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1. Microsatellite instability at U2AF-binding polypyrimidic tract sites perturbs alternative splicing during colorectal cancer initiation

Author: Vincent Jonchère, Hugo Montémont, Enora Le Scanf, Aurélie Siret, Quentin Letourneur, Emmanuel Tubacher, Christophe Battail, Assane Fall, Karim Labreche, Victor Renault, Toky Ratovomanana, Olivier Buhard, Ariane Jolly, Philippe Le Rouzic, Cody Feys, Emmanuelle Despras, Habib Zouali, Rémy Nicolle, Pascale Cervera, Magali Svrcek, Pierre Bourgoin, Hélène Blanché, Anne Boland, Jérémie Lefèvre, Yann Parc, Mehdi Touat, Franck Bielle, Danielle Arzur, Gwennina Cueff, Catherine Le Jossic-Corcos, Gaël Quéré, Gwendal Dujardin, Marc Blondel, Cédric Le Maréchal, Romain Cohen, Thierry André, Florence Coulet, Pierre de la Grange, Aurélien de Reyniès, Jean-François Fléjou, Florence Renaud, Agusti Alentorn, Laurent Corcos, Jean-François Deleuze, Ada Collura, and Alex Duval
Subjects: Colorectal cancer, Mismatch repair deficiency, Microsatellite instability, Whole-exome and RNA sequencing, Alternative splicing, Polypyrimidine U2AF binding site, Biology (General), QH301-705.5, Genetics, QH426-470
Abstract: Abstract Background Microsatellite instability (MSI) due to mismatch repair deficiency (dMMR) is common in colorectal cancer (CRC). These cancers are associated with somatic coding events, but the noncoding pathophysiological impact of this genomic instability is yet poorly understood. Here, we perform an analysis of coding and noncoding MSI events at the different steps of colorectal tumorigenesis using whole exome sequencing and search for associated splicing events via RNA sequencing at the bulk-tumor and single-cell levels. Results Our results demonstrate that MSI leads to hundreds of noncoding DNA mutations, notably at polypyrimidine U2AF RNA-binding sites which are endowed with cis-activity in splicing, while higher frequency of exon skipping events are observed in the mRNAs of MSI compared to non-MSI CRC. At the DNA level, these noncoding MSI mutations occur very early prior to cell transformation in the dMMR colonic crypt, accounting for only a fraction of the exon skipping in MSI CRC. At the RNA level, the aberrant exon skipping signature is likely to impair colonic cell differentiation in MSI CRC affecting the expression of alternative exons encoding protein isoforms governing cell fate, while also targeting constitutive exons, making dMMR cells immunogenic in early stage before the onset of coding mutations. This signature is characterized by its similarity to the oncogenic U2AF1-S34F splicing mutation observed in several other non-MSI cancer. Conclusions Overall, these findings provide evidence that a very early RNA splicing signature partly driven by MSI impairs cell differentiation and promotes MSI CRC initiation, far before coding mutations which accumulate later during MSI tumorigenesis.
Published: 2024
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2. Identification of Positively and Negatively Selected Driver Gene Mutations Associated With Colorectal Cancer With Microsatellite InstabilitySummary

Author: Vincent Jonchere, Laetitia Marisa, Malorie Greene, Alain Virouleau, Olivier Buhard, Romane Bertrand, Magali Svrcek, Pascale Cervera, Anastasia Goloudina, Erell Guillerm, Florence Coulet, Samuel Landman, Toky Ratovomanana, Sylvie Job, Mira Ayadi, Nabila Elarouci, Lucile Armenoult, Fatiha Merabtene, Sylvie Dumont, Yann Parc, Jérémie H. Lefèvre, Thierry André, Jean-François Fléjou, Agathe Guilloux, Ada Collura, Aurélien de Reyniès, and Alex Duval
Subjects: Diseases of the digestive system. Gastroenterology, RC799-869
Abstract: Background & Aims: Recent studies have shown that cancers arise as a result of the positive selection of driver somatic events in tumor DNA, with negative selection playing only a minor role, if any. However, these investigations were concerned with alterations at nonrepetitive sequences and did not take into account mutations in repetitive sequences that have very high pathophysiological relevance in the tumors showing microsatellite instability (MSI) resulting from mismatch repair deficiency investigated in the present study. Methods: We performed whole-exome sequencing of 47 MSI colorectal cancers (CRCs) and confirmed results in an independent cohort of 53 MSI CRCs. We used a probabilistic model of mutational events within microsatellites, while adapting pre-existing models to analyze nonrepetitive DNA sequences. Negatively selected coding alterations in MSI CRCs were investigated for their functional and clinical impact in CRC cell lines and in a third cohort of 164 MSI CRC patients. Results: Both positive and negative selection of somatic mutations in DNA repeats was observed, leading us to identify the expected true driver genes associated with the MSI-driven tumorigenic process. Several coding negatively selected MSI-related mutational events (n = 5) were shown to have deleterious effects on tumor cells. In the tumors in which deleterious MSI mutations were observed despite the negative selection, they were associated with worse survival in MSI CRC patients (hazard ratio, 3; 95% CI, 1.1–7.9; P = .03), suggesting their anticancer impact should be offset by other as yet unknown oncogenic processes that contribute to a poor prognosis. Conclusions: The present results identify the positive and negative driver somatic mutations acting in MSI-driven tumorigenesis, suggesting that genomic instability in MSI CRC plays a dual role in achieving tumor cell transformation. Exome sequencing data have been deposited in the European genome–phenome archive (accession: EGAS00001002477). Keywords: Colorectal Cancer, Microsatellite Instability, Tumorigenic Process, Driver Gene Mutations, Positive and Negative Selection
Published: 2018
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3. Prediction of Response to Immune Checkpoint Blockade in Patients with Metastatic Colorectal Cancer with Microsatellite Instability

Author: Alex Duval, Toky Ratovomanana, Remy Nicolle, Romain Cohen, Aurélien Diehl, Aurélie Siret, Quentin Letourneur, Olivier Buhard, Alexandre Perrier, Erell Guillerm, Florence Coulet, Raphaël Colle, Ada Collura, Emmanuelle Despras, Philippe Le Rouzic, Florence Renaud, Agusti Alentorn, Mehdi Touat, Mira Ayadi, Pierre Bourgoin, Celine Prunier, Vincent Jonchère, Jaafar Bennouna, Aurélien de Reynies, Jean-François Fléjou, Magali Svrcek, and Thierry André
Abstract: Tumors with microsatellite instability (MSI) represent a paradigm for the success of immune checkpoint inhibitor (ICI)-based immunotherapy, particularly in patients with metastatic colorectal cancer (mCRC). To date however, tools for predicting efficacy of these new therapies are lacking. Here we combined high-throughput DNA and RNA sequencing of tumors from 117 patients with MSI mCRC treated with anti-PD-1 +/- anti-CTLA-4 and enrolled into two cohorts, i.e., the NIPICOL clinical trial (NCT03350126) and the ImmunoMSI prospective cohort that were used as discovery and validation cohorts in this ancillary study, respectively. All analyses based on previously suggested DNA/RNA biomarkers of resistance failed to identify robust predictors of treatment response in patients, e.g., the level of MSI, mutational burden, the presence of specific somatic DNA variants as assessed by exome-sequencing and the activity of canonical signaling pathways or the presence of specific cellular contingents within the tumor bulk as estimated by RNA-sequencing. By contrast, resistance to ICI was found to depend both on a small subset of somatic DNA variants located in microsatellite-containing genes with very diverse biological functions and the expression of a stromal-oriented RNA component. Testing of these predictors in 5 large additional independent retrospective and prospective cohorts (IDEA and MOSAIC clinical trials) regrouping 446 patients with nonmetastatic or metastatic MSI CRC untreated with ICI allowed us to validate the specificity of the predictive nature of these indicators regarding ICI-treated MSI mCRC patients. The use of these DNA/RNA predictors will help to refine the ICI-based precision therapy of patients with metastatic MSI mCRC.
Published: 2022

4. The HIF1α/JMY pathway promotes glioblastoma stem-like cell invasiveness after irradiation

Author: Didier Busso, Ada Collura, Mahasen Saati, Marie-Pierre Junier, Karim Ben M'Barek, Romane Bertrand, Marc-André Mouthon, Hayet Bensalah-Pigeon, Oscar Gitton-Quent, François D. Boussin, José R Pineda, Laurent R. Gauthier, Hervé Chneiweiss, Institut de Radiobiologie Cellulaire et Moléculaire (IRCM), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay, Stabilité génétique, cellules souches et radiations (SGCSR (U_1274 / UMR_E_008)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay-Université Paris Cité (UPCité), Laboratoire de Radiopathologie (LRP), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Institut des cellules souches pour le traitement et l'étude des maladies monogéniques (I-STEM), Université d'Évry-Val-d'Essonne (UEVE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay-Généthon, Université d'Évry-Val-d'Essonne (UEVE), Centre de Recherche Saint-Antoine (CRSA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Instabilité des microsatellites et cancers [CRSA], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Neuroscience Paris Seine (NPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Gestionnaire, Hal Sorbonne Université, Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay-Université de Paris (UP), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Centre de Recherche Saint-Antoine (CR Saint-Antoine), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Instabilité des microsatellites et cancers [CHU Saint-Antoine], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Saint-Antoine [AP-HP], Neurosciences Paris Seine (NPS), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Biologie Paris Seine (IBPS), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Cytoplasm, medicine.medical_treatment, [SDV]Life Sciences [q-bio], Motility, lcsh:Medicine, Biology, Article, 03 medical and health sciences, 0302 clinical medicine, Cell Movement, Glioma, Cell Line, Tumor, Radiation, Ionizing, medicine, Humans, lcsh:Science, Actin, 030304 developmental biology, Regulation of gene expression, Cell Nucleus, 0303 health sciences, Multidisciplinary, Cancer stem cells, lcsh:R, Nuclear Proteins, medicine.disease, Hypoxia-Inducible Factor 1, alpha Subunit, 3. Good health, Cell invasion, Radiation therapy, CNS cancer, [SDV] Life Sciences [q-bio], 030220 oncology & carcinogenesis, Cancer cell, Cancer research, Trans-Activators, lcsh:Q, Glioblastoma, Signal Transduction
Abstract: Human glioblastoma (GBM) is the most common primary malignant brain tumor. A minor subpopulation of cancer cells, known as glioma stem-like cells (GSCs), are thought to play a major role in tumor relapse due to their stem cell-like properties, their high resistance to conventional treatments and their high invasion capacity. We show that ionizing radiation specifically enhances the motility and invasiveness of human GSCs through the stabilization and nuclear accumulation of the hypoxia-inducible factor 1α (HIF1α), which in turn transcriptionally activates the Junction-mediating and regulatory protein (JMY). Finally, JMY accumulates in the cytoplasm where it stimulates GSC migration via its actin nucleation-promoting activity. Targeting JMY could thus open the way to the development of new therapeutic strategies to improve the efficacy of radiotherapy and prevent glioma recurrence. The authors thank members of the LRP for helpful discussions and are indebted to V. Barroca and the staff of the animal facilities and to N. Deschamps and J. Baijer for cell sorting. We also thanks I. Naguibneva for the gift of the pTRIP shHIF1α plasmid. MS is the recipient of a doctoral fellowship from the Ministère de la Recherche. This work was supported by grants from CEA (Segment Radiobiologie), La Ligue contre le Cancer (Comité d’Ile de France), Electricité de France (EDF), Fondation de France (N° Engt: 2013-00042632) and Ramón y Cajal program (RYC-2013-13450).
Published: 2020

5. Consequences of the Hsp110DE9 mutation in tumorigenesis and the 5-fluorouracil-based chemotherapy response in Msh2-deficient mice

Author: Kathleen Noel, A.’dem Bokhari, Romane Bertrand, Florence Renaud, Pierre Bourgoin, Romain Cohen, Magali Svrcek, Anne-Christine Joly, Alex Duval, and Ada Collura
Subjects: Pharmacology, Cellular and Molecular Neuroscience, Mice, Carcinogenesis, Neoplasms, Mutation, Molecular Medicine, Animals, Microsatellite Instability, Cell Biology, Fluorouracil, HSP110 Heat-Shock Proteins, Molecular Biology
Abstract: Heat shock proteins (HSPs) play oncogenic roles in human tumours. We reported a somatic inactivating mutation of HSP110 (HSP110DE9) in mismatch repair-deficient (dMMR) cancers displaying microsatellite instability (MSI) but did not assess its impact. We evaluated the impact of the Hsp110DE9 mutation on tumour development and the chemotherapy response in a dMMR knock-in mouse model (Hsp110DE9
Published: 2021

6. Performance of Next-Generation Sequencing for the Detection of Microsatellite Instability in Colorectal Cancer With Deficient DNA Mismatch Repair

