Biological and prognostic impact of apobec-induced mutations in the spectrum of plasma cell dyscrasias

In multiple myeloma (MM), whole exome sequencing (WES) studies have revealed four mutational signatures: two associated with aberrant activities of APOBEC cytidine deaminases (Signatures #2 and #13) and two clock-like signatures associated with "cancer age" (Signatures #1 and #5). Mutational signatures have not been investigated systematically in larger series, nor in other primary plasma cell dyscrasias such as monoclonal gammopathy of unknown significance (MGUS) or primary plasma cell leukemia (pPCL). Finally, while APOBEC activity has been correlated to increased mutational burden and poor-prognosis MAF/MAFB translocations in MM at diagnosis, this has never been confirmed in multivariate analysis in an independent series. To answer these questions, we mined 1151 MM samples from public WES datasets, including samples from the IA9 public release of the CoMMpass trial. The CoMMpass data were generated as part of the Multiple Myeloma Research Foundation Personalized Medicine Initiatives. We also analyzed 6 MGUS/Smoldering MM as well as 5 previously published pPCLs. Extraction of mutational signatures was performed using the NNMF algorithm as previously described (Alexandrov et al. Nature 2013). NNMF in the whole cohort extracted the known 4 signatures pertaining to distinct mutational processes: the two clock-like processes (signatures #1 and #5) and aberrant APOBEC deaminase activity (signatures #2 and #13). While the clock-like processes were more prominent in the cohort as a whole (median 70%, range 0-100%), the APOBEC showed a heterogeneous contribution, more visible in samples with the highest mutation burden. In fact, the absolute and relative contribution of APOBEC activity to the mutational repertoire correlated with the overall number of mutations (r=0.71, p= < 0.0001). As previously described, APOBEC contribution was significantly enriched among MM patients with t(14;16) and with t(14;20) (p<0.001), but the association between relative APOBEC contribution and mutational load remained significant across all cytogenetic subgroups with the exception of t(11;14). In the MGUS/SMM series, APOBEC contribution was generally low. Conversely, APOBEC activity was preponderant in three out of five pPCL samples, all of them characterized by the t(14;16)( IGH / MAF); in the remaining two pPCL the absolute number of APOBEC mutations was similar to MM. Overall, the APOBEC contribution was characterized by a progressive increment from MGUS/SMM to MM and pPCL. We next went on to investigate the prognostic impact of APOBEC signatures at diagnosis. Patients with APOBEC contribution in the 4th quartile had shorter PFS (2-y PFS 47% vs 66%, p<0.0001) and OS (2-y OS 70% vs 85%, p=0.0033) than patients in quartiles 1-3 (Figure 1a-b). This was independent from the association of APOBEC activity with MAF translocations and higher mutational burden, as shown by multivariate analysis with Cox regression (Figure 1c-d). ISS stage III was the only other variable that retained its independent prognostic value for both PFS and OS. We therefore combined both variables and found that co-occurrence of ISS III and APOBEC 4th quartile identifies a fraction of high-risk patients with 2-y OS of 53.8% (95% CI 36.6%-79%), while their simultaneous absence identifies long term survivors with 2-y OS of 93.3% (95% CI 89.6-97.2%). In this study, we provided a global overview on the contribution of mutational processes in the largest whole exome series of plasma cell dyscrasias investigated to date by NNMF. We propose that cases with high APOBEC activity may represent a novel prognostic subgroup that is transversal to conventional cytogenetic subgroups, advocating for closer integration of next-generation sequencing studies and clinical annotation to confirm this finding in independent series

