Oncogenetic Unit

Paris, France

Oncogenetic Unit

Paris, France
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Barreau O.,Institute National Of La Sante Et Of La Recherche Medicale Unite 1016 | Barreau O.,University of Paris Descartes | Barreau O.,French National Center for Scientific Research | De Reynies A.,Programme Cartes dIdentite des Tumeurs | And 29 more authors.
Journal of Clinical Endocrinology and Metabolism | Year: 2012

Purpose: Diagnosing malignancy of adrenocortical tumors (ACT) and predicting prognosis in carcinomas are often challenging. Transcriptome markers have recently emerged, providing promising clinical relevance and improved pathophysiological knowledge. Whether tumoral chromosomal alterations provide similar information is not known. The aim was to evaluate the diagnostic and prognostic value of chromosomal alterations in ACT and to identify genes associated with benign and malignant tumorigenesis. Experimental Design: Chromosomal alterations of 86 adenomas and 52 carcinomas were identified by comparative genomic hybridization arrays and/or quantitative PCR. Results: A larger proportion of the genome is altered in carcinomas compared with adenomas (44 vs. 10%, P = 2.10-10). In adenomas, the 9q34 region, which includes the steroidogenic factor 1 locus, is commonly gained and associated with an overexpression of steroidogenic factor 1 (SF-1). In carcinomas, recurrent gains include chromosomes 5, 7, 12, 16, 19, and 20 and recurrent losses chromosomes 13 and 22. Filtering the genes from these regions according to their expression profile identified genes potentially relevant to adrenocortical tumorigenesis. A diagnostic tool was built by combining DNA copy number estimates at six loci (5q, 7p, 11p, 13q, 16q, and 22q). This tool discriminates carcinomas from adenomas in an independent validation cohort (sensitivity 100%, specificity 83%). In carcinomas, the number of chromosomal alterations was not associated with survival (Cox P = 0.84). A prognostic tool based on tumor DNA was designed with a clustering strategy and validated in an independent cohort. Conclusions: Chromosomal alterations in ACT discriminate carcinomas from adenomas and contain prognostic information. Chromosomal alterations alter the expression of genes important for tumorigenesis. Copyright © 2012 by The Endocrine Society.

Barreau O.,Institute National Of La Sante Et Of La Recherche Medicale Unite 1016 | Barreau O.,French National Center for Scientific Research | Barreau O.,University of Paris Descartes | Assie G.,Institute National Of La Sante Et Of La Recherche Medicale Unite 1016 | And 29 more authors.
Journal of Clinical Endocrinology and Metabolism | Year: 2013

Purpose: DNA methylation is a mechanism for gene expression silencing in cancer. Limited information is available for adrenocortical tumors. Abnormal methylation at the IGF2/H19 locus is common in adrenocortical carcinomas. Our aim was to characterize the methylation in adrenocortical carcinomas at a whole-genome scale and to assess its clinical significance and its impact on gene expression. Experimental Design: Methylation patterns of CpG islands in promoter regions of 51 adrenocortical carcinomas and 84 adenomas were studied by the Infinium Human Methylation 27 Beadchip (Illumina, San Diego, CA). Methylation of 33 genes was studied by methylation-specific multiplex ligation-dependent probe amplification (MRC-Holland, Amsterdam, The Netherlands) in 15 carcinomas. Gene expression data were available for 87 tumors from a previous study (HG-U133Plus2.0 AffymetrixGeneChip; Affymetrix, Santa Clara, CA). Clinical information, including patient features and survival, were available for all tumors. Results: Methylation was higher in carcinomas than in adenomas (t test P = 3.1 × 10-9). Unsupervised clustering of DNA methylation profiles identified two groups of carcinomas, one with an elevated methylation level, evoking a CpG island methylator phenotype (CIMP). The subgroup of hypermethylated carcinomas was further divided in two subgroups, with different levels of methylation (CIMP-high and CIMP-low). This classification could be confirmed by methylation-specific multiplex ligation-dependent probe amplification. Hypermethylation was associated with a poor survival (Cox model P = 0.02). The transcriptome/methylation correlation showed 1741 genes (of 12,250) negatively correlated; among the top genes were H19 and other tumor suppressors (PLAGL-1, G0S2, and NDRG2). Conclusions: This genome-wide methylation analysis reveals the existence of hypermethylated adrenocortical carcinomas, with a poorer prognosis. Hypermethylation in these tumors is important for silencing specific tumor suppressor genes. Copyright © 2013 by The Endocrine Society.