Author: Coralie Dorard, Olivier Buhard, Magali Svrcek, Vincent Jonchère, Franck Bielle, Ada Collura, Jean-François Fléjou, Erell Guillerm, Quentin Letourneur, Philippe Le Rouzic, Alex Duval, Mehdi Touat, François Ghiringhelli, Toky Ratovomanana, Florence Coulet, Mira Ayadi, Romain Cohen, Aurélien de Reyniès, Marie-Pierre Buisine, Pierre Bourgoin, Rémy Nicolle, Marc Sanson, Aurélie Siret, Thierry André, Pascale Cervera, Guillaume Piessen, Florence Renaud, and Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: 0301 basic medicine, Oncology, medicine.medical_specialty, Colorectal cancer, Concordance, Clinical Decision-Making, [SDV.CAN]Life Sciences [q-bio]/Cancer, DNA Mismatch Repair, 03 medical and health sciences, 0302 clinical medicine, Predictive Value of Tests, Internal medicine, Databases, Genetic, Exome Sequencing, medicine, PMS2, Biomarkers, Tumor, Humans, Prospective Studies, neoplasms, Exome, Immune Checkpoint Inhibitors, Exome sequencing, ComputingMilieux_MISCELLANEOUS, Retrospective Studies, Clinical Trials as Topic, Hepatology, business.industry, Gastroenterology, Microsatellite instability, High-Throughput Nucleotide Sequencing, Reproducibility of Results, medicine.disease, Immunohistochemistry, digestive system diseases, 3. Good health, MSH6, 030104 developmental biology, 030211 gastroenterology & hepatology, DNA mismatch repair, Microsatellite Instability, France, business, Colorectal Neoplasms, Multiplex Polymerase Chain Reaction, Algorithms
Abstract: Background & Aims Next-generation sequencing (NGS) was recently approved by the United States Food and Drug Administration to detect microsatellite instability (MSI) arising from defective mismatch repair (dMMR) in patients with metastatic colorectal cancer (mCRC) before treatment with immune checkpoint inhibitors (ICI). In this study, we aimed to evaluate and improve the performance of NGS to identify MSI in CRC, especially dMMR mCRC treated with ICI. Methods CRC samples used in this post hoc study were reassessed centrally for MSI and dMMR status using the reference methods of pentaplex polymerase chain reaction and immunohistochemistry. Whole-exome sequencing (WES) was used to evaluate MSISensor, the Food and Drug Administration-approved and NGS-based method for assessment of MSI. This was performed in (1) a prospective, multicenter cohort of 102 patients with mCRC (C1; 25 dMMR/MSI, 24 treated with ICI) from clinical trials NCT02840604 and NCT033501260, (2) an independent retrospective, multicenter cohort of 113 patients (C2; 25 mCRC, 88 non-mCRC, all dMMR/MSI untreated with ICI), and (3) a publicly available series of 118 patients with CRC from The Cancer Genome Atlas (C3; 51 dMMR/MSI). A new NGS-based algorithm, namely MSICare, was developed. Its performance for assessment of MSI was compared with MSISensor in C1, C2, and C3 at the exome level or after downsampling sequencing data to the MSK-IMPACT gene panel. MSICare was validated in an additional retrospective, multicenter cohort (C4) of 152 patients with new CRC (137 dMMR/MSI) enriched in tumors deficient in MSH6 (n = 35) and PMS2 (n = 9) after targeted sequencing of samples with an optimized set of microsatellite markers (MSIDIAG). Results At the exome level, MSISensor was highly specific but failed to diagnose MSI in 16% of MSI/dMMR mCRC from C1 (4 of 25; sensitivity, 84%; 95% confidence interval [CI], 63.9%–95.5%), 32% of mCRC (8 of 25; sensitivity, 68%; 95% CI, 46.5%–85.1%), and 9.1% of non-mCRC from C2 (8 of 88; sensitivity, 90.9%; 95% CI, 82.9%–96%), and 9.8% of CRC from C3 (5 of 51; sensitivity, 90.2%; 95% CI, 78.6%–96.7%). Misdiagnosis included 4 mCRCs treated with ICI, of which 3 showed an overall response rate without progression at this date. At the exome level, reevaluation of the MSI genomic signal using MSICare detected 100% of cases with true MSI status among C1 and C2. Further validation of MSICare was obtained in CRC tumors from C3, with 96.1% concordance for MSI status. Whereas misdiagnosis with MSISensor even increased when analyzing downsampled WES data from C1 and C2 with microsatellite markers restricted to the MSK-IMPACT gene panel (sensitivity, 72.5%; 95% CI, 64.2%–79.7%), particularly in the MSH6-deficient setting, MSICare sensitivity and specificity remained optimal (100%). Similar results were obtained with MSICare after targeted NGS of tumors from C4 with the optimized microsatellite panel MSIDIAG (sensitivity, 99.3%; 95% CI, 96%–100%; specificity, 100%). Conclusions In contrast to MSISensor, the new MSICare test we propose performs at least as efficiently as the reference method, MSI polymerase chain reaction, to detect MSI in CRC regardless of the defective MMR protein under both WES and targeted NGS conditions. We suggest MSICare may rapidly become a reference method for NGS-based testing of MSI in CRC, especially in mCRC, where accurate MSI status is required before the prescription of ICI.
Published: 2021

7. Instabilité des microsatellites et cancer

Author: Magali Svrcek, Alex Duval, Aziz Zaanan, Jérémie H. Lefevre, David Tougeron, and Ada Collura
Subjects: 0301 basic medicine, Genome instability, business.industry, Cancer Model, Cancer, Microsatellite instability, General Medicine, Biology, medicine.disease, General Biochemistry, Genetics and Molecular Biology, Lynch syndrome, 3. Good health, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, 030220 oncology & carcinogenesis, Cancer research, medicine, Microsatellite, DNA mismatch repair, Personalized medicine, business
Abstract: L’instabilité des séquences répétées du génome (appelées microsatellites) est une conséquence de l’inactivation fonctionnelle du système de réparation des erreurs produites au cours de la réplication de l’ADN (système MMR, mismatch repair). Elle signe un phénotype tumoral fréquent appelé MSI (microsatellite instable) qui a été mis en évidence il y a un peu plus de 20 ans. Les cancers MSI sont fréquents chez l’homme, associés à de nombreuses localisations primitives (côlon, estomac, endomètre, etc.). Ils peuvent être héréditaires ou, le plus souvent, de survenue sporadique. Cet article propose une synthèse des travaux dédiés à l’étude des cancers MSI menés par des chercheurs et médecins français récompensés par le prix Jean et Madeleine Schaeverbeke de la Fondation de France. Depuis 20 ans, leur activité a grandement contribué à améliorer nos connaissances sur ce mode original de tumorigenèse, jetant les bases d’une médecine personnalisée de ces tumeurs chez l’homme, en pleine émergence aujourd’hui.
Published: 2019

8. Targeting nonsense-mediated mRNA decay in colorectal cancers with microsatellite instability

Author: Dem Bokhari, A., Vincent Jonchere, Anaïs Lagrange, Romane Bertrand, Magali Svrcek, Laëtitia Marisa, Olivier Buhard, Malorie Greene, Anastasia Demidova, Jieshuang Jia, Eric Adriaenssens, Thierry Chassat, Denis Biard, Jean-François Fléjou, Fabrice Lejeune, Alexis Duval, Ada Collura, Centre de Recherche Saint-Antoine (CRSA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Site de recherche intégrée en cancérologie (SiRIC CURAMUS), Institut Universitaire de Cancérologie [Sorbonne Université] (IUC), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Mécanismes de tumorigenèse et thérapies ciblées, Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Université de Lille-Centre National de la Recherche Scientifique (CNRS), Signalisation des facteurs de croissance dans le cancer du sein. Protéomique fonctionnelle, Institut National de la Santé et de la Recherche Médicale (INSERM), Plateforme d'Expérimentations et de Hautes Technologies Animales [Lille], Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP), Institut des Maladies Emergentes et des Thérapies Innovantes (IMETI), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut Universitaire de Cancérologie [Paris] (IUC), and Collura, Ada
Subjects: [SDV] Life Sciences [q-bio], [SDV]Life Sciences [q-bio], [SDV.CAN]Life Sciences [q-bio]/Cancer, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, neoplasms, lcsh:RC254-282, digestive system diseases
Abstract: International audience; Abstract Nonsense-mediated mRNA decay (NMD) is responsible for the degradation of mRNAs with a premature termination codon (PTC). The role of this system in cancer is still quite poorly understood. In the present study, we evaluated the functional consequences of NMD activity in a subgroup of colorectal cancers (CRC) characterized by high levels of mRNAs with a PTC due to widespread instability in microsatellite sequences (MSI). In comparison to microsatellite stable (MSS) CRC, MSI CRC expressed increased levels of two critical activators of the NMD system, UPF1/2 and SMG1/6/7. Suppression of NMD activity led to the re-expression of dozens of PTC mRNAs. Amongst these, several encoded mutant proteins with putative deleterious activity against MSI tumorigenesis (e.g., HSP110DE9 chaperone mutant). Inhibition of NMD in vivo using amlexanox reduced MSI tumor growth, but not that of MSS tumors. These results suggest that inhibition of the oncogenic activity of NMD may be an effective strategy for the personalized treatment of MSI CRC.
Published: 2018

9. Identification of Positively and Negatively Selected Driver Gene Mutations Associated With Colorectal Cancer With Microsatellite Instability

Author: Agathe Guilloux, Sylvie Job, Nabila Elarouci, Olivier Buhard, Alex Duval, Thierry André, Lucile Armenoult, Mira Ayadi, Florence Coulet, Malorie Greene, Erell Guillerm, Anastasia R. Goloudina, Pascale Cervera, Toky Ratovomanana, Alain Virouleau, Samuel Landman, Yann Parc, Romane Bertrand, Vincent Jonchère, Aurélien de Reyniès, Magali Svrcek, Jérémie H. Lefevre, Sylvie Dumont, Fatiha Merabtene, Jean-François Fléjou, Laetitia Marisa, and Ada Collura
Subjects: bp, base pair, 0301 basic medicine, Genome instability, RTCA, Real-Time Cell Analyzer, Gene mutation, medicine.disease_cause, WES, whole-exome sequencing, Positive and Negative Selection, Negative selection, PCR, polymerase chain reaction, WGA, whole-genome amplification, Exome sequencing, Original Research, Mutation, Gastroenterology, MSI, microsatellite instability, indel, insertion/deletion, mRNA, messenger RNA, 3. Good health, UTR, untranslated region, Driver Gene Mutations, CRC, colorectal cancer, Colonic Neoplasms, shRNA, short hairpin RNA, MSH, MutS Homolog, Microsatellite, Microsatellite Instability, Tumorigenic Process, NR, nonrepetitive, PBS, phosphate-buffered saline, MMR, mismatch repair, Biology, R, repetitive, 03 medical and health sciences, RFS, relapse-free survival, medicine, Humans, lcsh:RC799-869, neoplasms, Colorectal Cancer, Hepatology, Microsatellite instability, medicine.disease, HR, hazard ratio, digestive system diseases, 030104 developmental biology, Attitude, siRNA, small interfering RNA, Cancer research, lcsh:Diseases of the digestive system. Gastroenterology, MLH1, MutL Homolog 1, Carcinogenesis
Abstract: Background & Aims Recent studies have shown that cancers arise as a result of the positive selection of driver somatic events in tumor DNA, with negative selection playing only a minor role, if any. However, these investigations were concerned with alterations at nonrepetitive sequences and did not take into account mutations in repetitive sequences that have very high pathophysiological relevance in the tumors showing microsatellite instability (MSI) resulting from mismatch repair deficiency investigated in the present study. Methods We performed whole-exome sequencing of 47 MSI colorectal cancers (CRCs) and confirmed results in an independent cohort of 53 MSI CRCs. We used a probabilistic model of mutational events within microsatellites, while adapting pre-existing models to analyze nonrepetitive DNA sequences. Negatively selected coding alterations in MSI CRCs were investigated for their functional and clinical impact in CRC cell lines and in a third cohort of 164 MSI CRC patients. Results Both positive and negative selection of somatic mutations in DNA repeats was observed, leading us to identify the expected true driver genes associated with the MSI-driven tumorigenic process. Several coding negatively selected MSI-related mutational events (n = 5) were shown to have deleterious effects on tumor cells. In the tumors in which deleterious MSI mutations were observed despite the negative selection, they were associated with worse survival in MSI CRC patients (hazard ratio, 3; 95% CI, 1.1–7.9; P = .03), suggesting their anticancer impact should be offset by other as yet unknown oncogenic processes that contribute to a poor prognosis. Conclusions The present results identify the positive and negative driver somatic mutations acting in MSI-driven tumorigenesis, suggesting that genomic instability in MSI CRC plays a dual role in achieving tumor cell transformation. Exome sequencing data have been deposited in the European genome–phenome archive (accession: EGAS00001002477)., Graphical abstract
Published: 2018

10. [Microsatellite instability and cancer: from genomic instability to personalized medicine]

Author: Ada, Collura, Jérémie H, Lefevre, Magali, Svrcek, David, Tougeron, Aziz, Zaanan, and Alex, Duval
Subjects: Neoplasms, Humans, Microsatellite Instability, HSP110 Heat-Shock Proteins, Precision Medicine, Colorectal Neoplasms, DNA Mismatch Repair, Genomic Instability
Abstract: The human tumor phenotype referred to as MSI (Microsatellite Instability) is associated with inactivating alterations in MMR genes (Mismatch Repair). MSI was first observed in inherited malignancies associated with Lynch syndrome and later in sporadic colon, gastric and endometrial cancers. MSI tumors develop through a distinctive molecular pathway characterized by genetic instability in numerous microsatellite DNA repeat sequences throughout the genome. In this article, french researchers and physicians who have been recently awarded by the Fondation de France (Jean and Madeleine Schaeverbeke prize) make a sum of their activity in the MSI cancer field for more than 20 years. Their findings have greatly contributed to increase our knowledge of this original cancer model, laying the foundation for a personalized medicine of MSI tumors.
Published: 2019