A polygenic risk score for multiple myeloma risk prediction

This work was partially supported by intramural funds of the University of Pisa, DKFZ, and University Hospital of Southern Jutland, Denmark, and by a grant of the French National Cancer Institute (INCA). The authors wish to thank Dr. Dominic Edelmann (Division of Biostatistics, DKFZ) for helpful advice about data analysis.There is overwhelming epidemiologic evidence that the risk of multiple myeloma (MM) has a solid genetic background. Genome-wide association studies (GWAS) have identified 23 risk loci that contribute to the genetic susceptibility of MM, but have low individual penetrance. Combining the SNPs in a polygenic risk score (PRS) is a possible approach to improve their usefulness. Using 2361 MM cases and 1415 controls from the International Multiple Myeloma rESEarch (IMMEnSE) consortium, we computed a weighted and an unweighted PRS. We observed associations with MM risk with OR = 3.44, 95% CI 2.53-4.69, p = 3.55 x 10(-15) for the highest vs. lowest quintile of the weighted score, and OR = 3.18, 95% CI 2.1 = 34-4.33, p = 1.62 x 10(-13) for the highest vs. lowest quintile of the unweighted score. We found a convincing association of a PRS generated with 23 SNPs and risk of MM. Our work provides additional validation of previously discovered MM risk variants and of their combination into a PRS, which is a first step towards the use of genetics for risk stratification in the general population.University of Pisa, DKFZUniversity Hospital of Southern Jutland, DenmarkInstitut National du Cancer (INCA) Franc

Heterogeneity of genomic evolution and mutational profiles in multiple myeloma.

Multiple myeloma is an incurable plasma cell malignancy with a complex and incompletely understood molecular pathogenesis. Here we use whole-exome sequencing, copy-number profiling and cytogenetics to analyse 84 myeloma samples. Most cases have a complex subclonal structure and show clusters of subclonal variants, including subclonal driver mutations. Serial sampling reveals diverse patterns of clonal evolution, including linear evolution, differential clonal response and branching evolution. Diverse processes contribute to the mutational repertoire, including kataegis and somatic hypermutation, and their relative contribution changes over time. We find heterogeneity of mutational spectrum across samples, with few recurrent genes. We identify new candidate genes, including truncations of SP140, LTB, ROBO1 and clustered missense mutations in EGR1. The myeloma genome is heterogeneous across the cohort, and exhibits diversity in clonal admixture and in dynamics of evolution, which may impact prognostic stratification, therapeutic approaches and assessment of disease response to treatment

Isolement et sequence du gene de la calcitonine et du peptide alternatif du gene de la calcitonine aviaire

SIGLECNRS T Bordereau / INIST-CNRS - Institut de l'Information Scientifique et TechniqueFRFranc

Complantation et complémentarités agraires, Les paysages de la vigne et de l’olivier revivifiés en Provence

International audienc

Complantation et complémentarités agraires : les paysages de la vigne et de l’olivier revivifiés en Provence. L’exemple de l’aire AOC Bandol (Var).

International audienceThe close relationship between vine and olive tree correponds to a landscape model often idealized and very widely distributed, far beyond the Mediterranean area. In a long term association within local agricultural systems, vineyards and olive groves have experienced divergent contemporary evolutions that have resulted in a separation of the two cultures with, most often, a disappearance of olive trees. However, recent changes tend to show a new complementarity of the vine and the olive tree in a landscape goal.L’union harmonieuse de la vigne et de l’olivier apparaît souvent comme une évidence pour le spectateur séduit par les paysages méditerranéens. La relation étroite qui lie vigne et olivier forme la base d’un modèle paysager souvent idéalisé et très largement diffusé, bien au-delà du monde méditerranéen. Longtemps associés au sein des systèmes agricoles locaux, vignobles et oliveraies ont connu des mutations contemporaines divergentes qui ont abouti à une séparation des deux cultures avec, le plus souvent, une disparition des oliviers. Toutefois, des changements récents tendent à montrer une nouvelle complémentarité de la vigne et de l’olivier dans une finalité paysagère. Aussi cette association régénérée demande-t-elle à être analysée et interrogée vis-à-vis de ses processus et ses intentionnalités. Notre propos développera successivement la prégnance de l’association vigne/olivier comme un paysage traditionnel en voie de disparition et la nouvelle complémentarité oléo-viticole dans des fins économiques, paysagères et environnementales