Personnier C.,Paediatric Endocrinology and Gynaecology | Personnier C.,Center Des Maladies Endocriniennes Rares Of La Croissance | Cazabat L.,French Institute of Health and Medical Research | Bertherat J.,French Institute of Health and Medical Research | And 12 more authors.
Hormone Research in Paediatrics | Year: 2011

Context: Pediatric somatotropinoma is uncommon but usually more aggressive than in adults, creating therapeutic challenges. No treatment guidelines are available. Objectives: To describe the features of pediatric somatotropinomas and to assess therapeutic strategies based on an extensive literature review. Design: We describe a pediatric case of aggressive somatotropinoma with an AIP mutation. We identified 137 pediatric somatotropinoma cases published between 1981 and 2010, and found 41 cases with AIP mutations in the main review. Results: We found a slight male preponderance (59%). Median age was 9 years at symptom onset and 14 years at diagnosis. Macroadenomas accounted for 90% of the tumors; 2/3 of the children had hyperprolactinemia at diagnosis. The first-line treatment was pharmacotherapy in one third and surgery in 2/3 of the patients. Pegvisomant was used in 7 patients and produced significant improvement in 4. The male preponderance was higher in the subgroup with AIP mutations. Mutations leading to severe protein abnormalities were more common than reported in adults. Conclusion: Higher invasiveness and tumor volume in pediatric somatotropinomas require complex treatment combinations, which produce variable results. Pegvisomant is an effective drug whose usefulness in children remains to be determined. Genetic screening, particularly for AIP mutations, should be performed routinely. Copyright © 2011 S. Karger AG, Basel.

Libe R.,Institute National Of La Sante Et Of La Recherche Medicale Unite 1016 | Libe R.,University of Paris Descartes | Horvath A.,U.S. National Institutes of Health | Vezzosi D.,Institute National Of La Sante Et Of La Recherche Medicale Unite 1016 | And 25 more authors.
Journal of Clinical Endocrinology and Metabolism | Year: 2011

Background: Carney complex (CNC) is an autosomal dominant multiple neoplasia, caused mostly by inactivating mutations of the regulatory subunit 1A of the protein kinase A (PRKAR1A). Primary pigmented nodular adrenocortical disease (PPNAD) is the most frequent endocrine manifestation of CNC with a great inter-individual variability. Germline, protein-truncating mutations of phosphodiesterase type 11A (PDE11A) have been described to predispose to a variety of endocrine tumors, including adrenal and testicular tumors. Objectives: Our objective was to investigate the role of PDE11A as a possible gene modifier of the phenotype in a series of 150 patients with CNC. Results: A higher frequency of PDE11A variants in patients with CNC compared with healthy controls was found (25.3 vs. 6.8%, P < 0.0001). Among CNC patients, those with PPNAD were significantly more frequently carriers of PDE11A variants compared with patients without PPNAD (30.8 vs.13%, P = 0.025). Furthermore, men with PPNAD were significantly more frequently carriers of PDE11A sequence variants (40.7%) than women with PPNAD (27.3%) (P < 0.001). A higher frequency of PDE11A sequence variants was also found in patients with large-cell calcifying Sertoli cell tumors (LCCSCT) compared with those without LCCSCT (50 vs. 10%, P = 0.0056). PDE11A variants were significantly associated with the copresence of PPNAD and LCCSCT in men: 81 vs. 20%, P < 0.004). The simultaneous inactivation of PRKAR1A and PDE11A by small inhibitory RNA led to an increase in cAMP-regulatory element-mediated transcriptional activity under basal conditions and after stimulation by forskolin. Conclusions: We demonstrate, in a large cohort of CNC patients, a high frequency of PDE11A variants, suggesting that PDE11A is a genetic modifying factor for the development of testicular and adrenal tumors in patients with germline PRKAR1A mutation. Copyright © 2011 by The Endocrine Society.