11. MSI/MMR-deficient tumor diagnosis: Which standard for screening and for diagnosis? Diagnostic modalities for the colon and other sites: Differences between tumors

Author: Magali Svrcek, Alex Duval, Romain Cohen, Jean-François Fléjou, Olivier Lascols, Ada Collura, Vincent Jonchère, Olivier Buhard, Service de Pathologie [CHU Saint-Antoine], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Centre de Recherche Saint-Antoine (CR Saint-Antoine), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Sorbonne Université (SU), Service d'Oncologie Médicale [CHU Saint -Antoine], Gestionnaire, Hal Sorbonne Université, Centre de Recherche Saint-Antoine (CRSA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), and Service d'Oncologie Médicale [CHU Saint-Antoine]
Subjects: 0301 basic medicine, Oncology, Cancer Research, medicine.medical_specialty, congenital, hereditary, and neonatal diseases and abnormalities, Colorectal cancer, medicine.medical_treatment, Genetic counseling, [SDV.CAN]Life Sciences [q-bio]/Cancer, DNA Mismatch Repair, Polymerase Chain Reaction, Mismatch repair, 03 medical and health sciences, 0302 clinical medicine, [SDV.CAN] Life Sciences [q-bio]/Cancer, Internal medicine, medicine, Humans, Mass Screening, Radiology, Nuclear Medicine and imaging, neoplasms, Chemotherapy, business.industry, Cancer, Microsatellite instability, Immunohistochimie, Hematology, General Medicine, medicine.disease, Colorectal Neoplasms, Hereditary Nonpolyposis, Immunohistochemistry, Lynch syndrome, digestive system diseases, 3. Good health, Instabilité des microsatellites, 030104 developmental biology, DNA Repair Enzymes, 030220 oncology & carcinogenesis, Next-generation sequencing, DNA mismatch repair, Syndrome de lynch, business, Colorectal Neoplasms, Algorithms, Séquençage nouvelle génération
Abstract: International audience; Microsatellite instability (MSI), which is caused by deficiency of the DNA mismatch repair (MMR) system, is the molecular abnormality observed in tumors associated with Lynch syndrome. Lynch syndrome represents one of the most frequent conditions of cancer predisposition in human, thus requiring specific care and genetic counseling. Moreover, research has recently focused increasingly on MMR deficiency due to its positive predictive value for the efficacy of immune checkpoints inhibitors (ICKi) in metastatic tumors, regardless of their primary origin. MSI has also been demonstrated to constitute an independent prognostic factor in several tumor types, being also associated with alternative response to chemotherapy. These observations have led many professional medical organizations to recommend universal screening of all newly diagnosed colorectal cancers for dMMR/MSI status and increasing evidence support the evaluation of MSI in all human tumors regardless of the cancer tissue of origin. Currently, two standard reference methods, namely immunohistochemistry and polymerase chain reaction, are recommended for the detection of dMMR/MSI status. These methods are equally valid as the initial screening test for dMMR/MSI in colorectal cancer. To date, there is no recommendation for the detection of dMMR/MSI in other primary tumors. In this review, we will present a comprehensive overview of the methods used for evaluation of tumor dMMR/MSI status in colorectal cancer, as well as in other tumor sites. We will see that the evaluation of this status remains challenging in some clinical settings, with the need to improve the above methods in these specific contexts.
Published: 2019

12. METHODS AND PHARMACEUTICAL COMPOSITIONS FOR TREATING CANCER

Author: Alex Duval, Vincent Jonchere, Ada Collura, Laëtitia Marisa, Aurelien de Reynies, Jonchere, Vincent, and Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: [SDV.CAN] Life Sciences [q-bio]/Cancer, [SDV.CAN]Life Sciences [q-bio]/Cancer
Published: 2019

13. Major improvement in the detection of microsatellite instability in colorectal cancer using HSP110 T17 E-ice-COLD-PCR

Author: Mourad Sahbatou, Jean-François Deleuze, Alexandre How-Kit, Ada Collura, Antoine Daunay, Olivier Buhard, Alex Duval, Clément Meiller, Centre d'Etude du Polymorphisme Humain (CEPH), Université Paris Diderot - Paris 7 (UPD7)-Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7)-Fondation Jean Dausset, Pathologies biliaires, fibrose et cancer du foie [CRSA], Centre de Recherche Saint-Antoine (CRSA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Génomique Fonctionnelle des Tumeurs Solides (U1162), Université Paris 13 (UP13)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre National de Génotypage (CNG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Fondation Jean Dausset-Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7)-Université Paris Diderot - Paris 7 (UPD7), Pathologies biliaires, fibrose et cancer du foie [CHU Saint-Antoine], Centre de Recherche Saint-Antoine (CR Saint-Antoine), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Pathologies biliaires, fibrose et cancer du foie (Inserm UMR_S 938), CHU Saint-Antoine [APHP]-Centre de Recherche Saint-Antoine (CR Saint-Antoine), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)
Subjects: 0301 basic medicine, Colorectal cancer, MSI detection method, [SDV]Life Sciences [q-bio], E-ice-COLD-PCR, colorectal cancer, Biology, Polymerase Chain Reaction, Germline, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Cell Line, Tumor, Genotype, Genetics, medicine, Humans, HSP110 Heat-Shock Proteins, Allele, neoplasms, Genetics (clinical), COLD-PCR, Microsatellite instability, Reference Standards, medicine.disease, Molecular biology, Lynch syndrome, digestive system diseases, 3. Good health, Cold Temperature, Germ Cells, 030104 developmental biology, chemistry, 030220 oncology & carcinogenesis, Mutation, microsatellite instability, Colorectal Neoplasms, DNA, HSP110
Abstract: International audience; Every colorectal cancer (CRC) patient should be tested for microsatellite instability (MSI) to screen for Lynch syndrome. Evaluation of MSI status involves screening tumor DNA for the presence of somatic deletions in DNA repeats using PCR followed by fragment analysis. While this method may lack sensitivity due to the presence of a high level of germline DNA, which frequently contaminates the core of primary colon tumors, no other method developed to date is capable of modifying the standard PCR protocol to achieve improvement of MSI detection. Here, we describe a new approach developed for the ultra-sensitive detection of MSI in CRC based on E-ice-COLDPCR, using HSP110 T17, a mononucleotide DNA repeat previously proposed as an optimal marker to detect MSI in tumor DNA, and an oligo(dT)(16) LNA blocker probe complementary to wild-type genotypes. The HT17 E-ice-COLD-PCR assay improved MSI detection by 20-200-fold compared with standard PCR using HT17 alone. It presents an analytical sensitivity of 0.1%-0.05% of mutant alleles in wild-type background, thus greatly improving MSI detection in CRC samples highly contaminated with normal DNA. HT17 E-ice-COLD-PCR is a rapid, cost-effective, easy-to-implement, and highly sensitive method, which could significantly improve the detection of MSI in routine clinical testing.
Published: 2018

14. Prevalence of Microsatellite Instability in Intraductal Papillary Mucinous Neoplasms of the Pancreas

Author: Jean-Christophe Vaillant, Nelson Dusetti, Jean-François Emile, Jean-Baptiste Bachet, Pascal Hammel, Anastasia R. Goloudina, Aurelie Scriva, Jean-Robert Delpero, Jean-François Fléjou, François Paye, Juan L. Iovanna, Christophe Louvet, Thierry André, Jean Closset, Jean-Luc Van Laethem, Alex Duval, Renato Micelli Lupinacci, Martine Antoine, Alain Sauvanet, Issam Abd Alsamad, Jérôme Cros, Vincent Jonchère, Olivier Buhard, Sylvie Dumont, Armelle Bardier-Dupas, Ada Collura, Raphaël Maréchal, Pieter Demetter, Anita Rodenas, Pascale Cervera, Magali Svrcek, Zayed Military Hospital, Department of Pathology, Hôpital Erasmes, Laboratoire électrotechnique et électronique industrielle (LEEI), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), Assistance publique-Hôpitaux de Paris - Espace éthique (AP-HP Espace éthique), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Unité Mixte de Service d'Imagerie et de Cytométrie (UMS LUMIC), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Beaujon, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Université Paris Diderot - Paris 7 (UPD7)-Hôpital Beaujon, Service de chirurgie hepato-pancreato-biliaire, Hôpital Beaujon-Université Paris Diderot - Paris 7 (UPD7)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Service d'Oncologie Médicale [Montsouris], Institut Mutualiste de Montsouris (IMM), Laboratoire épidémiologie et oncogénèse des tumeurs digestives, Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Erasme Hospital, Brussels, Service d’Anatomie et cytologie pathologiques [CHU Tenon], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Tenon [APHP], Service d'anatomie pathologique [CHU Tenon], Service d'anatomie et cytologie pathologiques [CHU Saint-Antoine], Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Saint-Antoine [APHP], Centre de Recherche en Cancérologie de Marseille (CRCM), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Aix Marseille Université (AMU), Physiopathologie du stress pancréatique, Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche Saint-Antoine (CR Saint-Antoine), Pathologies biliaires, fibrose et cancer du foie (Inserm UMR_S 938), CHU Saint-Antoine [APHP]-Centre de Recherche Saint-Antoine (CR Saint-Antoine), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire d'Excellence : Lipoprotéines et Santé : prévention et Traitement des maladies Inflammatoires et du Cancer (LabEx LipSTIC), Institut National de la Recherche Agronomique (INRA)-Université Montpellier 2 - Sciences et Techniques (UM2)-Université Paris-Sud - Paris 11 (UP11)-École pratique des hautes études (EPHE)-Institut Gustave Roussy (IGR)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Université de Bourgogne (UB)-Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon)-Centre Régional de Lutte contre le cancer - Centre Georges-François Leclerc (CRLCC - CGFL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Fédération Francophone de la Cancérologie Digestive, FFCD-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Etablissement français du sang [Bourgogne-France-Comté] (EFS [Bourgogne-France-Comté])-Centre National de la Recherche Scientifique (CNRS)-Centre Hospitalier Régional Universitaire [Besançon] (CHRU Besançon)-Université de Franche-Comté (UFC)-Université de Montpellier (UM), Service de chirurgie générale et digestive [CHU Saint-Antoine], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Saint-Antoine [APHP], Service d'Oncologie Médicale [CHU Saint -Antoine], Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7)-Hôpital Beaujon [AP-HP], Biomarqueurs et essais cliniques en Cancérologie et Onco-Hématologie (BECCOH), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Université Paris-Saclay, Hôpital Erasme [Bruxelles] (ULB), Faculté de Médecine [Bruxelles] (ULB), Université libre de Bruxelles (ULB)-Université libre de Bruxelles (ULB), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Tenon [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université-Sorbonne Université, Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Saint-Antoine [AP-HP], Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université, Institut National de la Recherche Agronomique (INRA)-Université Montpellier 2 - Sciences et Techniques (UM2)-Université Paris-Sud - Paris 11 (UP11)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut Gustave Roussy (IGR)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Université de Bourgogne (UB)-Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon)-Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER-UNICANCER-Institut National de la Santé et de la Recherche Médicale (INSERM)-Fédération Francophone de la Cancérologie Digestive, FFCD-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Etablissement français du sang [Bourgogne-France-Comté] (EFS [Bourgogne-France-Comté])-Centre National de la Recherche Scientifique (CNRS)-Centre Hospitalier Régional Universitaire [Besançon] (CHRU Besançon)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université de Montpellier (UM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Saint-Antoine [AP-HP], Centre de Recherche Saint-Antoine (CRSA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Groupe Hospitalier Diaconesses Croix Saint-Simon, CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Sorbonne Université (SU), Université Pierre et Marie Curie - Paris 6 (UPMC), Hôpital Erasme [Bruxelles], Hôpital Beaujon [AP-HP], Université Paris Diderot - Paris 7 (UPD7), CHU Saint-Antoine [AP-HP], Hôpitaux Universitaires de l'Est Parisien [Paris] (HUEP), Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), Hôpital Ambroise Paré [AP-HP], CHI Créteil, CHU Tenon [AP-HP], Aix Marseille Université (AMU)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Saint-Antoine [APHP], Laboratoire électrotechnique et électronique industrielle ( LEEI ), Institut National Polytechnique [Toulouse] ( INP ) -Centre National de la Recherche Scientifique ( CNRS ), Assistance publique-Hôpitaux de Paris - Espace éthique ( AP-HP Espace éthique ), Assistance publique - Hôpitaux de Paris (AP-HP), Unité Mixte de Service d'Imagerie et de Cytométrie ( UMS LUMIC ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Assistance publique - Hôpitaux de Paris (AP-HP)-Université Paris Diderot - Paris 7 ( UPD7 ) -Hôpital Beaujon, Institut Mutualiste de Montsouris ( IMM ), Laboratoire de Mathématiques Informatique et Applications ( LAMIA ), Université des Antilles et de la Guyane ( UAG ), Université de Versailles Saint-Quentin-en-Yvelines ( UVSQ ), Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Tenon [APHP], Service d'anatomie et cytologie pathologiques, Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Saint-Antoine [APHP], Centre de Recherche en Cancérologie de Marseille ( CRCM ), Aix Marseille Université ( AMU ) -Institut Paoli-Calmettes-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Institut National de la Santé et de la Recherche Médicale ( INSERM ), Centre de Recherche Saint-Antoine ( CR Saint-Antoine ), Pathologies biliaires, fibrose et cancer du foie ( Inserm UMR_S 938 ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -CHU Saint-Antoine [APHP], Laboratoire d'Excellence : Lipoprotéines et Santé : prévention et Traitement des maladies Inflammatoires et du Cancer ( LabEx LipSTIC ), Institut National de la Recherche Agronomique ( INRA ) -Université Montpellier 2 - Sciences et Techniques ( UM2 ) -Université Paris-Sud - Paris 11 ( UP11 ) -École pratique des hautes études ( EPHE ) -Institut Gustave Roussy ( IGR ) -Centre Hospitalier Régional Universitaire de Nancy ( CHRU Nancy ) -Université de Bourgogne ( UB ) -Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand ( CHU Dijon ) -Centre Régional de Lutte contre le cancer - Centre Georges-François Leclerc ( CRLCC - CGFL ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Fédération Francophone de la Cancérologie Digestive, FFCD-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Etablissement français du sang [Bourgogne-France-Comté] ( EFS [Bourgogne-France-Comté] ) -Centre National de la Recherche Scientifique ( CNRS ) -Centre Hospitalier Régional Universitaire [Besançon] ( CHRU Besançon ) -Université de Franche-Comté ( UFC ), and Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Saint-Antoine [APHP]
Subjects: 0301 basic medicine, Oncology, Male, Time Factors, endocrine system diseases, [SDV]Life Sciences [q-bio], CD8-Positive T-Lymphocytes, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, 0302 clinical medicine, PMS2, Cytokine Production, Mismatch Repair Endonuclease PMS2, Aged, 80 and over, Gastroenterology, Middle Aged, Lynch syndrome, 3. Good health, DNA-Binding Proteins, MutS Homolog 2 Protein, Phenotype, 030220 oncology & carcinogenesis, Female, Microsatellite Instability, MutL Protein Homolog 1, Carcinoma, Pancreatic Ductal, Adult, medicine.medical_specialty, congenital, hereditary, and neonatal diseases and abnormalities, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, MLH1, Disease-Free Survival, 03 medical and health sciences, Pancreatic Cancer, Lymphocytes, Tumor-Infiltrating, Internal medicine, Pancreatic cancer, medicine, Biomarkers, Tumor, Humans, Genetic Predisposition to Disease, neoplasms, Aged, Hepatology, Intraductal papillary mucinous neoplasm, [ SDV ] Life Sciences [q-bio], T-cell Activation, Microsatellite instability, nutritional and metabolic diseases, Marker, medicine.disease, digestive system diseases, MSH6, Pancreatic Neoplasms, 030104 developmental biology, MSH2, Neoplasms, Cystic, Mucinous, and Serous
Abstract: International audience; Microsatellite instability (MSI) caused by mismatch repair deficiency (dMMR) is detected in a small proportion of pancreatic ductal adenocarcinomas (PDACs). dMMR and MSI have been associated with responses of metastatic tumors, including PDACs, to immune checkpoint inhibitor therapy. We performed immunohistochemical analyses of a 445 PDAC specimens, collected from consecutive patients at multiple centers, to identify those with dMMR, based on loss of mismatch repair proteins MLH1, MSH2, MSH6, and/or PMS2. We detected dMMR in 1.6% of tumor samples; we found dMMR in a larger proportion of intraductal papillary mucinous neoplasms-related tumors (4/58, 6.9%) than non- intraductal papillary mucinous neoplasms PDAC (5/385, 1.3%) (P = .02). PDACs with dMMR contained potentially immunogenic mutations because of MSI in coding repeat sequences. PDACs with dMMR or MSI had a higher density of CD8+ T cells at the invasive front than PDACs without dMMR or MSI (P = .08; Fisher exact test). A higher proportion of PDACs with dMMR or MSI expressed the CD274 molecule (PD-L1, 8/9) than PDACs without dMMR or MSI (4/10) (P = .05). Times of disease-free survival and overall survival did not differ significantly between patients with PDACs with dMMR or MSI vs without dMMR or MSI. Studies are needed to determine whether these features of PDACs with dMMR or MSI might serve as prognostic factors.
Published: 2017

