15 research outputs found
Genetic Alterations in Mitochondrial DNA Are Complementary to Nuclear DNA Mutations in Pheochromocytomas
Background: Somatic mutations, copy-number variations, and genome instability of mitochondrial DNA (mtDNA) have been reported in different types of cancers and are suggested to play important roles in cancer development and metastasis. However, there is scarce information about pheochromocytomas and paragangliomas (PCCs/PGLs) formation. Material: To determine the potential roles of mtDNA alterations in sporadic PCCs/PGLs, we analyzed a panel of 26 nuclear susceptibility genes and the entire mtDNA sequence of seventy-seven human tumors, using next-generation sequencing, and compared the results with normal adrenal medulla tissues. We also performed an analysis of copy-number alterations, large mtDNA deletion, and gene and protein expression. Results: Our results revealed that 53.2% of the tumors harbor a mutation in at least one of the targeted susceptibility genes, and 16.9% harbor complementary mitochondrial mutations. More than 50% of the mitochondrial mutations were novel and predicted pathogenic, affecting mitochondrial oxidative phosphorylation. Large deletions were found in 26% of tumors, and depletion of mtDNA occurred in more than 87% of PCCs/PGLs. The reduction of the mitochondrial number was accompanied by a reduced expression of the regulators that promote mitochondrial biogenesis (PCG1α, NRF1, and TFAM). Further, P62 and LC3a gene expression suggested increased mitophagy, which is linked to mitochondrial dysfunction. Conclusion: The pathogenic role of these finding remains to be shown, but we suggest a complementarity and a potential contributing role in PCCs/PGLs tumorigenesis.Funding: This study was supported by ALF Grants (RĂ-532021), Region Ăstergötland, a grant from the Medical Research Council of Southeast Sweden (FORSS) (FORSS-481781), and by a grant from LiU Cancer, Linköping University (LiU-2019).</p
Utilisation du logiciel PELICAN pour la saisie et lâexport de comptes rendus standardisĂ©s dans les tumeurs du systĂšme nerveux central : application aux mĂ©ningiomes
International audienceIntroduction : Lâapplication PELICAN (« Partager efficacement en laboratoire les informations des comptes rendus anatomopathologiques ») est un outil permettant de gĂ©nĂ©rer des comptes rendus standardisĂ©s et de renseigner automatiquement une base de donnĂ©es, utilisĂ©e au CHRU de Nancy depuis 2014 en neuropathologie tumorale. Lâobjectif de cet article Ă©tait dâillustrer lâutilisation de cette application pour les mĂ©ningiomes, avec une premiĂšre exploitation statistique.MatĂ©riels et mĂ©thodes : LâĂ©tude inclut les cas de mĂ©ningiomes enregistrĂ©s dans lâapplication PELICAN jusquâen juillet 2018. Lâapplication PELICAN est un fichier Microsoft Excel comportant un logiciel Ă©crit en Visual Basic pour Applications, utilisĂ© par le pathologiste pour Ă©laborer le compte rendu. Les principales donnĂ©es cliniques ont Ă©tĂ© recueillies Ă partir de la fiche de recensement du Registre de lâHĂ©rault. Le suivi Ă©tait renseignĂ© de façon systĂ©matique pour les mĂ©ningiomes atypiques.RĂ©sultats : Deux cent quatre-vingt-quinze mĂ©ningiomes ont Ă©tĂ© analysĂ©s dont 250 mĂ©ningiomes de grade I, 42 mĂ©ningiomes de grade II et 3 mĂ©ningiomes de grade III. Dans les mĂ©ningiomes de grade II, on constatait une proportion significativement plus Ă©levĂ©e dâhommes (p = 0,002) et dâinfiltration de la dure-mĂšre (p < 0,001), une augmentation significative de lâindice Ki-67 (p < 0,0001) et une diminution significative de lâexpression des rĂ©cepteurs Ă la progestĂ©rone (p < 0,001). Dans les mĂ©ningiomes atypiques, un indice Ki-67 de plus de 20 % Ă©tait corrĂ©lĂ© significativement Ă une survie sans progression plus courte (p = 0,032).Conclusion : Lâapplication PELICAN est un outil dâutilisation simple, permettant de gĂ©nĂ©rer des comptes rendus standardisĂ©s tout en alimentant une base de donnĂ©es, ouvrant de trĂšs intĂ©ressantes perspectives dâun point de vue Ă©pidĂ©miologique et scientifique
Large-Scale Proteomics Identifies Distinct Signatures for Richter Syndrome and De Novo Diffuse Large B-Cell Lymphoma: A French Study from the Filo Group
International audienc
Clinical, biological, and molecular genetic features of Richter syndrome and prognostic significance: a study of the French Innovative Leukemia Organization
International audienc
Humoral immunity to SARS-CoV-2 and seasonal coronaviruses in children and adults in north-eastern France