Understanding delays in acute stroke care: a systematic review of reviews

International audienceBackgroundStroke is the leading cause of adult long-term disability in Western countries. Intravenous thrombolytic therapy with recombinant tissue plasminogen activator is safe and effective within the first 4.5 h after the onset of stroke. Various factors delaying acute stroke care have been identified in the literature. This review aimed to provide an overview of factors delaying acute stroke care and attempted to show how they interact in a synthetic framework.MethodsWe conducted a systematic review of literature reviews published in Medline and DORIS until 2016 on factors influencing acute stroke pathway timeframe.ResultsWe analyzed 31 reviews that cover all factors of delays from stroke onset to treatment. We identified 27 factors that had a significant impact on acute stroke care and can be categorized into four distinct categories: patient-related factors, training, resources and lack of coordination. We also reported associations between factors observed in both between categories (mainly between patients and organizational/logistical factors) and within categories.ConclusionThis review provides a wide overview of factors influencing acute stroke pathway. Since it was observed that the identified factors were interrelated, they needed to be analyzed in a systematic way. We hence created a synthetic framework that combines several categories of factors while assuming that factor weight varies from a study context to another. Better knowledge on underlying mechanisms between factors would provide crucial improvement of the interventions aiming at reducing delays in both pre-hospital and inhospital stages. For future research, we recommend adopting a systemic perspective on factors influencing acute stroke pathway

Complantation et complémentarités agraires : les paysages de la vigne et de l’olivier revivifiés en Provence. L’exemple de l’aire AOC Bandol (Var).

International audienceThe close relationship between vine and olive tree correponds to a landscape model often idealized and very widely distributed, far beyond the Mediterranean area. In a long term association within local agricultural systems, vineyards and olive groves have experienced divergent contemporary evolutions that have resulted in a separation of the two cultures with, most often, a disappearance of olive trees. However, recent changes tend to show a new complementarity of the vine and the olive tree in a landscape goal.L’union harmonieuse de la vigne et de l’olivier apparaît souvent comme une évidence pour le spectateur séduit par les paysages méditerranéens. La relation étroite qui lie vigne et olivier forme la base d’un modèle paysager souvent idéalisé et très largement diffusé, bien au-delà du monde méditerranéen. Longtemps associés au sein des systèmes agricoles locaux, vignobles et oliveraies ont connu des mutations contemporaines divergentes qui ont abouti à une séparation des deux cultures avec, le plus souvent, une disparition des oliviers. Toutefois, des changements récents tendent à montrer une nouvelle complémentarité de la vigne et de l’olivier dans une finalité paysagère. Aussi cette association régénérée demande-t-elle à être analysée et interrogée vis-à-vis de ses processus et ses intentionnalités. Notre propos développera successivement la prégnance de l’association vigne/olivier comme un paysage traditionnel en voie de disparition et la nouvelle complémentarité oléo-viticole dans des fins économiques, paysagères et environnementales

Prognostic value of involved/uninvolved free light chain ratio determined by Freelite and N Latex FLC assays for identification of high-risk smoldering myeloma patients

International audienceBackground Smoldering multiple myeloma (SMM) is an asymptomatic plasma cell disorder with a high risk of progression to symptomatic multiple myeloma (MM). The serum free light chain (sFLC) ratio is a powerful prognostic factor for SMM an sFLC ratio ≥8 has been reported to be associated with a high risk of progression to MM, and an sFLC ratio ≥100 has been described as a criterion for ultra-high-risk SMM, and has been integrated into the definition criteria for MM since 2014. However, all recommendations were based on sFLC measured using the first commercialized assay, Freelite™, while other assays are now available. We aimed to evaluate the safety and accuracy of N-Latex sFLC to identify high-risk and ultra-high-risk SMM.Methods The sFLC ratio was measured at diagnosis with both Freelite and N-Latex assays in a cohort of 176 SMM patients on a BN Prospec nephelometer. Demographic, clinical, therapeutic and laboratory data were collected at the time of diagnosis and at follow-up.Results Sixty-two patients (35.2%) progressed to MM within 2 years. Compared to Freelite™ sFLC, N Latex sFLC ratios ≥8 and ≥100 provided similar performances for the identification of high-risk and ultra-high risk SMM patients.Conclusions Our results evidenced that the N-Latex assay could be used for SMM monitoring, like Freelite. However, an N-Latex sFLC ratio ≥70 appears to provide similar performances to a Freelite sFLC ratio ≥100, with a slightly better positive predictive value. Both assays provided accurate identification of high-risk and ultra-high risk SMM patients. These results should be confirmed in an independent study