15. HSP110 promotes colorectal cancer growth through STAT3 activation

Author: Gaëtan Jego, Oleg N. Demidov, Kevin Berthenet, Anaïs Lagrange, Anastasia R. Goloudina, Alex Duval, A’dem Bokhari, Arlette Hammann, Christophe Boudesco, Ada Collura, Carmen Garrido, Sebastien Causse, S Dumont, A de Thonel, Denis Biard, Renaud Seigneuric, Magali Svrcek, Guillaume Marcion, Lipides - Nutrition - Cancer (U866) (LNC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Bourgogne (UB)-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon (ENSBANA)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Centre de Recherche Saint-Antoine (UMRS893), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre épigénétique et destin cellulaire (EDC (UMR_7216)), Centre National de la Recherche Scientifique (CNRS)-Université Paris Diderot - Paris 7 (UPD7), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon (ENSBANA), Centre de Recherche Saint-Antoine (CR Saint-Antoine), Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Centre épigénétique et destin cellulaire (EDC), Lipides - Nutrition - Cancer (U866) ( LNC ), Université de Bourgogne ( UB ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon ( ENSBANA ), Centre de Recherche Saint-Antoine ( CR Saint-Antoine ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Centre épigénétique et destin cellulaire ( EDC ), and Université Paris Diderot - Paris 7 ( UPD7 ) -Centre National de la Recherche Scientifique ( CNRS )
Subjects: STAT3 Transcription Factor, 0301 basic medicine, Cancer Research, Colorectal cancer, Biopsy, Mice, Nude, colorectal cancer, [SDV.CAN]Life Sciences [q-bio]/Cancer, Mouse model of colorectal and intestinal cancer, Biology, medicine.disease_cause, Molecular oncology, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, STAT3, Mice, 03 medical and health sciences, 0302 clinical medicine, Growth factor receptor, Cell Line, Tumor, Genetics, medicine, Animals, Humans, HSP110 Heat-Shock Proteins, Intestinal Mucosa, Phosphorylation, Molecular Biology, Cell Proliferation, Microsatellite instability, Cell cycle, medicine.disease, Molecular biology, digestive system diseases, 3. Good health, 030104 developmental biology, 030220 oncology & carcinogenesis, Cancer research, biology.protein, Female, Colorectal Neoplasms, Carcinogenesis, Neoplasm Transplantation, HSP110, Protein Binding
Abstract: IF 7.932; International audience; Heat shock protein 110 (HSP110) is induced by different stresses and, through its anti-apoptotic and chaperoning properties, helps cells survive these adverse situations. In colon cancers, HSP110 is abnormally abundant. We have recently shown that colorectal cancer patients with microsatellite instability (MSI) had an improved response to chemotherapy because they harbor an HSP110-inactivating mutation (HSP110DE9). In this work, we used patient biopsies, human colorectal cancer cells grown in vitro and in vivo (xenografts), and intestinal crypts to demonstrate that HSP110 is also involved in colon cancer growth. We showed that HSP110 induces colon cancer cell proliferation and that this effect is associated with STAT3 activation, specifically an increase in STAT3 phosphorylation, nuclear translocation and transcription factor activity. STAT3 inhibition blocks the proliferative effect of HSP110. From a molecular standpoint, we demonstrated that HSP110 directly binds to STAT3, thereby facilitating its phosphorylation by JAK2. Finally, we showed a correlation between HSP110 expression and STAT3 phosphorylation in colon cancer patient samples. Thus, the expression of HSP110 in colon cancer contributes to STAT3-dependent tumor growth and the frequent inactivating mutation of this chaperone is probably an important event underlying the improved prognosis in colon cancer displaying MSI.
Published: 2017

16. The Balance Between Cytotoxic T-cell Lymphocytes and Immune Checkpoint Expression in the Prognosis of Colon Tumors

Author: Côme Lepage, Thierry André, Dominique Guenot, Alex Duval, Kristell Wanherdrick, Etienne Becht, Janick Selves, Yann Parc, Valentin Derangère, François Ghiringhelli, Jean-François Fléjou, Vincent Jonchère, Anastasia R. Goloudina, Romain Cohen, Pierre Laurent-Puig, Sylviane Olschwang, Pascale Cervera, Chrystelle Colas, Valérie Boige, Laetitia Marisa, Ada Collura, Magali Svrcek, Gérard Milano, Olivier Buhard, Jérémie H. Lefevre, Aurélien de Reyniès, Programme Cartes d'Identité des Tumeurs (CIT), Ligue Nationale Contre le Cancer, Pathologies biliaires, fibrose et cancer du foie ( Inserm UMR_S 938 ), Centre de Recherche Saint-Antoine ( CR Saint-Antoine ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -CHU Saint-Antoine [APHP], Service d'Anatomie Pathologique [CHU Saint-Antoine], Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Saint-Antoine [APHP], Institut Universitaire du Cancer de Toulouse - Oncopole ( IUCT Oncopole - UMR 1037 ), Université Paul Sabatier - Toulouse 3 ( UPS ) -CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Centre Antoine Lacassagne, CRLCC Antoine Lacassagne, Développement et physiopathologie de l'intestin et du pancréas, Institut National de la Santé et de la Recherche Médicale ( INSERM ), Service d'Oncologie Médicale [CHU Saint -Antoine], Service d'Oncogénétique et Angiogénétique Moléculaire [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Pitié-Salpêtrière [APHP], Service de chirurgie générale et digestive [CHU Saint-Antoine], UMR S775, Université Paris Descartes - Paris 5 ( UPD5 ), Département de médecine oncologique [Gustave Roussy], Institut Gustave Roussy ( IGR ), Registre Bourguignon des Cancers Digestifs, Lipides - Nutrition - Cancer (U866) ( LNC ), Université de Bourgogne ( UB ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon ( ENSBANA ) -Université de Bourgogne ( UB ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon ( ENSBANA ) -Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand ( CHU Dijon ), Lipides - Nutrition - Cancer [Dijon - U1231] ( LNC ), Université de Bourgogne ( UB ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Centre Régional de Lutte contre le cancer - Centre Georges-François Leclerc ( CRLCC - CGFL ), Pathologies biliaires, fibrose et cancer du foie (Inserm UMR_S 938), CHU Saint-Antoine [APHP]-Centre de Recherche Saint-Antoine (CR Saint-Antoine), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Saint-Antoine [APHP], Institut Universitaire du Cancer de Toulouse - Oncopole (IUCT Oncopole - UMR 1037), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP], Marseille medical genetics - Centre de génétique médicale de Marseille (MMG), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Département d'Oncologie [Hôpital Clairval - Marseille], Hôpital Privé Clairval [Marseille], Département de génétique médicale [Hôpital de la Timone - APHM], Institut National de la Santé et de la Recherche Médicale (INSERM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Assistance Publique - Hôpitaux de Marseille (APHM)-Aix Marseille Université (AMU), Université Paris Descartes - Paris 5 (UPD5), Institut Gustave Roussy (IGR), Lipides - Nutrition - Cancer (U866) (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon (ENSBANA)-Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon (ENSBANA)-Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Centre Régional de Lutte contre le cancer - Centre Georges-François Leclerc (CRLCC - CGFL), (le programme) Cartes d'identité des tumeurs (CIT), Ligue Nationales Contre le Cancer (LNCC), Pathologies biliaires, fibrose et cancer du foie [CHU Saint-Antoine], Centre de Recherche Saint-Antoine (CR Saint-Antoine), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Centre de Lutte contre le Cancer Antoine Lacassagne [Nice] (UNICANCER/CAL), UNICANCER-Université Côte d'Azur (UCA), Unité fonctionnelle d'Oncogénétique et Angiogénétique Moléculaire [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Aix Marseille Université (AMU), Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER, Pathologies biliaires, fibrose et cancer du foie [CRSA], Centre de Recherche Saint-Antoine (CRSA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: 0301 basic medicine, Oncology, Male, Cancer Research, Colorectal cancer, Lymphocyte, Programmed Cell Death 1 Receptor, neoplasms, Gene Expression, B7-H1 Antigen, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, 0302 clinical medicine, t-lymphocyte, CTLA-4 Antigen, programmed cell death 1 ligand 1, genes, Hepatitis A Virus Cellular Receptor 2, colonic neoplasms, Middle Aged, Prognosis, Lymphocyte Activation Gene 3 Protein, 3. Good health, Survival Rate, medicine.anatomical_structure, 030220 oncology & carcinogenesis, cytotoxicity, Female, Microsatellite Instability, cell cycle checkpoint, Colorectal Neoplasms, medicine.medical_specialty, Colon, T cell, CD8 Antigens, [SDV.CAN]Life Sciences [q-bio]/Cancer, colorectal cancer, lymphocyte, patient prognosis, Inducible T-Cell Co-Stimulator Protein, 03 medical and health sciences, Lymphocytes, Tumor-Infiltrating, Antigens, CD, Internal medicine, medicine, Biomarkers, Tumor, Humans, Survival rate, Neoplasm Staging, Retrospective Studies, business.industry, Proportional hazards model, Microsatellite instability, Th1 Cells, medicine.disease, Programmed Cell Death 1 Ligand 2 Protein, Immune checkpoint, digestive system diseases, 030104 developmental biology, consensus, business, CD8, T-Lymphocytes, Cytotoxic
Abstract: IF 12.589; International audience; BackgroundImmune checkpoint (ICK) expression might represent a surrogate measure of tumor-infiltrating T cell (CTL) exhaustion and therefore be a more accurate prognostic biomarker for colorectal cancer (CRC) patients than CTL enumeration as measured by the Immunoscore.MethodsThe expression of ICKs, Th1, CTLs, cytotoxicity-related genes, and metagenes, including Immunoscore-like metagenes, were evaluated in three independent cohorts of CRC samples (260 microsatellite instable [MSI], 971 non-MSI). Their associations with patient survival were analyzed by Cox models, taking into account the microsatellite instability (MSI) status and affiliation with various Consensus Molecular Subgroups (CMS). PD-L1 and CD8 expression were examined on a subset of tumors with immunohistochemistry. All statistical tests were two-sided.ResultsThe expression of Immunoscore-like metagenes was statistically significantly associated with improved outcome in non-MSI tumors displaying low levels of both CTLs and immune checkpoints (ICKs; CMS2 and CMS3; hazard ratio [HR] = 0.63, 95% confidence interval [CI] = 0.43 to 0.92, P = .02; and HR = 0.55, 95% CI = 0.34 to 0.90, P = .02, respectively), but clearly had no prognostic relevance in CRCs displaying higher levels of CTLs and ICKs (CMS1 and CMS4; HR = 0.46, 95% CI = 0.10 to 2.10, P = .32; and HR = 1.13, 95% CI = 0.79 to 1.63, P = .50, respectively), including MSI tumors. ICK metagene expression was statistically significantly associated with worse prognosis independent of tumor staging in MSI tumors (HR = 3.46, 95% CI = 1.41 to 8.49, P = .007). ICK expression had a negative impact on the proliferation of infiltrating CD8 T cells in MSI neoplasms (median = 0.56 in ICK low vs median = 0.34 in ICK high, P = .004).ConclusionsICK expression cancels the prognostic relevance of CTLs in highly immunogenic colon tumors and predicts a poor outcome in MSI CRC patients.
Published: 2016