International audienceBackground: Children are underrepresented in the COVID-19 pandemic and often experience milder disease than adolescents and adults. Reduced severity is possibly due to recent and more frequent seasonal human coronaviruses (HCoV) infections. We assessed the seroprevalence of SARS-CoV-2 and seasonal HCoV specific antibodies in a large cohort in north-eastern France. Methods: In this cross-sectional seroprevalence study, serum samples were collected from children and adults requiring hospital admission for non-COVID-19 between February and August 2020. Antibody responses to SARS-CoV-2 and seasonal HCoV (229E, HKU1, NL63, OC43) were assessed using a bead-based multiplex assay, Luciferase-Linked ImmunoSorbent Assay, and a pseudotype neutralisation assay. Findings: In 2,408 individuals, seroprevalence of SARS-CoV-2-specific antibodies was 7-8% with three different immunoassays. Antibody levels to seasonal HCoV increased substantially up to the age of 10. Antibody responses in SARS-CoV-2 seropositive individuals were lowest in adults 18-30 years. In SARS-CoV-2 seronegative individuals, we observed cross-reactivity between antibodies to the four HCoV and SARS-CoV-2 Spike. In contrast to other antibodies to SARS-CoV-2, specific antibodies to sub-unit 2 of Spike (52) in seronegative samples were highest in children. Upon infection with SARS-CoV-2, antibody levels to Spike of betacoronavirus OC43 increased across the whole age spectrum. No SARS-CoV-2 seropositive individuals with low levels of antibodies to seasonal HCoV were observed. Interpretation: Our findings underline significant cross-reactivity between antibodies to SARS-CoV-2 and seasonal HCoV, but provide no significant evidence for cross-protective immunity to SARS-CoV-2 infection due to a recent seasonal HCoV infection. In particular, across all age groups we did not observe SARS-CoV-2 infected individuals with low levels of antibodies to seasonal HCoV
Molecular characterization of Richter syndrome identifies de novo diffuse large B-cell lymphomas with poor prognosis
International audienceRichter syndrome (RS) is the transformation of chronic lymphocytic leukemia (CLL) into aggressive lymphoma, most commonly diffuse large B-cell lymphoma (DLBCL). We characterize 58 primary human RS samples by genome-wide DNA methylation and whole-transcriptome profiling. Our comprehensive approach determines RS DNA methylation profile and unravels a CLL epigenetic imprint, allowing CLL-RS clonal relationship assessment without the need of the initial CLL tumor DNA. DNA methylation - and transcriptomic-based classifiers were developed, and testing on landmark DLBCL datasets identifies a poor-prognosis, activated B-cell-like DLBCL subset in 111/1772 samples. The classification robustly identifies phenotypes very similar to RS with a specific genomic profile, accounting for 4.3-8.3% of de novo DLBCLs. In this work, RS multi-omics characterization determines oncogenic mechanisms, establishes a surrogate marker for CLL-RS clonal relationship, and provides a clinically relevant classifier for a subset of primary âRS-type DLBCLâ with unfavorable prognosis
Molecular characterization of Richter syndrome identifies de novo diffuse large B-cell lymphomas with poor prognosis
Richter syndrome (RS) is the transformation of chronic lymphocytic leukaemia (CLL) into aggressive lymphoma, in most cases diffuse large B-cell lymphoma (DLBCL). Here, the authors characterize the DNA methylation and transcriptomic profiles of RS samples, find a clonally-related CLL epigenetic imprint, and develop classifiers for âRS-typeâ de novo DLBCLs
Prospective Multicenter Validation of the Detection of ALK Rearrangements of Circulating Tumor Cells for Noninvasive Longitudinal Management of Patients With Advanced NSCLC
International audienceIntroduction: Patients with advanced-stage NSCLC whose tumors harbor an ALK gene rearrangement benefit from treatment with multiple ALK inhibitors (ALKi). Approximately 30% of tumor biopsy samples contain insufficient tissue for successful ALK molecular characterization. This study evaluated the added value of analyzing circulating tumor cells (CTCs) as a surrogate to ALK tissue analysis and as a function of the response to ALKi.Methods: We conducted a multicenter, prospective observational study (NCT02372448) of 203 patients with stage IIIB/IV NSCLC across nine French centers, of whom 81 were ALK positive (immunohistochemistry or fluorescence in situ hybridization [FISH]) and 122 ALK negative on paraffin-embedded tissue specimens. Blood samples were collected at baseline and at 6 and 12 weeks after ALKi initiation or at disease progression. ALK gene rearrangement was evaluated with CTCs using immunocytochemistry and FISH analysis after enrichment using a filtration method.Results: At baseline, there was a high concordance between the detection of an ALK rearrangement in the tumor tissue and in CTCs as determined by immunocytochemistry (sensitivity, 94.4%; specificity 89.4%). The performance was lower for the FISH analysis (sensitivity, 35.6%; specificity, 56.9%). No significant association between the baseline levels or the dynamic change of CTCs and overall survival (hazard ratio = 0.59, 95% confidence interval: 0.24-1.5, p = 0.244) or progression-free survival (hazard ratio = 0.84, 95% confidence interval: 0.44-1.6, p = 0.591) was observed in the patients with ALK-positive NSCLC.Conclusions: CTCs can be used as a complementary tool to a tissue biopsy for the detection of ALK rearrangements. Longitudinal analyses of CTCs revealed promise for real-time patient monitoring and improved delivery of molecularly guided therapy in this population
Efficacy and Safety of Rovalpituzumab Tesirine Compared With Topotecan as Second-Line Therapy in DLL3-High SCLC: Results From the Phase 3 TAHOE Study
International audienc