Dysfunction System (LODS) score (r(2) = 0.374; P < 0.001). Nonsurvivors had significantly higher CGA and PCT concentrations than survivors [median (interquartile range): 293.0 microg/L (163.5-699.5 microg/L) vs 86.0 microg/L (53.8-175.3 microg/L) for CGA, and 6.78 microg/L (2.39-22.92 microg/L) vs 0.54 microg/L (0.16-6.28 microg/L) for PCT; P < 0.001 for both comparisons]. In a multivariable linear regression analysis, creatinine (P < 0.001), age (P < 0.001), and SAPS II (P = 0.002) were the only significant independent variables predicting CGA concentration (r(2) = 0.352). A multivariate Cox regression analysis identified 3 independent factors predicting death: log-normalized CGA concentration [hazard ratio (HR), 7.248; 95% confidence interval (CI), 3.004-17.487], SAPS II (HR, 1.046; 95% CI, 1.026-1.067), and cardiogenic shock (HR, 3.920; 95% CI, 1.731-8.880). CGA is a strong and independent indicator of prognosis in critically ill nonsurgical patients.
    Clinical Chemistry 09/2008; 54(9):1497-503. DOI:10.1373/clinchem.2007.102442 · 7.77 Impact Factor
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    ABSTRACT: Recent clinical success of epidermal growth factor (EGFR)-tyrosine kinase inhibitors (TKIs) in non-small cell lung cancer (NSCLC) have raised hopes that targeting other deregulated growth factor signaling, such as the hepatocyte growth factor/MET pathway, will lead to new therapeutic options for NSCLC. Furthermore, NSCLC present secondary EGFR-TKIs resistance related to exons 20 and 19 EGFR mutations or more recently to MET amplification. The aim of this study was to determine MET copy number related to EGFR copy number and K-Ras mutations in a targeted TKI naive NSCLC cohort. We investigated 106 frozen tumors from surgically resected NSCLC patients. Genes copy number of MET and EGFR were assessed by quantitative relative real-time polymerase chain reaction and K-Ras mutations by sequencing. MET is amplified in 22 cases (21%) and deleted in nine cases (8.5%). EGFR is amplified in 31 cases (29%). K-Ras is mutated in 11 cases (10.5%). As observed for EGFR amplification, MET amplification is never associated with K-Ras mutation. MET amplification could be associated with EGFR amplification. MET amplification is not related to clinical and pathologic features. MET amplification and EGFR amplification showed a trend toward poor prognosis in adenocarcinomas. In EGFR-TKIs naive NSCLC patients, MET amplification is a frequent event, which could be associated with EGFR amplification, but not with K-Ras mutation. MET amplification may identify a subset of NSCLC for new targeted therapy. It will also be important to evaluate MET copy number to properly interpret future clinical trials.
    Journal of thoracic oncology: official publication of the International Association for the Study of Lung Cancer 05/2008; 3(4):331-9. DOI:10.1097/JTO.0b013e318168d9d4 · 5.80 Impact Factor