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

Etude d'un nouveau milieu réactionnel pour la synthèse organique

Doctorat en sciences chimiques -- UCL, 199

Recherche de nouveaux composés silylés : modulation de l'activité catalytique ou pharmacologique

Doctorat en science chimiques -- UCL, 199

Diels-alder Reactions With 2-substituted-alpha,Beta-unsaturated Hydrazones in Concentrated Organic Solutions of Lintf2

alpha,beta-Unsaturated hydrazones bearing an ester or a nitrile at C-2 position have been synthesized. They are unreactive towards electron-rich dienophiles but react with electron-poor dienophiles. Dramatic rate enhancements have been observed in concentrated organic solutions of LiNTf(2)

Multi-omics data integration approach for resilience of dairy cattle to heat stress

peer reviewedBreeding for resilience to heat stress (HS) is a topic where associating multiple omics data has the potential to get a better view of the issues and to allow significant advances to overcome undesirable consequences of future extreme weather scenarios. An example of omics is here epigenomics (e.g. early programming due to heat-stress) allowing new insights to explain biological mechanisms of resilience to HS and G×E interactions. Even if biological mechanisms are complex and still elusive, this study tried to use a holistic approach integrating milk-based biomarkers, climate conditions, and genomics. Data used included 65,907 third-lactation test-day records for production traits (milk, fat and protein yields), specific fatty acids (FA) and metabolites predicted from mid-infrared spectra (C4:0, C18:1cis9, long chain ‘LCFA’, mono- and unsaturated FA ‘MUFA and UFA’, acetone and BHB) of 9,327 Holstein cows. Phenotypes were merged with a temperature humidity index (THI) from public weather stations. For each trait, the response to THI was estimated via days in milk (DIM) × THI combination, and for each cow by using a random regression model with a common threshold of THI=62. The slope (heat tolerance)-to-intercept (general) genetic variance ratios increased as THI increased. They were higher during mid-lactation (140-245 DIM) for C18:1 cis9, acetone, BHB and for production traits, whereas higher in early lactation (≤125 DIM) for C4:0, LCFA, MUFA, and UFA. At extreme high THI scale, slope-to-intercept ratios for C18:1 cis9, MUFA, UFA, and LCFA were 3.8, 3.4, 3.1, 2.8 fold higher than milk yield. These findings indicate that tolerance to HS and traditional production trait responses to THI are marginally related, and changes in milk-based biomarkers under high THI better elucidate physiological and metabolic pathways in HS dairy cows. Ongoing genomic wide association studies will better explain genetic markers unravelling the biological background of resilience to HS

Early-programming of dairy cattle, a potential explanation to the adaptation to climate change

peer reviewedBreeding for robustness and considering genotype by environment interaction (G×E) is linked to adaptation. Recently, it has been established that gene expression can be affected by the environment during the embryo development. The concept of early programming has been demonstrated in many settings. This study aimed to assess the impact of thermal stress when dairy cows been conceived on their lifetime performances. Studied traits were milk yield and some novel milk-based biomarkers, fertility (days open), health (somatic cell score and ketosis), and heat tolerance. Data used compromised 905,391 test day of 58,297 cows in parity 1 to 3 for production traits, health and ketosis status, 104,635 records of 48,125 cows for days open, and 399,449 test days recorded (linked with temperature humidity index values, THI) of 28,203 cows for heat tolerance trait. Date of conception was estimated using the next calving date of the cow and subtracting 280 d from the calving interval. Cows being conceived in summer (June- August) were considered as influenced by heat stress (environment 1) and those conceived in winter (December- February) as neutral-thermal conditions (environment 2). G×E was analysed by a multi-trait model for days open in which each of the 3 lactations measured in heat stress and thermo-neutral conditions were considered as separate traits. For the rest of the traits, it was analysed using reaction norm models, in which the trait is considered a function of an environmental descriptor (i.e. THI, days in milk) in the two discrete environments. First results showed that genetic correlations across both early-life defined environments and lactations were substantially lower than unity, implying that effects of genes for cows conceived under neutral-thermal conditions may be different of the effects for the same genes for cows conceived under heat stressed conditions

Prognostic Effect of BRAF and KRAS Mutations in Patients With Stage III Colon Cancer Treated With Leucovorin, Fluorouracil, and Oxaliplatin With or Without Cetuximab

