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Formation of an unprecedented (CuBr)5 cluster and a zeolite-type 2D-coordination polymer: a surprising halide effect

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Les nouveaux profils moléculaires dans le cancer de l’ovaire peuvent-ils modifier les stratégies thérapeutiques ?

National audienceEpithelial ovarian cancer (EOC) affects 4500 women a year in France, with a survival of 30% at 5 years. Treatment is based on extensive surgery and chemotherapy. Around 15% of EOCs are due to genetic mutation predisposition essentially with mutated BRCA1 and BRCA2 genes. Four histological subtypes are described (serous, endometrioid, and mucinous cells to clear), corresponding to different carcinogenesis and distinct molecular mutations. High-grade serous EOCs have a mutation of the BRCA genes in 20-30% of cases. This mutation causes a deficit of repair by homologous recombination of DNA in case of double strand break, allowing greater sensitivity to platinum salts and the use of PARP inhibitors, a protein involved in the repair of single-strand breaks of DNA. PARP inhibitors have shown efficacy in patients mutated BRCA but this effectiveness remains to be demonstrated in patients without congenital mutation, but with acquired BRCAness profile EOC. The BRCAness profile is defined by a tumor having a defect in DNA repair counterpart (not limited to BRCA mutation). Molecular definition of BRCAness is still not consensual but is necessary for the use of PARP inhibitors. Gene expression analyses have identified four subgroups of high-grade serous CEO: mesenchymal, proliferative, differentiated and immunoreactive. These four subtypes, not mutually exclusive, although correlated with prognosis, are not yet used in clinical routine

THE BRCA1 c.5434C>G (p.PRO1812ALA) VARIANT INDUCES A DELETERIOUS EXON 23 SKIPPING BY AFFECTING EXONIC SPLICING REGULATORY ELEMENTS

International audienceA large fraction of the sequence variants of unknown significance or unclassified variants (UVs), including exonic variants, could be pathogenic by affecting mRNA splicing. The breast and ovarian cancer susceptibility gene BRCA1 exhibits a large spectrum of sequence variation but only two variants, both located in exon 18, have been shown experimentally to affect splicing regulatory elements. In the present study, we investigate the impact on splicing of the variant BRCA1 c.5434C>G (p.Pro1812Ala), identified in an ovarian cancer patient. This variant has previously been studied at the protein level with inconclusive results concerning its pathogenicity. Here, we show, using patient RNA analyses and hybrid minigene assays, that this variant induces nearly complete skipping of exon 23, resulting in frameshift and predicted protein termination within the second BRCT domain. This argues for its classification as a pathogenic splicing mutation. Moreover, we demonstrate, using an exonic splicing enhancer-dependent minigene assay, that the segment c.5420-5449 of BRCA1, in the centre of exon 23, exhibits splicing enhancer properties. This enhancement is abolished by the c.5434C>G mutation, indicating that the nucleotide change, in this highly conserved region, affects a splicing regulatory element. Bioinformatics analyses predict that the mutation c.5434C>G creates an hnRNPA1-dependent splicing silencer. These results also suggest that UVs in highly conserved nucleotide sequences of short exons may be good candidates for detecting functionally relevant splicing regulatory elements

SpliceLauncher: a tool for detection, annotation and relative quantification of alternative junctions from RNAseq data

SpliceLauncher is available at https://github.com/raphaelleman/SpliceLauncher.International audienceAlternative splicing is an important biological process widely analyzed in molecular diagnostic settings. Indeed, a variant can be pathogenic by splicing alteration and a suspected pathogenic variant (e.g. truncating variant) can be rescued by splicing. In this context, detecting and quantifying alternative splicing is challenging. We developed SpliceLauncher, a fast and easy to use open source tool that aims at detecting, annotating and quantifying alternative splice junctions at high resolutio

Genetic profiles of cervical tumors by high-throughput sequencing for personalized medical care

International audienceCancer treatment is facing major evolution since the advent of targeted therapies. Building genetic profiles could predict sensitivity or resistance to these therapies and highlight disease-specific abnormalities, supporting personalized patient care. In the context of biomedical research and clinical diagnosis, our laboratory has developed an oncogenic panel comprised of 226 genes and a dedicated bioinformatic pipeline to explore somatic mutations in cervical carcinomas, using high-throughput sequencing. Twenty-nine tumors were sequenced for exons within 226 genes. The automated pipeline used includes a database and a filtration system dedicated to identifying mutations of interest and excluding false positive and germline mutations. One-hundred and seventy-six total mutational events were found among the 29 tumors. Our cervical tumor mutational landscape shows that most mutations are found in PIK3CA (E545K, E542K) and KRAS (G12D, G13D) and others in FBXW7 (R465C, R505G, R479Q). Mutations have also been found in ALK (V1149L, A1266T) and EGFR (T259M). These results showed that 48% of patients display at least one deleterious mutation in genes that have been already targeted by the Food and Drug Administration approved therapies. Considering deleterious mutations, 59% of patients could be eligible for clinical trials. Sequencing hundreds of genes in a clinical context has become feasible, in terms of time and cost. In the near future, such an analysis could be a part of a battery of examinations along the diagnosis and treatment of cancer, helping to detect sensitivity or resistance to targeted therapies and allow advancements towards personalized oncology

