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

Evolutionary origin of Bone Morphogenetic Protein 15 and growth and differentiation factor 9 and differential selective pressure between mono- and polyovulating species

Bone morphogenetic protein 15 (BMP15) and growth and differentiation factor 9 (GDF9) are TGFbeta-like oocyte-derived growth factors involved in ovarian folliculogenesis as critical regulators of many granulosa cell processes and ovulation rate. Ovarian phenotypic effect caused by alterations in BMP15 and GDF9 genes appears to differ between species and may be relevant to their mono- or poly-ovulating status. Through phylogenetic analysis we recently showed that these two paralogous genes are strongly divergent and in rapid evolution as compared to other members of the TGFbeta superfamily. Here, we evaluate the amino-acid substitution rates of a set of proteins implicated in the ovarian function, including BMP15 and GDF9, with special attention to the mono- or poly-ovulating status of the species. Among a panel of mono- and poly-ovulating mammals, we demonstrate a better conservation of some areas in BMP15 and GDF9 within mono-ovulating species. Homology modeling of BMP15 and GDF9 homodimers and heterodimers 3D structures was suggestive that these areas may be involved in dimer formation and stability. A phylogenetic study of BMP15/GDF9 related proteins reveals that these two genes diverged from the same ancestral gene along with BMP3 and GDF10, two other paralogous genes. A substitution rate analysis based on this phylogenetic tree leads to the hypothesis of an acquisition of BMP15/GDF9 specific functions in ovarian folliculogenesis in mammals. We propose that high variations observed in specific areas of BMP15 and GDF9 in poly-ovulating species change the equilibrium between homodimers and heterodimers, modifying the biological activity and thus allowing poly-ovulation to occur

An Incidental Finding of Maternal Multiple Myeloma by Non Invasive Prenatal Testing

status: publishe

[Development of a standardized guide for optimizing drug adherence information to be dispensed during a pharmaceutical counseling with a multiple myeloma patient: Final validation]

International audienceAn initial validation of a standardized pharmaceutical counselling guide was carried out in a previous study to improve medication adherence in patients treated for multiple myeloma with oral anticancer therapies. The main objective of this work was the final validation of this guide with 10 naive patients. The main secondary objectives were to assess for the patient the evolution of knowledge about the treatment, understanding of the purpose of the pharmaceutical counselling, adherence to the tools. Each patient completed a self-administered questionnaire: before and after the first pharmaceutical counselling. The primary endpoint was the average success rate per question after the pharmaceutical counselling (a value of >= 90% validated knowledge acquisition). Secondary judgement criteria were: change in average success rates per patient and question, rate of reformulation of the objective of the pharmaceutical counselling, response rate to presentation questions, readability and understanding. No average success rate per question after the pharmaceutical counselling was statistically less than 90%. The average success rates per patient before and after the pharmaceutical counselling were 78.9\textpm13.7% vs 96.1\textpm3.9% (P=0.01). The average success rates per question were different for 4 questions. All patients were able to reformulate the objective of the pharmaceutical counselling and validated the presentation, readability and understanding of the documents. This study led to the final validation of the pharmaceutical counselling guide

An incidental finding of maternal multiple myeloma by non invasive prenatal testing

International audienc

Carfilzomib Weekly Plus Melphalan and Prednisone in Newly Diagnosed Elderly Multiple Myeloma (IFM 2012-03) / 57th Annual Meeting of the American-Society-of-Hematology - Orlando, FL

WOS:000368020103223International audienceConference: 57th Annual Meeting of the American-Society-of-Hematology - Orlando, FL - DEC 05-08, 201