International audienceIMPORTANCE The prognostic value of BRAF and KRAS mutations in patients who have undergone resection for colon cancer and have been treated with combination leucovorin, fluorouracil, and oxaliplatin (FOLFOX)-based adjuvant chemotherapy is controversial, possibly owing to a lack of stratification on mismatch repair status.OBJECTIVE To examine the prognostic effect of BRAF and KRAS mutations in patients with stage III colon cancer treated with adjuvant FOLFOX with or without cetuximab.DESIGN, SETTING, AND PARTICIPANTS This study included patients with available tumor blocks of resected stage III colon adenocarcinoma who participated between December 2005 and November 2009 in the PETACC-8 phase III randomized trial. Mismatch repair, BRAF V600E, and KRAS exon 2 mutational status were determined on prospectively collected tumor blocks from 2559 patients enrolled in the PETACC-8 trial. The data were analyzed in April 2015.INTERVENTION Patients were randomly assigned to receive 6 months of FOLFOX4 or FOLFOX4 plus cetuximab after surgical resection for stage III colon cancer.MAIN OUTCOMES AND MEASURES Associations between these biomarkers and disease-free survival (DFS) and overall survival (OS) were analyzed with Cox proportional hazards models. Multivariate models were adjusted for covariates (age, sex, tumor grade, T/N stage, tumor location, Eastern Cooperative Oncology Group performance status).RESULTS Among the 2559 patients enrolled in the PETACC-8 trial (42.9% female; median [range] age, 60.0[19.0-75.0] years), microsatellite instability (MSI) phenotype, KRAS, and BRAF V600E mutationswere detected in, respectively, 9.9%(177 of 1791), 33.1%(588 of 1776), and 9.0%(148 of 1643) of cases. In multivariate analysis, MSI (hazard ratio [HR] for DFS: 1.10 [95% CI, 0.73-1.64], P =.67; HR for OS: 1.02 [95% CI, 0.61-1.69], P =.94) and BRAF V600E mutation (HR for DFS: 1.22 [95% CI, 0.81-1.85], P =.34; HRfor OS: 1.13 [95% CI, 0.64-2.00], P =.66) were not prognostic, whereas KRAS mutationwas significantly associated with shorter DFS (HR, 1.55 [95% CI, 1.23-1.95]; P <.001) and OS (HR, 1.56 [95% CI, 1.12-2.15]; P =.008). The subgroup analysis showed in patients with microsatellite-stable tumors that both KRAS (HR for DFS: 1.64 [95% CI, 1.29-2.08], P <.001; HRfor OS: 1.71 [95% CI, 1.21-2.41], P =.002) and BRAFV600Emutation (HR for DFS: 1.74 [95% CI, 1.14-2.69], P =.01; HR for OS: 1.84 [95% CI, 1.01-3.36], P =.046) were independently associated withworse clinical outcomes. In patients with MSI tumors, KRAS statuswas not prognostic, whereas BRAF V600E mutation was associated with significantly longer DFS (HR, 0.23 [95% CI, 0.06-0.92]; P =.04) but not OS (HR, 0.19 [95% CI, 0.03-1.24]; P =.08).CONCLUSIONS AND RELEVANCE BRAF V600E and KRAS mutationswere significantly associated with shorter DFS and OS in patients with microsatellite-stable tumors but not in patients with MSI tumors. Future trials in the adjuvant setting will have to take into account mismatch repair, BRAF, and KRAS status for stratification

Phase II study evaluating the association of gemcitabine, trastuzumab and erlotinib as first‐line treatment in patients with metastatic pancreatic adenocarcinoma ( GATE 1)

International audienceIn a previous phase II study (THERAPY), cetuximab and trastuzumab combination, as second-line after progression with gemcitabine, showed disease stabilization in 27% of 33 patients with pancreatic carcinoma. In the present phase II multicenter study, we assessed the efficacy and tolerance of gemcitabine, trastuzumab plus erlotinib as first-line treatment of metastatic pancreatic cancer. The primary endpoint was disease control rate (DCR, RECIST v.1); secondary endpoints were progression-free (PFS), overall (OS) survival and toxicity (NCI-CTCAE v3.0). Ancillary study addressed the predictive value of both EGFR/HER2 expression and KRAS mutational status. Sixty-three patients from four centers were included (62 evaluable for toxicity, 59 for efficacy), median age was 62 years (35-77), 59.7% men. The median treatment duration was 16.1 weeks (2.1-61). Eleven patients (19%) reported a partial tumor response, and 33 (56%) disease stabilization. DCR was 74.6% (95%CI: 61.8-85.0; 44/59 patients). After a median follow-up of 23.3 months (0.6-23.6), median PFS was 3.5 months (95%CI: 2.4-3.8) and median OS 7.9 months (95%CI: 5.1-10.2). PFS was significantly longer in patients with grade ≥ 2 cutaneous toxicities vs patients with grade 0-1 toxicities (HR = 0.55, 95%CI: 0.33-0.92, P = .020). Expression of EGFR and HER2 was correlated with PFS and OS in multivariate analysis; HER2 expression was correlated with the tumor response. Main severe toxicities were neutropenia (32%), cutaneous rash (37%) and thrombosis/embolisms (35.5%). This triplet combination is effective in terms of disease control, PFS and OS, and acceptable for safety. A larger study to investigate this combination compared to the standard regimen should be discussed

Clinical Relevance of Viable Circulating Tumor Cells in Patients with Metastatic Colorectal Cancer: The COLOSPOT Prospective Study

International audienceBackground: Circulating tumor cells (CTCs) allow the real-time monitoring of tumor course and treatment response. This prospective multicenter study evaluates and compares the early predictive value of CTC enumeration with EPISPOT, a functional assay that detects only viable CTCs, and with the CellSearch® system in patients with metastatic colorectal cancer (mCRC).Methods: Treatment-naive patients with mCRC and measurable disease (RECIST criteria 1.1) received FOLFIRI–bevacizumab until progression or unacceptable toxicity. CTCs in peripheral blood were enumerated at D0, D14, D28, D42, and D56 (EPISPOT assay) and at D0 and D28 (CellSearch® system). Progression-free survival (PFS) and overall survival (OS) were assessed with the Kaplan–Meier method and log-rank test.Results: With the EPISPOT assay, at least 1 viable CTC was detected in 21% (D0), 15% (D14), 12% (D28), 10% (D42), and 12% (D56) of 155 patients. PFS and OS were shorter in patients who remained positive, with viable CTCs between D0 and D28 compared with the other patients (PFS = 7.36 vs. 9.43 months, p = 0.0161 and OS = 25.99 vs. 13.83 months, p = 0.0178). The prognostic and predictive values of ≥3 CTCs (CellSearch® system) were confirmed.Conclusions: CTC detection at D28 and the D0–D28 CTC dynamics evaluated with the EPISPOT assay were associated with outcomes and may predict response to treatment

Bevacizumab plus FOLFIRI after failure of platinum–etoposide first-line chemotherapy in patients with advanced neuroendocrine carcinoma (PRODIGE 41-BEVANEC): a randomised, multicentre, non-comparative, open-label, phase 2 trial

International audienc