Exome sequencing identifies germline variants in DIS3 in familial multiple myeloma

[Excerpt] Multiple myeloma (MM) is the third most common hematological malignancy, after Non-Hodgkin Lymphoma and Leukemia. MM is generally preceded by Monoclonal Gammopathy of Undetermined Significance (MGUS) [1], and epidemiological studies have identified older age, male gender, family history, and MGUS as risk factors for developing MM [2]. The somatic mutational landscape of sporadic MM has been increasingly investigated, aiming to identify recurrent genetic events involved in myelomagenesis. Whole exome and whole genome sequencing studies have shown that MM is a genetically heterogeneous disease that evolves through accumulation of both clonal and subclonal driver mutations [3] and identified recurrently somatically mutated genes, including KRAS, NRAS, FAM46C, TP53, DIS3, BRAF, TRAF3, CYLD, RB1 and PRDM1 [3,4,5]. Despite the fact that family-based studies have provided data consistent with an inherited genetic susceptibility to MM compatible with Mendelian transmission [6], the molecular basis of inherited MM predisposition is only partly understood. Genome-Wide Association (GWAS) studies have identified and validated 23 loci significantly associated with an increased risk of developing MM that explain ~16% of heritability [7] and only a subset of familial cases are thought to have a polygenic background [8]. Recent studies have identified rare germline variants predisposing to MM in KDM1A [9], ARID1A and USP45 [10], and the implementation of next-generation sequencing technology will allow the characterization of more such rare variants. [...]French National Cancer Institute (INCA) and the Fondation Française pour la Recherche contre le Myélome et les Gammapathies (FFMRG), the Intergroupe Francophone du Myélome (IFM), NCI R01 NCI CA167824 and a generous donation from Matthew Bell. This work was supported in part through the computational resources and staff expertise provided by Scientific Computing at the Icahn School of Medicine at Mount Sinai. Research reported in this paper was supported by the Office of Research Infrastructure of the National Institutes of Health under award number S10OD018522. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The authors thank the Association des Malades du Myélome Multiple (AF3M) for their continued support and participation. Where authors are identified as personnel of the International Agency for Research on Cancer / World Health Organization, the authors alone are responsible for the views expressed in this article and they do not necessarily represent the decisions, policy or views of the International Agency for Research on Cancer / World Health Organizatio

Systemic light chain amyloidosis and Sjogren syndrome: an uncommon association.

International audienceSjogren syndrome is associated with lymphoproliferative disease in 7% of cases; however, association with AL amyloidosis is uncommon. We present a patient who presented simultaneously with Sjogren syndrome (supported by dry mouth, positive Schirmer's test, anti-Ro/SSA antibodies, and a lower lip salivary gland biopsy) and AL amyloidosis revealed by heart failure without myeloma. Although is it know that amyloidosis can masquerade as Sjogren syndrome, the occurrence of simultaneous AL amyloidosis and primary Sjogren syndrome has been reported rarely

Cognitive decline in an old woman: do not miss a rare etiology!

Delirium is common in older people. It is a crucial diagnosis because it raises the morbidity and the mortality. Diagnostic tools like Mini Mental State Examination (MMSE), the confusion assessment method (CAM), and the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSMIV), can help with the diagnosis. We report a case of a woman with neurological symptoms which look like dementia. We diagnosed systemic lupus erythematosus (SLE). The apparition of late-onset SLE is more insidious, which leads to misdiagnosis. We will discuss about the difficulty of the differential diagnosis between delirium, depression and dementia in our patient and the difficulty to manage treatment of neurolupus in older people.Case ReportsJournal ArticleSCOPUS: ar.jinfo:eu-repo/semantics/publishe

Renal Dysfunction in Patients With Direct Infiltration by B-Cell Lymphoma

Background: B-cell lymphoproliferative disorders with renal involvement are relatively frequent, but remain poorly described. A kidney biopsy is usually required to detect the renal lesions that are often missed using other diagnostic tools. Methods: We retrospectively identified 34 patients with renal lymphoma diagnosed by percutaneous kidney biopsy (PKB) at Rennes University Hospital and its affiliated hospital centers between January 1, 2004, and May 1, 2016. Clinical, biological, radiological, and histological characteristics were collected at biopsy time. Results: The included patients had Waldenström macroglobulinemia (n = 12; 35.3%), chronic lymphocytic leukemia/lymphocytic lymphoma (n = 10; 29.5%), high-grade B-cell lymphoma (n = 6; 17.6%), and low-grade B-cell lymphoma (n = 6; 17.6%). The median follow-up was 29 months. Renal involvement led to renal function impairment in 29 patients (85.3%), among whom 20 had acute kidney injury (70%), and to nephrotic syndrome in 4 patients (11.8%). Only 13 patients (38.2%) presented morphological kidney anomalies among whom 5 showed bilateral infiltration. Histologically, interstitial infiltrate (97.1%) was the most common kidney lesion, and 9 patients (26.5%) had specific lymphomatous intraglomerular lesions. After hematological treatment (n = 29), a renal response was observed only in 8 patients (27.6%). Conclusion: Renal involvement in the context of B-cell lymphoproliferative disorders is not uncommon. PKB is the best method to confirm this diagnosis. It should be performed early to rapidly initiate the hematological treatment to preserve kidney function. Keywords: acute kidney injury, kidney biopsy, renal lymphom