17. The HSP90 inhibitor, 17AAG, protects the intestinal stem cell niche and inhibits graft versus host disease development

Author: Arlette Hammann, Eric Solary, Oleg N. Demidov, Gaëtan Jego, Robinet E, A. Seignez, Sarah Richaud, Anastasia R. Goloudina, Evelyne Kohli, Magali Svrcek, Carmen Garrido, Eric Fourmaux, Deepti A, Anne-Laure Joly, Sophie Hébrard, Ada Collura, Elise Schmitt, Lipides - Nutrition - Cancer (U866) (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon (ENSBANA), Laboratoire d'Excellence : Lipoprotéines et Santé : prévention et Traitement des maladies Inflammatoires et du Cancer (LabEx LipSTIC), Institut National de la Recherche Agronomique (INRA)-Université Montpellier 2 - Sciences et Techniques (UM2)-Université Paris-Sud - Paris 11 (UP11)-École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut Gustave Roussy (IGR)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon)-Université de Bourgogne (UB)-Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon)-Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER-UNICANCER-Institut National de la Santé et de la Recherche Médicale (INSERM)-Fédération Francophone de la Cancérologie Digestive, FFCD-Université de Montpellier (UM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS BFC)-Centre National de la Recherche Scientifique (CNRS)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), CHU Dijon, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Centre de Recherche Saint-Antoine (UMRS893), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Interaction virus-hôte et maladies du foie, Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hématopoïèse normale et pathologique, Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER, Institut National de la Recherche Agronomique (INRA)-Université Montpellier 2 - Sciences et Techniques (UM2)-Université Paris-Sud - Paris 11 (UP11)-École pratique des hautes études (EPHE)-Institut Gustave Roussy (IGR)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Université de Bourgogne (UB)-Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon)-Centre Régional de Lutte contre le cancer - Centre Georges-François Leclerc (CRLCC - CGFL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Fédération Francophone de la Cancérologie Digestive, FFCD-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Etablissement français du sang [Bourgogne-France-Comté] (EFS [Bourgogne-France-Comté])-Centre National de la Recherche Scientifique (CNRS)-Centre Hospitalier Régional Universitaire [Besançon] (CHRU Besançon)-Université de Franche-Comté (UFC)-Université de Montpellier (UM), Centre de Recherche Saint-Antoine (CR Saint-Antoine), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Gustave Roussy (IGR)-Université Paris-Sud - Paris 11 (UP11), Centre Régional de Lutte contre le cancer - Centre Georges-François Leclerc (CRLCC - CGFL), Institut National de la Recherche Agronomique (INRA)-Université Montpellier 2 - Sciences et Techniques (UM2)-Université Paris-Sud - Paris 11 (UP11)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut Gustave Roussy (IGR)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Université de Bourgogne (UB)-Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon)-Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER-UNICANCER-Institut National de la Santé et de la Recherche Médicale (INSERM)-Fédération Francophone de la Cancérologie Digestive, FFCD-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS [Bourgogne-Franche-Comté])-Centre National de la Recherche Scientifique (CNRS)-Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université de Montpellier (UM), Lipides - Nutrition - Cancer (U866) ( LNC ), Université de Bourgogne ( UB ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon ( ENSBANA ), Laboratoire d'Excellence : Lipoprotéines et Santé : prévention et Traitement des maladies Inflammatoires et du Cancer ( LabEx LipSTIC ), Institut National de la Recherche Agronomique ( INRA ) -Université Montpellier 2 - Sciences et Techniques ( UM2 ) -Université Paris-Sud - Paris 11 ( UP11 ) -École pratique des hautes études ( EPHE ) -Institut Gustave Roussy ( IGR ) -Centre Hospitalier Régional Universitaire de Nancy ( CHRU Nancy ) -Université de Bourgogne ( UB ) -Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand ( CHU Dijon ) -Centre Régional de Lutte contre le cancer - Centre Georges-François Leclerc ( CRLCC - CGFL ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Fédération Francophone de la Cancérologie Digestive, FFCD-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Etablissement français du sang [Bourgogne-France-Comté] ( EFS [Bourgogne-France-Comté] ) -Centre National de la Recherche Scientifique ( CNRS ) -Centre Hospitalier Régional Universitaire [Besançon] ( CHRU Besançon ) -Université de Franche-Comté ( UFC ), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand ( CHU Dijon ), Centre de Recherche Saint-Antoine ( CR Saint-Antoine ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Institut National de la Santé et de la Recherche Médicale ( INSERM ), Université Paris-Sud - Paris 11 ( UP11 ) -Institut Gustave Roussy ( IGR ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Centre Régional de Lutte contre le cancer - Centre Georges-François Leclerc ( CRLCC - CGFL ), and UNICANCER-UNICANCER-Institut National de la Santé et de la Recherche Médicale (INSERM)-Fédération Francophone de la Cancérologie Digestive, FFCD-Université de Montpellier (UM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS [Bourgogne-Franche-Comté])-Centre National de la Recherche Scientifique (CNRS)-Université de Franche-Comté (UFC)
Subjects: 0301 basic medicine, X-Box Binding Protein 1, Cancer Research, Lactams, Macrocyclic, RNA Splicing, T-Cells, Graft vs Host Disease, [SDV.CAN]Life Sciences [q-bio]/Cancer, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Biology, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, Hsp90 inhibitor, 03 medical and health sciences, Mice, Sensitivity, Inflammatory-Bowel-disease, Genetics, medicine, Benzoquinones, Animals, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Neural progenitor cells, HSP90 Heat-Shock Proteins, Intestinal Mucosa, Stem Cell Niche, [ SDV.GEN.GH ] Life Sciences [q-bio]/Genetics/Human genetics, [ SDV.BBM ] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Molecular Biology, Leukemia, [ SDV.BC ] Life Sciences [q-bio]/Cellular Biology, Bone-Marrow-Transplantation, Molecules, medicine.disease, Stem cell niche, 3. Good health, Ire1-Alpha, Intestines, Mice, Inbred C57BL, 030104 developmental biology, Graft-versus-host disease, Er Stress, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Cytoprotection, Immunology, Multiple-Myeloma, Female
Abstract: IF 7.932; International audience; Graft versus host disease (GvHD), which is the primary complication of allogeneic bone marrow transplantation, can alter the intestinal barrier targeted by activated donor T-cells. Chemical inhibition of the stress protein HSP90 was demonstrated in vitro to inhibit T-cell activation and to modulate endoplasmic reticulum (ER) stress to which intestinal cells are highly susceptible. Since the HSP90 inhibitor 17-allylamino-demethoxygeldanamycin (17AAG) is developed in clinics, we explored here its ability to control intestinal acute GvHD in vivo in two mouse GvHD models (C57BL/6 -> BALB/c and FVB/N -> Lgr5-eGFP), ex vivo in intestine organoids and in vitro in intestinal epithelial cultures. We show that 17AAG decreases GvHD-associated mortality without impairing graft versus leukemia effect. While 17AAG effect in T-cell activation is just moderate at the dose used in vivo, we observe a striking intestinal integrity protection. At the intestine level, the drug promotes the splicing of the transcription factor X-box binding protein 1 (XBP1), which is a key component of the ER stress. This effect is associated with a decrease in intestinal damage and an increase in Lgr5(+) stem cells, Paneth cells and defensins production. The importance of XBP1 splicing control is further confirmed in cultured cells and organoids of primary intestinal epithelium where XBP1 is either shRNA depleted or inhibited with toyocamycin. In conclusion, 17AAG has a protective effect on the epithelial intestinal barrier in mouse models of acute GvHD. This compound deserves to be tested in the therapeutic control of acute GvHD.
Published: 2016

18. HSP110 T17 simplifies and improves the microsatellite instability testing in patients with colorectal cancer

Author: Coralie Dorard, Richard Hamelin, Kristell Wanherdrick, Magali Svrcek, Anne-Marie Bouvier, Pascale Cervera, Mouna Chouchène, Yann Parc, Anaïs Lagrange, Chrystelle Colas, Florence Coulet, Richie Soong, Carmen Garrido, Jérémie H. Lefevre, Janick Selves, Alex Duval, Erell Guillerm, Olivier Lascols, Sahra Bodo, Thierry André, Laetitia Marisa, Jean-François Fléjou, Ada Collura, Côme Lepage, Olivier Buhard, Kerryn Garrett, Caroline Chapusot, Marie-Pierre Gaub, A’dem Bokhari, Barry Iacopetta, Malorie Greene, Isabelle Sourouille, Agathe Guilloux, Martine Muleris, Hélène Blanché, Nizar El-Murr, Centre de Recherche Saint-Antoine (UMRS893), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), École polytechnique (X), (le programme) Cartes d'identité des tumeurs (CIT), Ligue Nationales Contre le Cancer (LNCC), Université Pierre et Marie Curie - Paris 6 (UPMC), CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Fondation Jean Dausset CEPH, Registre Bourguignon des Cancers Digestifs, Lipides - Nutrition - Cancer (U866) (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon (ENSBANA)-Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon (ENSBANA)-Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), National University of Singapore (NUS), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon (ENSBANA), Développement et physiopathologie de l'intestin et du pancréas, Institut National de la Santé et de la Recherche Médicale (INSERM), St John God HealthCare, The University of Western Australia (UWA), Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER, Service de Pathologie [CHU Saint-Antoine], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Service d'anatomie et cytologie pathologiques [CHU Saint-Antoine], Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Saint-Antoine [AP-HP], Service de chirurgie générale et digestive [CHU Saint-Antoine], National University of Singapore - Cancer Science Institute of Singapore, Laboratoire commun de biologie et génétique moléculaires [CHU Saint-Antoine], Service d'Oncologie Médicale [CHU Saint -Antoine], Centre de Recherche Saint-Antoine ( CR Saint-Antoine ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), École polytechnique ( X ), (le programme) Cartes d'identité des tumeurs ( CIT ), Université Pierre et Marie Curie - Paris 6 ( UPMC ), Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Saint-Antoine [APHP], Service d'anatomie et cytologie pathologiques, Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Saint-Antoine [APHP], Lipides - Nutrition - Cancer (U866) ( LNC ), Université de Bourgogne ( UB ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon ( ENSBANA ) -Université de Bourgogne ( UB ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon ( ENSBANA ) -Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand ( CHU Dijon ), National University of Singapore ( NUS ), Université de Bourgogne ( UB ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon ( ENSBANA ), Institut National de la Santé et de la Recherche Médicale ( INSERM ), The University of Western Australia ( UWA ), and Centre Régional de Lutte contre le cancer - Centre Georges-François Leclerc ( CRLCC - CGFL )
Subjects: 0301 basic medicine, Oncology, medicine.medical_specialty, Genotype, Colorectal cancer, Population, Mismatch Repair, Biology, Guidelines, Bioinformatics, DNA Mismatch Repair, Colon-Cancer, 03 medical and health sciences, 0302 clinical medicine, Molecular genetics, Internal medicine, Diagnostic-Tests, Genetics, medicine, Biomarkers, Tumor, Humans, Chemotherapy, HSP110 Heat-Shock Proteins, education, [ SDV.GEN.GH ] Life Sciences [q-bio]/Genetics/Human genetics, Genotyping, neoplasms, Genetics (clinical), Tumors, education.field_of_study, Pentaplex Pcr, Microsatellite instability, DNA, medicine.disease, Colorectal Neoplasms, Hereditary Nonpolyposis, Lynch syndrome, digestive system diseases, 3. Good health, Mononucleotide Repeats, 030104 developmental biology, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, 030220 oncology & carcinogenesis, DNA mismatch repair, Microsatellite Instability, Lynch-Syndrome, Colorectal Neoplasms, Mutations
Abstract: IF 5.65; International audience; Background Every colorectal cancer (CRC) patient should be tested for microsatellite instability (MSI, a marker for defective DNA mismatch repair) as a first screen for Lynch syndrome (LS). In this study, we investigated whether it may be possible to improve the detection of MSI in CRC. We examined whether the HT17 DNA repeat (critical for correct splicing of the chaperone HSP110) might constitute a superior marker for diagnosis of the MSI phenotype in patients with CRC compared with the standard panel of markers (pentaplex).Methods The HT17 polymorphism was analysed in germline DNA from 1037 multi-ethnic individuals. We assessed its sensitivity and specificity for detecting MSI in a multicentre, population-based cohort of 685 patients with CRC and an additional series of 70 patients with CRC considered to be at-risk of LS. All cases were screened earlier for MSI using pentaplex markers. Cases showing discordant HT17/pentaplex results were further examined for the expression of mismatch repair proteins.Results HT17 status was analysed independently and blinded to previous results from pentaplex genotyping. HT17 showed no germline allelic variation outside a very narrow range. Compared with the pentaplex panel, HT17 showed better sensitivity (0.984 (95% CI 0.968 to 0.995) vs 0.951 (95% CI 0.925 to 0.972)) and similar specificity (0.997 (95% CI 0.989 to 1.000) for both) for the detection of MSI. Furthermore, HT17 alone correctly classified samples judged to be uncertain with the pentaplex panel and showed excellent ability to detect MSI in patients with LS.Conclusions HT17 simplifies and improves the current standard molecular methods for detecting MSI in CRC.
Published: 2016

