Small Cell Carcinoma of the Ovary, Hypercalcemic Type (SCCOHT) beyond SMARCA4 Mutations: A Comprehensive Genomic Analysis.

Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) is an aggressive malignancy that occurs in young women, is characterized by recurrent loss-of-function mutations in the SMARCA4 gene, and for which effective treatments options are lacking. The aim of this study was to broaden the knowledge on this rare malignancy by reporting a comprehensive molecular analysis of an independent cohort of SCCOHT cases. We conducted Whole Exome Sequencing in six SCCOHT, and RNA-sequencing and array comparative genomic hybridization in eight SCCOHT. Additional immunohistochemical, Sanger sequencing and functional data are also provided. SCCOHTs showed remarkable genomic stability, with diploid profiles and low mutation load (mean, 5.43 mutations/Mb), including in the three chemotherapy-exposed tumors. All but one SCCOHT cases exhibited 19p13.2-3 copy-neutral LOH. SMARCA4 deleterious mutations were recurrent and accompanied by loss of expression of the SMARCA2 paralog. Variants in a few other genes located in 19p13.2-3 (e.g., PLK5) were detected. Putative therapeutic targets, including MAGEA4, AURKB and CLDN6, were found to be overexpressed in SCCOHT by RNA-seq as compared to benign ovarian tissue. Lastly, we provide additional evidence for sensitivity of SCCOHT to HDAC, DNMT and EZH2 inhibitors. Despite their aggressive clinical course, SCCOHT show remarkable inter-tumor homogeneity and display genomic stability, low mutation burden and few somatic copy number alterations. These findings and preliminary functional data support further exploration of epigenetic therapies in this lethal disease

TWIST1 a New Determinant of Epithelial to Mesenchymal Transition in EGFR Mutated Lung Adenocarcinoma

Metastasis is a multistep process and the main cause of mortality in lung cancer patients. We previously showed that EGFR mutations were associated with a copy number gain at a locus encompassing the TWIST1 gene on chromosome 7. TWIST1 is a highly conserved developmental gene involved in embryogenesis that may be reactivated in cancers promoting both malignant conversion and cancer progression through an epithelial to mesenchymal transition (EMT). The aim of this study was to investigate the possible implication of TWIST1 reactivation on the acquisition of a mesenchymal phenotype in EGFR mutated lung cancer. We studied a series of consecutive lung adenocarcinoma from Caucasian non-smokers for which surgical frozen samples were available (n = 33) and showed that TWIST1 expression was linked to EGFR mutations (P<0.001), to low CDH1 expression (P<0.05) and low disease free survival (P = 0.044). To validate that TWIST1 is a driver of EMT in EGFR mutated lung cancer, we used five human lung cancer cell lines and demonstrated that EMT and the associated cell mobility were dependent upon TWIST1 expression in cells with EGFR mutation. Moreover a decrease of EGFR pathway stimulation through EGF retrieval or an inhibition of TWIST1 expression by small RNA technology reversed the phenomenon. Collectively, our in vivo and in vitro findings support that TWIST1 collaborates with the EGF pathway in promoting EMT in EGFR mutated lung adenocarcinoma and that large series of EGFR mutated lung cancer patients are needed to further define the prognostic role of TWIST1 reactivation in this subgroup

EMT Inducers Catalyze Malignant Transformation of Mammary Epithelial Cells and Drive Tumorigenesis towards Claudin-Low Tumors in Transgenic Mice

The epithelial-mesenchymal transition (EMT) is an embryonic transdifferentiation process consisting of conversion of polarized epithelial cells to motile mesenchymal ones. EMT–inducing transcription factors are aberrantly expressed in multiple tumor types and are known to favor the metastatic dissemination process. Supporting oncogenic activity within primary lesions, the TWIST and ZEB proteins can prevent cells from undergoing oncogene-induced senescence and apoptosis by abolishing both p53- and RB-dependent pathways. Here we show that they also downregulate PP2A phosphatase activity and efficiently cooperate with an oncogenic version of H-RAS in malignant transformation of human mammary epithelial cells. Thus, by down-regulating crucial tumor suppressor functions, EMT inducers make cells particularly prone to malignant conversion. Importantly, by analyzing transformed cells generated in vitro and by characterizing novel transgenic mouse models, we further demonstrate that cooperation between an EMT inducer and an active form of RAS is sufficient to trigger transformation of mammary epithelial cells into malignant cells exhibiting all the characteristic features of claudin-low tumors, including low expression of tight and adherens junction genes, EMT traits, and stem cell–like characteristics. Claudin-low tumors are believed to be the most primitive breast malignancies, having arisen through transformation of an early epithelial precursor with inherent stemness properties and metaplastic features. Challenging this prevailing view, we propose that these aggressive tumors arise from cells committed to luminal differentiation, through a process driven by EMT inducers and combining malignant transformation and transdifferentiation

ANALYSE GENETIQUE DES TUMEURS GERMINALES (RECHERCHE D'INSTABILITE GENETIQUE ET CARACTERISTIQUES GENOTYPIQUES (DOCTORAT BIOLOGIE))

LYON1-BU Santé (693882101) / SudocPARIS-BIUM (751062103) / SudocPARIS-BIUP (751062107) / SudocSudocFranceF

Le carcinome tubaire (étude anatomo-clinique d'une série de 27 cas)

LYON1-BU Santé (693882101) / SudocSudocFranceF

[Genomic profiling by comparative genomic hybridization: analysis of ten enucleated uveal melanoma cases].