Zidan J.,Oncology Institute | Zidan J.,Technion - Israel Institute of Technology | Sikorsky N.,Lynn Medical Center | Basher W.,Oncology Institute | And 3 more authors.
International Journal of Cancer | Year: 2012

Breast cancer (BC) does not affect ethnic groups equally. BC mortality is higher in Israeli Palestinian Arab women than among Israeli Jewish women. This study aims to compare clinical, biological and pathological characteristics of breast cancer in the two populations. Records of 1,140 women with BC treated at Northern Israel between 2002 and 2007 were reviewed: 872 Jews and 268 Arabs. Age at diagnosis, tumor stage, pathological differentiation, estrogen receptor (ER) and HER-2 expression were evaluated. The main age at diagnosis was 49.9 years for Arabs and 59.4 years for Jews (p < 0.0001). Mean tumor size was < 2 cm in 25% of Arabs and 53% of Jews (p < 0.0001). Lymph node metastases presented in 64.6% of Arabs and 37.2% of Jews (p < 0.0001). Stage I disease was 19% in Arab and 49.2% in Jewish women while Stages III and IV disease was 42% and 11.3% respectively (p < 0.001). ER was positive in 69% of Arabs and in 78.5% of Jews (p < 0.001). Poorly differentiated tumors were found in 28.8% of Arabs vs. 12.8% in Jews (p < 0.0001). Overexpression of HER-2 was present in 35.4% of Arab and 22% of Jewish women (p < 0.001). We found that race is an important predictive factor for breast cancer. Arab women are diagnosed at younger age, with more advanced stage and biologically more aggressive disease than in Jewish women. Socioeconomic factors alone are not sufficient to explain significant effects of race on tumor characteristics. Findings suggest a different genetic susceptibility in the two populations which needs further research. Copyright © 2011 UICC.

PubMed | Oncology, Bergonie Institute, Francois Mitterand Hospital, Radiotherapy Unit and 8 more.
Type: | Journal: Oncotarget | Year: 2016

Until recently, the molecular diagnosis of hereditary breast and ovarian cancer (HBOC) was mostly based on BRCA1/2 testing. Next generation sequencing and the recent discovery of new genes involved in HBOC now permit the transfer of genomic capture targeting multiple candidate genes from research to clinical use. However, the implications for the management of patients and their families have not been extensively studied, in particular since some of these genes are not well-established cancer predisposing genes. We studied 583 consecutive patients from Burgundy (France) fulfilling the criteria for BRCA testing using a next generation sequencing 25-genes panel including 20 well-established high-risk cancer genes as well as more recently identified predisposing HBOC cancer. A pathogenic BRCA1/2 mutation was found in 51 patients (9%). Besides, we found 37 pathogenic or likely pathogenic mutations in 10 different high to low-risk genes in 34 patients (6%). The most frequently mutated genes were CHEK2 (n = 12; 2%), ATM (n = 9; 1.5%), and PALB2 (n = 4; 0.6%). Three patients had a mutation in two different predisposing genes. The analysis of clinical actionability conducted in mutation-positive individuals revealed that additional disease-specific screening and/or prevention measures beyond those based on personal and family history alone had been recommended in 69% of cases. In conclusion, multigene panel testing is a powerful tool to identifying high to low-risk HBOC susceptibility genes. The penetrance and spectrum of cancers with these other genes are sometimes undefined, and further collaborative work is crucial to address this question.

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