19. Extracellular HSP110 skews macrophage polarization in colorectal cancer

Author: Gaëtan Jego, Carmen Garrido, Sebastien Causse, Nadhir Yousfi, Magali Svrcek, Alex Duval, Christophe Boudesco, Kevin Berthenet, Arlette Hammann, Laurence Duplomb, Kristell Wanherdrick, Sarah Richaud, Ada Collura, Laboratoire d'Excellence : Lipoprotéines et Santé : prévention et Traitement des maladies Inflammatoires et du Cancer ( LabEx LipSTIC ), Institut National de la Recherche Agronomique ( INRA ) -Université Montpellier 2 - Sciences et Techniques ( UM2 ) -Université Paris-Sud - Paris 11 ( UP11 ) -École pratique des hautes études ( EPHE ) -Institut Gustave Roussy ( IGR ) -Centre Hospitalier Régional Universitaire de Nancy ( CHRU Nancy ) -Université de Bourgogne ( UB ) -Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand ( CHU Dijon ) -Centre Régional de Lutte contre le cancer - Centre Georges-François Leclerc ( CRLCC - CGFL ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Fédération Francophone de la Cancérologie Digestive, FFCD-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Etablissement français du sang [Bourgogne-France-Comté] ( EFS [Bourgogne-France-Comté] ) -Centre National de la Recherche Scientifique ( CNRS ) -Centre Hospitalier Régional Universitaire [Besançon] ( CHRU Besançon ) -Université de Franche-Comté ( UFC ), Lipides - Nutrition - Cancer (U866) ( LNC ), Université de Bourgogne ( UB ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon ( ENSBANA ), Centre de Recherche Saint-Antoine ( CR Saint-Antoine ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Laboratoire d'Immunologie et Immunothérapie des Cancers ( LIIC ), Université de Bourgogne ( UB ) -École pratique des hautes études ( EPHE ), Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand ( CHU Dijon ), Génétique des Anomalies du Développement ( GAD ), Université de Bourgogne ( UB ) -IFR100 - Structure fédérative de recherche Santé-STIC, Centre Régional de Lutte contre le cancer - Centre Georges-François Leclerc ( CRLCC - CGFL ), Laboratoire d'Excellence : Lipoprotéines et Santé : prévention et Traitement des maladies Inflammatoires et du Cancer (LabEx LipSTIC), Institut National de la Recherche Agronomique (INRA)-Université Montpellier 2 - Sciences et Techniques (UM2)-Université Paris-Sud - Paris 11 (UP11)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut Gustave Roussy (IGR)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Université de Bourgogne (UB)-Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon)-Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER-UNICANCER-Institut National de la Santé et de la Recherche Médicale (INSERM)-Fédération Francophone de la Cancérologie Digestive, FFCD-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS [Bourgogne-Franche-Comté])-Centre National de la Recherche Scientifique (CNRS)-Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université de Montpellier (UM), Lipides - Nutrition - Cancer (U866) (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon (ENSBANA), Centre de Recherche Saint-Antoine (UMRS893), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire d'Immunologie et Immunothérapie des Cancers (LIIC), Université de Bourgogne (UB)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Génétique des Anomalies du Développement (GAD), IFR100 - Structure fédérative de recherche Santé-STIC-Université de Bourgogne (UB), Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER, Institut National de la Recherche Agronomique (INRA)-Université Montpellier 2 - Sciences et Techniques (UM2)-Université Paris-Sud - Paris 11 (UP11)-École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut Gustave Roussy (IGR)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon)-Université de Bourgogne (UB)-Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon)-Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER-UNICANCER-Institut National de la Santé et de la Recherche Médicale (INSERM)-Fédération Francophone de la Cancérologie Digestive, FFCD-Université de Montpellier (UM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS BFC)-Centre National de la Recherche Scientifique (CNRS)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université de Bourgogne (UB), Université de Bourgogne (UB)-IFR100 - Structure fédérative de recherche Santé-STIC, UNICANCER-UNICANCER-Institut National de la Santé et de la Recherche Médicale (INSERM)-Fédération Francophone de la Cancérologie Digestive, FFCD-Université de Montpellier (UM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS [Bourgogne-Franche-Comté])-Centre National de la Recherche Scientifique (CNRS)-Université de Franche-Comté (UFC), École pratique des hautes études (EPHE), Institut National de la Recherche Agronomique (INRA)-Université Montpellier 2 - Sciences et Techniques (UM2)-Université Paris-Sud - Paris 11 (UP11)-École pratique des hautes études (EPHE)-Institut Gustave Roussy (IGR)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Université de Bourgogne (UB)-Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon)-Centre Régional de Lutte contre le cancer - Centre Georges-François Leclerc (CRLCC - CGFL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Fédération Francophone de la Cancérologie Digestive, FFCD-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Etablissement français du sang [Bourgogne-France-Comté] (EFS [Bourgogne-France-Comté])-Centre National de la Recherche Scientifique (CNRS)-Centre Hospitalier Régional Universitaire [Besançon] (CHRU Besançon)-Université de Franche-Comté (UFC)-Université de Montpellier (UM), Centre de Recherche Saint-Antoine (CR Saint-Antoine), École pratique des hautes études (EPHE)-Université de Bourgogne (UB), and Centre Régional de Lutte contre le cancer - Centre Georges-François Leclerc (CRLCC - CGFL)
Subjects: 0301 basic medicine, Macrophage, Immunology, Macrophage polarization, Activation, [SDV.CAN]Life Sciences [q-bio]/Cancer, Expression, Biology, Colon-Cancer, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, 03 medical and health sciences, 0302 clinical medicine, In vivo, Polarization, Extracellular, medicine, Immunology and Allergy, Cytotoxic T cell, Kappa-B, Colorectal, Heat-Shock Proteins, Original Research, Cancer, Tumor-infiltrating lymphocytes, Heat-Shock Protein, Dendritic Cells, medicine.disease, Ikk-Beta, Molecular biology, 3. Good health, 030104 developmental biology, Oncology, 030220 oncology & carcinogenesis, TLR4, Tumor-Infiltrating Lymphocytes, Microsatellite Instability, Chaperone Machines
Abstract: IF 7.644; International audience; HSP110 is induced by different stresses and, through its anti-apoptotic and chaperoning properties, helps the cells to survive these adverse situations. In colon cancers, HSP110 is abnormally abundant. We have recently showed that colorectal cancer (CRC) patients with microsatellite instability (MSI) had an improved response to chemotherapy because they harbor an HSP110 inactivating mutation (HSP110DE9). In this work, we have used patients' biopsies and human CRC cells grown in vitro and in vivo (xenografts) to demonstrate that (1) HSP110 is secreted by CRC cells and that the amount of this extracellular HSP110 is strongly decreased by the expression of the mutant HSP110DE9, (2) Supernatants from CRC cells overexpressing HSP110 or purified recombinant human HSP110 (LPS-free) affect macrophage differentiation/polarization by favoring a pro-tumor, anti-inflammatory profile, (3) Conversely, inhibition of HSP110 (expression of siRNA, HSP110DE9 or immunodepletion) induced the formation of macrophages with a cytotoxic, pro-inflammatory profile. (4) Finally, this effect of extracellular HSP110 on macrophages seems to implicate TLR4. These results together with the fact that colorectal tumor biopsies with HSP110 high were infiltrated with macrophages with a pro-tumoral profile while those with HSP110 low were infiltrated with macrophages with a cytotoxic profile, suggest that the effect of extracellular HSP110 function on macrophages may also contribute to the poor outcomes associated with HSP110 expression.
Published: 2016

20. Tumours with loss of MSH6 expression are MSI-H when screened with a pentaplex of five mononucleotide repeats

Author: Anja Wagner, Winand N.M. Dinjens, Alex Duval, Robert M.W. Hofstra, J.F. You, Jean-François Fléjou, Olivier Buhard, Renee C. Niessen, Ada Collura, Chrystelle Colas, Marjolijn J. L. Ligtenberg, Richard Hamelin, Olivier Lascols, Carolien M. Kets, Clinical Genetics, and Pathology
Subjects: Cancer Research, congenital, hereditary, and neonatal diseases and abnormalities, GENES, COLORECTAL-CANCER PATIENTS, Biology, MLH1, Polymerase Chain Reaction, LYNCH-SYNDROME, PANEL, Germline mutation, MARKERS, SDG 3 - Good Health and Well-being, Translational research [ONCOL 3], Neoplasms, medicine, PMS2, Humans, IMMUNOHISTOCHEMISTRY, Molecular Diagnostics, neoplasms, Repetitive Sequences, Nucleic Acid, Genetics, UTILITY, Hereditary cancer and cancer-related syndromes [ONCOL 1], MUTATIONS, Microsatellite instability, nutritional and metabolic diseases, DNA MISMATCH REPAIR, MSH6, medicine.disease, Lynch syndrome, digestive system diseases, DNA-Binding Proteins, Oncology, MSH2, Cancer research, DNA mismatch repair, microsatellite instability, MICROSATELLITE INSTABILITY ANALYSIS
Abstract: BACKGROUND: Microsatellite instability (MSI) is commonly screened using a panel of two mononucleotide and three dinucleotide repeats as recommended by a consensus meeting on MSI tumours held at the National Cancer Institute (Bethesda, MD, USA). According to these recommendations, tumours are classified as MSI-H when at least two of the five microsatellite markers show instability, MSI-L when only one marker shows instability and MSS when none of the markers show instability. Almost all MSI-H tumours are characterised by alterations in one of the four major proteins of the mismatch repair (MMR) system (MLH1, MSH2, MSH6 or PMS2) that renders them MMR deficient, whereas MSI-L and MSS tumours are generally MMR proficient. However, tumours from patients with a pathogenic germline mutation in MSH6 can sometimes present an MSI-L phenotype with the NCI panel. The MSH6 protein is not involved in the repair of mismatches of two nucleotides in length and consequently the three dinucleotide repeats of the NCI panel often show stability in MSH6-deficient tumours.METHODS: A pentaplex panel comprising five mononucleotide repeats has been recommended as an alternative to the NCI panel to determine tumour MSI status. Several studies have confirmed the sensitivity, specificity and ease of use of the pentaplex panel; however, its sensitivity for the detection of MSH6-deficient tumours is so far unknown. Here, we used the pentaplex panel to evaluate MSI status in 29 tumours known to harbour an MSH6 defect.RESULTS: MSI-H status was confirmed in 15 out of 15 (100%) cases where matching normal DNA was available and in 28 out of 29 (97%) cases where matching DNA was not available or was not analysed.CONCLUSION: These results show that the pentaplex assay efficiently discriminates the MSI status of tumours with an MSH6 defect. British Journal of Cancer (2010) 103, 1840-1845. doi:10.1038/sj.bjc.6605988 www.bjcancer.com Published online 16 November 2010 (C) 2010 Cancer Research UK
Published: 2010