International audienceAIM: To detect major chromosomal aberrations from enucleated uveal melanoma and relate them to hepatic metastasis and survival. PATIENTS AND METHODS: Ten uveal melanomas enucleated between 2005 and 2008 in the Lyon Croix-Rousse Hospital were retrospectively analyzed using a 19 000-clone comparative genomic hybridization microarray. RESULTS: The most frequent imbalances were the loss of chromosome 3 (8/10), gain of the 8q arm (7/10) or the entire chromosome 8 (2/10), and gain of the 6p arm (2/10). Most metastatic tumors (6/7) and all cases of death (5/5) concerned melanoma with monosomy 3 and gain of the 8q arm. DISCUSSION AND CONCLUSION: Genome-wide array comparative genomic hybridization is a reliable tool for identifying uveal melanoma genomic imbalances. Gains of the 8q arm with monosomy 3 are frequent and are strongly associated with poor outcome. Gains of the 6p arm are rare and have a better prognosis. There is a mutually exclusive relationship between monosomy 3 and chromosome 6 abnormalities in our study. These results confirm previously published reports

Proposition of a multiparametric model-based method for breast lesion differentiation: a feasibility study

International audienceElastography has been introduced to complement mammography and sonography with the purpose of better differentiating benign from malignant lesions. With this regard, criteria such as elasticity score and strain index, also termed strain ratio (SR), have been introduced. SR was defined as the mean strain value of the background divided by the mean strain value within the lesion

Transcriptome profiling of gastric-type endocervical adenocarcinomas identifies key signaling pathways for tumor progression

International audienceObjective: Gastric-type endocervical carcinoma is a rare entity of carcinoma of the cervix. In contrast to the intestinal type, the gastric type is not related to Human Papilloma Virus (HPV) infection and has been reported to be much more aggressive than the usual type. Oncogenic pathways involved in this poor-prognosis phenotype are largely unexplored.Methods: We compared activation of the main signaling pathways involved in cancer progression between the intestinal- (n = 5), gastric- (n = 6) and usual-type (n = 6) adenocarcinomas of the cervix using a targeted transcriptomic approach (expression of 770 genes) on FFPE samples.Results: We identified a gene-expression signature composed of 11 genes that allows the classification of these endocervical carcinoma as three distinct molecular entities. There were similarities between mucinous endocervical carcinomas (gastric and intestinal types) despite difference in pathogenesis related to HPV infection. Among HPV-related endocervical carcinoma, the intestinal type could be molecularly distinguished from the usual type by high expression of EIF2AK3 and low expression of PPFIBP2 genes, supporting its classification as a distinct entity. Overexpression of TAL1 and S1PR1 genes were characteristic of the gastric type. The usual type was characterized by high expression of occludin and VAV3 genes. Tight junction disruptions might play an essential role in the metastatic potential of mucinous endocervical carcinoma with concomitant loss of OCLN and claudin 4 proteins. An overexpression of NTRK1 transcript was observed in mucinous endocervical carcinomas when compared to the usual type.Conclusions: This transcriptomic study identified a signature that supports the classification of endocervical carcinomas as three distinct entities: usual-, intestinal- and gastric-type. It also points out to disruption of tight junctions as a potential mechanism of metastatic dissemination of these rare tumors

Diagnostic yield and therapeutic impact of open lung biopsy in the critically ill patient.

Open lung biopsy (OLB) is a rare procedure in intensive care units (ICUs) for therapeutic management of acute respiratory failure (ARF). The purpose of this study was to analyze the diagnostic yield, therapeutic contribution and complications of OLB in ICU patients with ARF of unclear etiology, including acute respiratory distress syndrome (ARDS) and ARDS mimics.Retrospective study conducted in a 10-bed ICU over a 13-year period. Patients undergoing OLB for ARF with undiagnosed infiltrates on CT scan were included. ARDS was defined according to Berlin criteria, and ARDS mimics as a condition looking like ARDS except for the presence of a known cause. OLB was contributive when the OLB findings yielded a specific diagnosis resulting in a change in the patients' treatment or management.Forty six patients were included (sex ratio = 2.5, median and [interquartile range] age = 69 [59-77] years, and admission SAPS II = 42 [33-50]. ARF corresponded to ARDS in 22 patients and to ARDS mimics in 16. OLB yielded 61 diagnoses in 45 patients including diffuse alveolar damage (N = 21), lung fibrosis (N = 18), and organizing pneumonia (N = 11). OLB was contributive in 37 patients (80%), including 13/16 ARDS mimickers. The main contributions of OLB were the introduction or maintenance of steroids (N = 32) and discontinuation of antibiotics (N = 9). In 4 patients OLB resulted directly in the decision to forgo life-sustaining treatment. OLB complications occurred in 16 patients (35%), in one case associated with fatal outcome.OLB can play a useful role in the management of ICU patients with ARF of undetermined origin, including ARDS mimickers. Further studies should be done to identify the groups of ICU patients likely to benefit from the procedure with minimum risk