Anémie et myélopathie: une colle inhabituelle

SCOPUS: ar.jinfo:eu-repo/semantics/publishe

Atypical bortezomib-induced neutrophilic dermatosis

International audienc

Cardioprotective effects of α‐cardiac actin on oxidative stress in a dilated cardiomyopathy mouse model

International audienceThe expression of α‐cardiac actin, a major constituent of the cytoskeleton of cardiomyocytes, is dramatically decreased in a mouse model of dilated cardiomyopathy triggered by inducible cardiac‐specific serum response factor (Srf) gene disruption that could mimic some forms of human dilated cardiomyopathy. To investigate the consequences of the maintenance of α‐cardiac actin expression in this model, we developed a new transgenic mouse based on Cre/LoxP strategy, allowing together the induction of SRF loss and a compensatory expression of α‐cardiac actin. Here, we report that maintenance of α‐cardiac actin within cardiomyocytes temporally preserved cytoarchitecture from adverse cardiac remodeling through a positive impact on both structural and transcriptional levels. These protective effects were accompanied in vivo by the decrease of ROS generation and protein carbonylation and the downregulation of NADPH oxidases NOX2 and NOX4. We also show that ectopic expression of α‐cardiac actin protects HEK293 cells against oxidative stress induced by H2O2. Oxidative stress plays an important role in the development of cardiac remodeling and contributes also to the pathogenesis of heart failure. Taken together, these findings indicate that α‐cardiac actin could be involved in the regulation of oxidative stress that is a leading cause of adverse remodeling during dilated cardiomyopathy development

Rituximab for induction and maintenance treatment of ANCA-associated vasculitides: a multicentre retrospective study on 80 patients

International audienceOBJECTIVES: Rituximab has been shown to induce remission of ANCA-associated vasculitides (AAVs). Our study was undertaken to describe AAV clinical responses to rituximab used for remission-induction and/or maintenance therapy, assess rituximab's safety profile and evaluate French clinical practices. METHODS: This retrospective study concerned AAV patients who had received one or more rituximab infusion between 2002 and January 2011 and had follow-up lasting ≥12 months. RESULTS: Eighty patients were included, most with refractory or relapsing AAV: 70 (88%) with granulomatosis with polyangiitis (GPA), 9 (11%) with microscopic polyangiitis and 1 (1%) with eosinophilic GPA. Rituximab was the first agent used to induce remission in 73 patients. The two most commonly administered regimens were an infusion of 375 mg/m(2)/week for 4 weeks (54 patients) and an infusion of 1 g every 2 weeks for a month (16 patients). Rituximab was first prescribed to maintain remission in seven patients. Respective 1-, 2-, and 3-year relapse-free survival rates after the first infusion were 80% (95% CI 72, 89), 63% (51, 77) and 52% (39, 70). Relapse-free survival was longer for patients receiving rituximab maintenance therapy (P = 0.002). Among 22 (28%) rituximab-treated patients experiencing severe adverse events, 12 (15%) had infectious complications leading to 4 (5%) deaths. Only 15 (19%) patients had received anti-pneumococcal vaccine before rituximab. CONCLUSION: Rituximab was able to induce AAV remission and seemed to maintain remission better than other agents, but caution is needed concerning its safety, especially regarding bacterial infections, in this population

The DNA methylation landscape of multiple myeloma shows extensive inter- and intrapatient heterogeneity that fuels transcriptomic variability

International audienceAbstract Background Cancer evolution depends on epigenetic and genetic diversity. Historically, in multiple myeloma (MM), subclonal diversity and tumor evolution have been investigated mostly from a genetic perspective. Methods Here, we performed an analysis of 42 MM samples from 21 patients by using enhanced reduced representation bisulfite sequencing (eRRBS). We combined several metrics of epigenetic heterogeneity to analyze DNA methylation heterogeneity in MM patients. Results We show that MM is characterized by the continuous accumulation of stochastic methylation at the promoters of development-related genes. High combinatorial entropy change is associated with poor outcomes in our pilot study and depends predominantly on partially methylated domains (PMDs). These PMDs, which represent the major source of inter- and intrapatient DNA methylation heterogeneity in MM, are linked to other key epigenetic aberrations, such as CpG island (CGI)/transcription start site (TSS) hypermethylation and H3K27me3 redistribution as well as 3D organization alterations. In addition, transcriptome analysis revealed that intratumor methylation heterogeneity was associated with low-level expression and high variability. Conclusions We propose that disrupted DNA methylation in MM is responsible for high epigenetic and transcriptomic instability allowing tumor cells to adapt to environmental changes by tapping into a pool of evolutionary trajectories