21. Azathioprine induction of tumors with microsatellite instability: risk evaluation using a mouse model

Author: Sahra, Bodo, Magali, Svrcek, Isabelle, Sourrouille, Peggy, Cuillières-Dartigues, Tatiana, Ledent, Sylvie, Dumont, Laetitia, Dinard, Philippe, Lafitte, Camille, Capel, Ada, Collura, Olivier, Buhard, Kristell, Wanherdrick, Alexandra, Chalastanis, Virginie, Penard-Lacronique, Bettina, Fabiani, Jean-François, Fléjou, Nicole, Brousse, Laurent, Beaugerie, Alex, Duval, and Martine, Muleris
Subjects: Adult, Male, congenital, hereditary, and neonatal diseases and abnormalities, Time Factors, Lymphoma, Kaplan-Meier Estimate, DNA Mismatch Repair, Risk Assessment, Young Adult, thiopurine tolerance, Risk Factors, Azathioprine, Animals, Humans, neoplasms, Aged, pharmacogenetics, Mice, Knockout, Dose-Response Relationship, Drug, Middle Aged, Inflammatory Bowel Diseases, iatrogenic cancer, Immunohistochemistry, digestive system diseases, Disease Models, Animal, MutS Homolog 2 Protein, Phenotype, Female, microsatellite instability, Immunosuppressive Agents, Research Paper
Abstract: Mismatch-repair (MMR)-deficient cells show increased in vitro tolerance to thiopurines because they escape apoptosis resulting from MMR-dependent signaling of drug-induced DNA damage. Prolonged treatment with immunosuppressants including azathioprine (Aza), a thiopurine prodrug, has been suggested as a risk factor for the development of late onset leukemias/lymphomas displaying a microsatellite instability (MSI) phenotype, the hallmark of a defective MMR system. We performed a dose effect study in mice to investigate the development of MSI lymphomas associated with long term Aza treatment. Over two years, Aza was administered to mice that were wild type, null or heterozygous for the MMR gene Msh2. Ciclosporin A, an immunosuppressant with an MMR-independent signaling, was also administered to Msh2(wt) mice as controls. Survival, lymphoma incidence and MSI tumor phenotype were investigated. Msh2(+/-) mice were found more tolerant than Msh2(wt) mice to the cytotoxicity of Aza. In Msh2(+/-) mice, Aza induced a high incidence of MSI lymphomas in a dose-dependent manner. In Msh2(wt) mice, a substantial lifespan was only observed at the lowest Aza dose. It was associated with the development of lymphomas, one of which displayed the MSI phenotype, unlike the CsA-induced lymphomas. Our findings define Aza as a risk factor for an MSI-driven lymphomagenesis process.
Published: 2015

22. Patients with colorectal tumors with microsatellite instability and large deletions in HSP110 T17 have improved response to 5-fluorouracil–based chemotherapy

Author: Patrick Senet, Gérard Milano, Olivier Buhard, Jean François Fléjou, Coralie Dorard, Patrice Delarue, Alex Duval, Leila Bengrine Lefevre, Arnaud Saget, Anne Marie Bouvier, Magali Svrcek, Yann Parc, Kristell Wanherdrick, Denis Biard, Christophe Tournigand, Arnaud Coquelle, Nikolajs Zeps, Marie Pierre Gaub, Anaïs Lagrange, Janick Selves, Guillaume Marcion, Hayat Arzouk, Jérémie H. Lefevre, Caroline Chapusot, Andrew Mews, Richie Soong, Carmen Garrido, Aurélie de Thonel, Laetitia Marisa, Cameron Platell, Agathe Guilloux, Côme Lepage, Ada Collura, Renaud Seigneuric, Marie Loh, Claire Lacoste, Anna Taieb, Barry Iacopetta, Centre épigénétique et destin cellulaire (EDC (UMR_7216)), and Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP)
Subjects: Male, Models, Molecular, Organoplatinum Compounds, Colorectal cancer, medicine.medical_treatment, [SDV]Life Sciences [q-bio], Leucovorin, 0302 clinical medicine, Antineoplastic Combined Chemotherapy Protocols, HSP110 Heat-Shock Proteins, ComputingMilieux_MISCELLANEOUS, Colectomy, Sequence Deletion, 0303 health sciences, Gastroenterology, Primary tumor, 3. Good health, Oxaliplatin, Treatment Outcome, Fluorouracil, Chemotherapy, Adjuvant, 030220 oncology & carcinogenesis, Female, Microsatellite Instability, Colorectal Neoplasms, medicine.drug, Blotting, Western, Antineoplastic Agents, Biology, 03 medical and health sciences, Cell Line, Tumor, medicine, Biomarkers, Tumor, Humans, 030304 developmental biology, Aged, Retrospective Studies, Chemotherapy, Hepatology, Base Sequence, Microsatellite instability, Cancer, Surface Plasmon Resonance, medicine.disease, Molecular biology, Survival Analysis, Introns, Cancer cell, Cancer research, Follow-Up Studies
Abstract: Background & Aims Patients with colorectal tumors with microsatellite instability (MSI) have better prognoses than patients with tumors without MSI, but have a poor response to 5-fluorouracil–based chemotherapy. A dominant-negative form of heat shock protein (HSP)110 (HSP110DE9) expressed by cancer cells with MSI, via exon skipping caused by somatic deletions in the T 17 intron repeat, sensitizes the cells to 5-fluorouracil and oxaliplatin. We investigated whether HSP110 T 17 could be used to identify patients with colorectal cancer who would benefit from adjuvant chemotherapy with 5-fluorouracil and oxaliplatin. Methods We characterized the interaction between HSP110 and HSP110DE9 using surface plasmon resonance. By using polymerase chain reaction and fragment analysis, we examined how the size of somatic allelic deletions in HSP110 T 17 affected the HSP110 protein expressed by tumor cells. We screened 329 consecutive patients with stage II–III colorectal tumors with MSI who underwent surgical resection at tertiary medical centers for HSP110 T 17 . Results HSP110 and HSP110DE9 interacted in a 1:1 ratio. Tumor cells with large deletions in T 17 had increased ratios of HSP110DE9:HSP110, owing to the loss of expression of full-length HSP110. Deletions in HSP110 T 17 were mostly biallelic in primary tumor samples with MSI. Patients with stage II–III cancer who received chemotherapy and had large HSP110 T 17 deletions (≥5 bp; 18 of 77 patients, 23.4%) had longer times of relapse-free survival than patients with small or no deletions (≤4 bp; 59 of 77 patients, 76.6%) in multivariate analysis (hazard ratio, 0.16; 95% confidence interval, 0.012–0.8; P = .03). We found a significant interaction between chemotherapy and T 17 deletion ( P = .009). Conclusions About 25% of patients with stages II–III colorectal tumors with MSI have an excellent response to chemotherapy, due to large, biallelic deletions in the T 17 intron repeat of HSP110 in tumor DNA.
Published: 2013

23. Extensive characterization of sphere models established from colorectal cancer cell lines

Author: Olivier Buhard, Diletta Trojan, Arnaud Saget, Marianne Bombled, Patricia Méchighel, Martine Muleris, Magali Svrcek, Anaïs Lagrange, Florence Mahuteau-Betzer, Anne-Marie Faussat, Aurélien de Reyniès, Laetitia Marisa, Jean-Claude Florent, Ada Collura, Alex Duval, Mira Ayadi, and Jean-François Fléjou
Subjects: musculoskeletal diseases, Antimetabolites, Antineoplastic, Colorectal cancer, Colon, Mice, Nude, Gene mutation, Biology, Cellular and Molecular Neuroscience, Mice, Cancer stem cell, Cell Line, Tumor, Spheroids, Cellular, medicine, Biomarkers, Tumor, Tumor Cells, Cultured, Animals, Humans, Molecular Biology, Cell Proliferation, Pharmacology, Microarray analysis techniques, Rectum, virus diseases, Cancer, Cell Biology, medicine.disease, Gene Expression Regulation, Neoplastic, Cell culture, Immunology, Cancer cell, Cancer research, Molecular Medicine, Fluorouracil, Stem cell, Neoplasm Recurrence, Local, Colorectal Neoplasms
Abstract: Links between cancer and stem cells have been proposed for many years. As the cancer stem cell (CSC) theory became widely studied, new methods were developed to culture and expand cancer cells with conserved determinants of “stemness”. These cells show increased ability to grow in suspension as spheres in serum-free medium supplemented with growth factors and chemicals. The physiological relevance of this phenomenon in established cancer cell lines remains unclear. Cell lines have traditionally been used to explore tumor biology and serve as preclinical models for the screening of potential therapeutic agents. Here, we grew cell-forming spheres (CFS) from 25 established colorectal cancer cell lines. The molecular and cellular characteristics of CFS were compared to the bulk of tumor cells. CFS could be isolated from 72 % of the cell lines. Both CFS and their parental CRC cell lines were highly tumorigenic. Compared to their parental cells, they showed similar expression of putative CSC markers. The ability of CRC cells to grow as CFS was greatly enhanced by prior treatment with 5-fluorouracil. At the molecular level, CFS and parental CRC cells showed identical gene mutations and very similar genomic profiles, although microarray analysis revealed changes in CFS gene expression that were independent of DNA copy-number. We identified a CFS gene expression signature common to CFS from all CRC cell lines, which was predictive of disease relapse in CRC patients. In conclusion, CFS models derived from CRC cell lines possess interesting phenotypic features that may have clinical relevance for drug resistance and disease relapse.
Published: 2012

24. Lynch or not Lynch? Is that always a question?

Author: Chrystelle, Colas, Florence, Coulet, Magali, Svrcek, Ada, Collura, Jean-François, Fléjou, Alex, Duval, and Richard, Hamelin
Subjects: Adenomatous Polyposis Coli, Humans, Genetic Predisposition to Disease, Microsatellite Instability, Genetic Testing, Colorectal Neoplasms, Hereditary Nonpolyposis, DNA Mismatch Repair, Germ-Line Mutation, Microsatellite Repeats
Abstract: The familial cancer syndrome referred to as Lynch I and II was renamed hereditary nonpolyposis colorectal cancer (HNPCC) only to revert later to Lynch syndrome (LS). LS is the most frequent human predisposition for the development of colorectal cancer (CRC), and probably also for endometrial and gastric cancers, although it has yet to acquire a consensus name. Its estimated prevalence ranges widely from 2% to 7% of all CRCs due to the fact that tumors from patients with LS are difficult to recognize at both the clinical and molecular level. This review is based on two assumptions. First, all LS patients inherit a predisposition to develop CRC (without polyposis) and/or other tumors from the Lynch spectrum. Second, all LS patients have a germline defect in one of the DNA mismatch repair (MMR) genes. When a somatic second hit inactivates the relevant MMR gene, the consequence is instability of DNA repeat sequences such as microsatellites and the tumors are referred to as having the microsatellite instability (MSI) phenotype. However, some of the inherited predisposition to develop CRC without concurrent polyposis, termed HNPCC, is found in non-LS patients, while not all MSI tumors are from LS cases. LS tumors are therefore at the junction of inherited and MSI cases. We describe here the defining characteristics of LS tumors that differentiate them from inherited non-MSI tumors and from non-inherited MSI tumors.
Published: 2012

25. Lynch or Not Lynch? Is that Always a Question?

Author: Magali Svrcek, Richard Hamelin, Ada Collura, Alex Duval, Jean-François Fléjou, Chrystelle Colas, and Florence Coulet
Subjects: congenital, hereditary, and neonatal diseases and abnormalities, medicine.diagnostic_test, Colorectal cancer, business.industry, nutritional and metabolic diseases, Microsatellite instability, medicine.disease, Bioinformatics, Phenotype, digestive system diseases, Lynch syndrome, Germline, Germline mutation, medicine, Cancer research, DNA mismatch repair, business, neoplasms, Genetic testing
Abstract: The familial cancer syndrome referred to as Lynch I and II was renamed hereditary nonpolyposis colorectal cancer (HNPCC) only to revert later to Lynch syndrome (LS). LS is the most frequent human predisposition for the development of colorectal cancer (CRC), and probably also for endometrial and gastric cancers, although it has yet to acquire a consensus name. Its estimated prevalence ranges widely from 2% to 7% of all CRCs due to the fact that tumors from patients with LS are difficult to recognize at both the clinical and molecular level. This review is based on two assumptions. First, all LS patients inherit a predisposition to develop CRC (without polyposis) and/or other tumors from the Lynch spectrum. Second, all LS patients have a germline defect in one of the DNA mismatch repair (MMR) genes. When a somatic second hit inactivates the relevant MMR gene, the consequence is instability of DNA repeat sequences such as microsatellites and the tumors are referred to as having the microsatellite instability (MSI) phenotype. However, some of the inherited predisposition to develop CRC without concurrent polyposis, termed HNPCC, is found in non-LS patients, while not all MSI tumors are from LS cases. LS tumors are therefore at the junction of inherited and MSI cases. We describe here the defining characteristics of LS tumors that differentiate them from inherited non-MSI tumors and from non-inherited MSI tumors.
Published: 2012