Reactivity of CuI and CuBr toward Dialkyl Sulfides RSR: From Discrete Molecular Cu₄I₄S₄ and Cu₈I₈S₆ Clusters to Luminescent Copper(I) Coordination Polymers

The 1D coordination polymer (CP) [(Me₂S)₃{Cu₂(μ-I)₂}]_<i>n</i> (<b>1</b>) is formed when CuI reacts with SMe₂ in <i>n</i>-heptane, whereas in acetonitrile (MeCN), the reaction forms exclusively the 2D CP [(Me₂S)₃{Cu₄(μ-I)₄}]_<i>n</i> (<b>2</b>) containing “flower-basket” Cu₄I₄ units. The reaction product of CuI with MeSEt is also solvent-dependent, where the 1D polymer [(MeSEt)₂{Cu₄(μ₃-I)₂(μ₂-I)₂}­(MeCN)₂]_<i>n</i> (<b>3</b>) containing “stepped-cubane” Cu₄I₄ units is isolated in MeCN. In contrast, the reaction in <i>n</i>-heptane affords the 1D CP [(MeSEt)₃{Cu₄(μ₃-I)₄}]_<i>n</i> (<b>4</b>) containing “closed-cubane” Cu₄I₄ clusters. The reaction of MeSPr with CuI provides the structurally related 1D CP [(MeSPr)₃{Cu₄(μ₃-I)₄}]_<i>n</i> (<b>5</b>), for which the X-ray structure has been determined at 115, 155, 195, 235, and 275 K, addressing the evolution of the metric parameters. Similarly to <b>4</b> and the previously reported CP [(Et₂S)₃{Cu₄(μ₃-I)₄}]_<i>n</i> (<i>Inorg. Chem.</i> <b>2010</b>, <i>49</i>, 5834), the 1D chain is built upon closed cubanes Cu₄(μ₃-I)₄ as secondary building units (SBUs) interconnected via μ-MeSPr ligands. The 0D tetranuclear clusters [(L)₄{Cu₄(μ₃-I)₄}] [L = EtSPr (<b>6</b>), Pr₂S (<b>7</b>)] respectively result from the reaction of CuI with EtSPr and <i>n</i>-Pr₂S. With <i>i</i>-Pr₂S, the octanuclear cluster [(<i>i</i>-Pr₂S)₆{Cu₈(μ₃-I)₃}­(μ₄-I)₂}] (<b>8</b>) is formed. An X-ray study has also been performed at five different temperatures for the 2D polymer [(Cu₃Br₃)­(MeSEt)₃]_<i>n</i> (<b>9</b>) formed from the reaction between CuBr and MeSEt in heptane. The unprecedented framework of <b>9</b> consists of layers with alternating Cu­(μ₂-Br)₂Cu rhomboids, which are connected through two μ-MeSEt ligands to tetranuclear open-cubane Cu₄Br₄ SBUs. MeSPr forms with CuBr in heptane the 1D CP [(Cu₃Br₃)­(MeSPr)₃]_<i>n</i> (<b>10</b>), which is converted to a 2D metal–organic framework [(Cu₅Br₅)­(μ₂-MeSPr)₃]_<i>n</i> (<b>11</b>) incorporating pentanuclear [(Cu₅(μ₄-Br)­(μ₂-Br)] SBUs when recrystallized in MeCN. The thermal stability and photophysical properties of these materials are also reported

Genetic profiles of cervical tumors by high‐throughput sequencing for personalized medical care

International audienceCancer treatment is facing major evolution since the advent of targeted therapies. Building genetic profiles could predict sensitivity or resistance to these therapies and highlight disease-specific abnormalities, supporting personalized patient care. In the context of biomedical research and clinical diagnosis, our laboratory has developed an oncogenic panel comprised of 226 genes and a dedicated bioinformatic pipeline to explore somatic mutations in cervical carcinomas, using high-throughput sequencing. Twenty-nine tumors were sequenced for exons within 226 genes. The automated pipeline used includes a database and a filtration system dedicated to identifying mutations of interest and excluding false positive and germline mutations. One-hundred and seventy-six total mutational events were found among the 29 tumors. Our cervical tumor mutational landscape shows that most mutations are found in PIK3CA (E545K, E542K) and KRAS (G12D, G13D) and others in FBXW7 (R465C, R505G, R479Q). Mutations have also been found in ALK (V1149L, A1266T) and EGFR (T259M). These results showed that 48% of patients display at least one deleterious mutation in genes that have been already targeted by the Food and Drug Administration approved therapies. Considering deleterious mutations, 59% of patients could be eligible for clinical trials. Sequencing hundreds of genes in a clinical context has become feasible, in terms of time and cost. In the near future, such an analysis could be a part of a battery of examinations along the diagnosis and treatment of cancer, helping to detect sensitivity or resistance to targeted therapies and allow advancements towards personalized oncology

1,4-Bis(arylthio)but-2-enes as Assembling Ligands for (Cu₂X₂)_<i>n</i> (X = I, Br; <i>n</i> = 1, 2) Coordination Polymers: Aryl Substitution, Olefin Configuration, and Halide Effects on the Dimensionality, Cluster Size, and Luminescence Properties

CuI reacts with <i>E</i>-PhS­(CH₂CHCHCH₂)­SPh, <b>L1</b>, to afford the coordination polymer (CP) [Cu₂I₂­{μ-<i>E</i>-PhS­(CH₂CHCHCH₂)­SPh}₂]_<i>n</i> (<b>1a</b>). The unprecedented square-grid network of <b>1</b> is built upon alternating two-dimensional (2D) layers with an ABAB sequence and contains rhomboid Cu₂(μ₂-I)₂ clusters as secondary building units (SBUs). Notably, layer A, interconnected by bridging <b>L1</b> ligands, contains exclusively dinuclear units with short Cu···Cu separations [2.6485(7) Å; 115 K]. In contrast, layer B exhibits Cu···Cu distances of 2.8133(8) Å. The same network is observed when CuBr reacts with <b>L1</b>. In the 2D network of [Cu₂Br₂­{μ-<i>E</i>-PhS­(CH₂CHCHCH₂)­SPh}₂]_<i>n</i> (<b>1b</b>), isotype to <b>1a</b>, one square-grid-type layer contains Cu₂(μ₂-Br)₂ SBUs with short Cu···Cu contacts [2.7422(6) Å at 115K], whereas the next layer incorporates exclusively Cu₂(μ₂-Br)₂ SBUs with a significantly longer Cu···Cu separation [2.9008(10) Å]. The evolution of the crystallographic parameters of <b>1a</b> and <b>1b</b> was monitored between 115 and 275 K. Conversely, the isomeric <i>Z</i>-PhS­(CH₂CHCHCH₂)­SPh ligand <b>L2</b> reacts with CuI to form the 2D CP [Cu₄(μ₃-I)₄(μ-<i>­Z</i>-PhS­(CH₂CHCHCH₂)­SPh}₂]_<i>n</i> (<b>2a</b>) with closed-cubane SBUs. A dinuclear zero-dimensional complex [Cu₂Br₂­{μ-<i>Z</i>-PhS­(CH₂CHCHCH₂)­SPh}₂] (<b>2b</b>) is formed when CuBr is reacted with <b>L2</b>. Upon reaction of <i>E</i>-TolS­(CH₂CHCHCH₂)­STol, <b>L3</b>, with CuI, the 2D CP [{Cu­(μ₃-I)}₂­(μ-<b>L3</b>)]_<i>n</i> containing parallel-arranged infinite inorganic staircase ribbons, is generated. When CuX reacts with <i>Z</i>-TolS­(CH₂CHCHCH₂)­STol, <b>L4</b>, the isostructural 2D CPs [Cu₂X₂­{μ-<i>Z</i>-TolS­(CH₂CHCHCH₂)­STol}₂] <b>(4a</b> X = I; <b>4b</b> X = Br) are formed. In contrast to the CPs <b>1a,b</b>, the layers based on rhombic grids of <b>4a,b</b> incorporate Cu₂(μ₂-X)₂ SBUs featuring uniformly identical Cu···Cu distances within each layer. The TGA traces showed that all these materials are stable up to ∼200 °C. Moreover, the photophysical properties have been studied, including absorption, emission, excitation spectra, and emission lifetimes at 298 and 77 K. The spectra were interpreted using density functional theory (DFT) and time-dependent DFT calculations