26. Expression of a mutant HSP110 sensitizes colorectal cancer cells to chemotherapy and improves disease prognosis

Author: Kristell Wanherdrick, Alex Duval, Emmanuel Tiret, Gérard Milano, Olivier Buhard, Janick Selves, Marie-Christine Etienne-Grimaldi, Christophe Tournigand, Leila Bengrine-Lefevre, Sylvain Kirzin, Carmen Garrido, Gaëtan Jego, Anaïs Lagrange, Emmanuel Tubacher, Virginie Penard-Lacronique, Yann Parc, Coralie Dorard, Habib Zouali, Aurélie de Thonel, Magali Svrcek, Christophe Louvet, Jérémie H. Lefevre, Marie-Pierre Gaub, Anne Laure Joly, Laetitia Marisa, Ada Collura, Jean-François Fléjou, Jessica Gobbo, Centre épigénétique et destin cellulaire (EDC (UMR_7216)), and Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP)
Subjects: Organoplatinum Compounds, Colorectal cancer, medicine.medical_treatment, [SDV]Life Sciences [q-bio], Blotting, Western, Fluorescent Antibody Technique, Antineoplastic Agents, Biology, Bioinformatics, Real-Time Polymerase Chain Reaction, Transfection, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, 0302 clinical medicine, Heat shock protein, Cell Line, Tumor, medicine, Humans, Immunoprecipitation, HSP110 Heat-Shock Proteins, neoplasms, Cellular localization, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, DNA Primers, 0303 health sciences, Chemotherapy, Microsatellite instability, General Medicine, medicine.disease, Prognosis, digestive system diseases, 3. Good health, Oxaliplatin, 030220 oncology & carcinogenesis, Cancer cell, Mutation, Cancer research, Regression Analysis, Microsatellite Instability, Fluorouracil, Colorectal Neoplasms, medicine.drug, Plasmids
Abstract: Heat shock proteins (HSPs) are necessary for cancer cell survival. We identified a mutant of HSP110 (HSP110ΔE9) in colorectal cancer showing microsatellite instability (MSI CRC), generated from an aberrantly spliced mRNA and lacking the HSP110 substrate-binding domain. This mutant was expressed at variable levels in almost all MSI CRC cell lines and primary tumors tested. HSP110ΔE9 impaired both the normal cellular localization of HSP110 and its interaction with other HSPs, thus abrogating the chaperone activity and antiapoptotic function of HSP110 in a dominant-negative manner. HSP110ΔE9 overexpression caused the sensitization of cells to anticancer agents such as oxaliplatin and 5-fluorouracil, which are routinely prescribed in the adjuvant treatment of people with CRC. The survival and response to chemotherapy of subjects with MSI CRCs was associated with the tumor expression level of HSP110ΔE9. HSP110 may thus constitute a major determinant for both prognosis and treatment response in CRC.
Published: 2011

27. Abasic sites linked to dUTP incorporation in DNA are a major cause of spontaneous mutations in absence of base excision repair and Rad17-Mec3-Ddc1 (9-1-1) DNA damage checkpoint clamp in Saccharomyces cerevisiae

Author: Ada Collura, Serge Boiteux, and Patricia Auffret van der Kemp
Subjects: Saccharomyces cerevisiae Proteins, DNA Repair, DNA repair, Saccharomyces cerevisiae, Biology, Biochemistry, chemistry.chemical_compound, Mutation Rate, AP site, DNA, Fungal, Molecular Biology, Microbial Viability, Mutagenesis, Cell Biology, Base excision repair, Cell Cycle Checkpoints, G2-M DNA damage checkpoint, Molecular biology, chemistry, DNA glycosylase, Mutation, Deoxyuracil Nucleotides, DNA, Nucleotide excision repair, DNA Damage
Abstract: In Saccharomyces cerevisiae , inactivation of base excision repair (BER) AP endonucleases (Apn1p and Apn2p) results in constitutive phosphorylation of Rad53p and delay in cell cycle progression at the G2/M transition. These data led us to investigate genetic interactions between Apn1p, Apn2p and DNA damage checkpoint proteins. The results show that mec1 sml1 , rad53 sml1 and rad9 is synthetic lethal with apn1 apn2 . In contrast, apn1 apn2 rad17 , apn1 apn2 ddc1 and apn1 apn2 rad24 triple mutants are viable, although they exhibit a strong Can R spontaneous mutator phenotype. In these strains, high Can R mutation rate is dependent upon functional uracil DNA N -glycosylase (Ung1p) and mutation spectra are dominated by AT to CG events. The results point to a role for Rad17–Mec3–Ddc1 (9–1–1) checkpoint clamp in the prevention of mutations caused by abasic (AP) sites linked to incorporation of dUTP into DNA followed by the excision of uracil by Ung1p. The antimutator role of the (9–1–1) clamp can either rely on its essential function in the induction of the DNA damage checkpoint or to another function that specifically impacts DNA repair and/or mutagenesis at AP sites. Here, we show that the abrogation of the DNA damage checkpoint is not sufficient to enhance spontaneous mutagenesis in the apn1 apn2 rad9 sml1 quadruple mutant. Spontaneous mutagenesis was also explored in strains deficient in the two major DNA N -glycosylases/AP-lyases (Ntg1p and Ntg2p). Indeed, apn1 apn2 ntg1 ntg2 exhibits a strong Ung1p-dependent Can R mutator phenotype with a spectrum enriched in AT to CG, like apn1 apn2 rad17. However, genetic analysis reveals that ntg1 ntg2 and rad17 are not epistatic for spontaneous mutagenesis in apn1 apn2 . We conclude that under normal growth conditions, dUTP incorporation into DNA is a major source of AP sites that cause high genetic instability in the absence of BER factors (Apn1p, Apn2p, Ntg1p and Ntg2p) and Rad17–Mec3–Ddc1 (9–1–1) checkpoint clamp in yeast.
Published: 2011

28. Methylation tolerance due to an O6-methylguanine DNA methyltransferase (MGMT) field defect in the colonic mucosa: an initiating step in the development of mismatch repair-deficient colorectal cancers

Author: Florence Coulet, Michèle Legrain, Raquel Seruca, Carla Oliveira, Magali Svrcek, Emmanuel Tiret, Richard C. Hamelin, Alex Duval, Illiasse Massaoudi, Ada Collura, Chrystelle Colas, Jacques Cosnes, Olivier Lascols, Jean-François Fléjou, Sylvie Dumont, Olivier Buhard, Marie-Pierre Gaub, Amel Lamri, Service Canadien des Forêts, Centre de foresterie des Laurentides, SCF, Service de Gastro-Entérologie et Nutrition, Université Pierre et Marie Curie - Paris 6 (UPMC), Développement et physiopathologie de l'intestin et du pancréas, Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de Biologie Moléculaire et Biochimie, CHU Strasbourg-Hôpital de Hautepierre [Strasbourg], Laboratoire de Biochimie et de Biologie Moléculaire, Service d'anatomie et cytologie pathologiques [CHU Saint-Antoine], Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Instabilité des microsatellites et cancers [CHU Saint-Antoine], Centre de Recherche Saint-Antoine (CR Saint-Antoine), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Instabilité des microsatellites et cancers [CRSA], Centre de Recherche Saint-Antoine (CRSA), and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)
Subjects: Male, Methyltransferase, Colorectal cancer, Gastroenterology, DNA Mismatch Repair, 0302 clinical medicine, Intestinal Mucosa, Promoter Regions, Genetic, Aged, 80 and over, 0303 health sciences, [CHIM.ORGA]Chemical Sciences/Organic chemistry, Nuclear Proteins, Methylation, DNA, Neoplasm, Middle Aged, 3. Good health, 030220 oncology & carcinogenesis, DNA mismatch repair, Female, Microsatellite Instability, Colorectal Neoplasms, MutL Protein Homolog 1, Adult, Proto-Oncogene Proteins B-raf, medicine.medical_specialty, Context (language use), Biology, DNA methyltransferase, Proto-Oncogene Proteins p21(ras), 03 medical and health sciences, O(6)-Methylguanine-DNA Methyltransferase, Young Adult, Internal medicine, Proto-Oncogene Proteins, medicine, Humans, neoplasms, 030304 developmental biology, Adaptor Proteins, Signal Transducing, Aged, Neoplasm Staging, Cancer, Microsatellite instability, DNA Methylation, medicine.disease, digestive system diseases, Mutation, Cancer research, ras Proteins, Precancerous Conditions
Abstract: International audience; BACKGROUND AND AIMS: O(6)-Methylguanine-DNA methyltransferase (MGMT) removes methyl adducts from O(6)-guanine. Known as methylation tolerance, selection for mismatch repair (MMR)-deficient cells that are unable to initiate lethal processing of O(6)-methylguanine-induced mismatches in DNA is observed in vitro as a consequence of MGMT deficiency. It was therefore hypothesised that an MGMT field defect may constitute a preneoplastic event for the development of MMR-deficient tumours displaying microsatellite instability (MSI). METHODS: MGMT expression was investigated by immunohistochemistry and the methylation status of the gene promoter by PCR in neoplastic, adjacent and distant mucosal tissues of patients with MSI or non-MSI (MSS) colorectal cancer (CRC). The cancers were familial (42 MSI, 13 MSS) or sporadic (40 MSI, 49 MSS) in origin, or arose in the context of inflammatory bowel disease (IBD; 13 MSI, 36 MSS). Colonic mucosa from patients with diverticulitis (n=20) or IBD (n=39 in 27 patients) without cancer served as controls. RESULTS: Loss of MGMT expression was more frequent in MSI than MSS CRC (p=0.047). In comparison with MSS tumours, MSI CRC occurred more frequently adjacent to patches of mucosa that lacked MGMT expression (p=0.002). Overall, loss of MGMT expression was associated with MGMT gene promoter methylation (p=0.03). CONCLUSION: MGMT field defects are more frequently associated with MSI than MSS CRC. These findings indicate that methylation tolerance may be a crucial initiating step prior to MMR deficiency in the development of MSI CRC in familial, sporadic and IBD settings.
Published: 2010

29. The Fission Yeast Crb2/Chk1 Pathway Coordinates the DNA Damage and Spindle Checkpoint in Response to Replication Stress Induced by Topoisomerase I Inhibitor

Author: Ada Collura, Giuseppe Baldacci, Joël Blaisonneau, Stefania Francesconi, and Centre National de la Recherche Scientifique (CNRS)
Subjects: MESH: Signal Transduction, Cell cycle checkpoint, [SDV]Life Sciences [q-bio], Cell Cycle Proteins, MESH: Cell Cycle, MESH: DNA Replication, Gene Expression Regulation, Fungal, Enzyme Inhibitors, DNA, Fungal, Checkpoint Kinase 2, 0303 health sciences, Kinetochore, Cell Cycle, 030302 biochemistry & molecular biology, Nuclear Proteins, MESH: Chromosomes, Fungal, Cell biology, Spindle checkpoint, MESH: Topoisomerase I Inhibitors, MESH: Schizosaccharomyces, DNA Topoisomerases, Type I, MESH: Enzyme Inhibitors, Mad2 Proteins, MESH: Genome, Fungal, MESH: Camptothecin, Chromosomes, Fungal, Genome, Fungal, biological phenomena, cell phenomena, and immunity, MESH: Mad2 Proteins, MESH: Gene Expression Regulation, Fungal, Signal Transduction, DNA Replication, MESH: Mutation, DNA repair, Chromosome Structure and Dynamics, Spindle Apparatus, Protein Serine-Threonine Kinases, Topoisomerase-I Inhibitor, Biology, MESH: Checkpoint Kinase 2, MESH: Checkpoint Kinase 1, MESH: Protein-Serine-Threonine Kinases, MESH: Drug Resistance, Fungal, 03 medical and health sciences, MESH: Cell Cycle Proteins, Drug Resistance, Fungal, Schizosaccharomyces, CHEK1, MESH: Spindle Apparatus, Molecular Biology, MESH: Protein Kinases, Alleles, 030304 developmental biology, MESH: DNA Damage, MESH: Alleles, MESH: Schizosaccharomyces pombe Proteins, Cell Biology, G2-M DNA damage checkpoint, MESH: DNA, Fungal, Checkpoint Kinase 1, Mutation, Camptothecin, Schizosaccharomyces pombe Proteins, Topoisomerase I Inhibitors, Protein Kinases, MESH: Nuclear Proteins, MESH: DNA Topoisomerases, Type I, DNA Damage
Abstract: International audience; Living organisms experience constant threats that challenge their genome stability. The DNA damage checkpoint pathway coordinates cell cycle progression with DNA repair when DNA is damaged, thus ensuring faithful transmission of the genome. The spindle assembly checkpoint inhibits chromosome segregation until all chromosomes are properly attached to the spindle, ensuring accurate partition of the genetic material. Both the DNA damage and spindle checkpoint pathways participate in genome integrity. However, no clear connection between these two pathways has been described. Here, we analyze mutants in the BRCT domains of fission yeast Crb2, which mediates Chk1 activation, and provide evidence for a novel function of the Chk1 pathway. When the Crb2 mutants experience damaged replication forks upon inhibition of the religation activity of topoisomerase I, the Chk1 DNA damage pathway induces sustained activation of the spindle checkpoint, which in turn delays metaphase-to-anaphase transition in a Mad2-dependent fashion. This new pathway enhances cell survival and genome stability when cells undergo replicative stress in the absence of a proficient G(2)/M DNA damage checkpoint.
Published: 2005

30. The fission yeast spSet1p is a histone H3-K4 methyltransferase that functions in telomere maintenance and DNA repair in an ATM kinase Rad3-dependent pathway

Author: Vincent Géli, Ada Collura, Giuseppe Baldacci, Vera Schramke, Stefania Francesconi, Junko Kanoh, Fuyuki Ishikawa, and Centre National de la Recherche Scientifique (CNRS)
Subjects: DNA Repair, [SDV]Life Sciences [q-bio], Cell Cycle Proteins, Histones, MESH: Saccharomyces cerevisiae Proteins, Structural Biology, Hydroxyurea, MESH: Gene Silencing, DNA-PKcs, MESH: Histones, MESH: DNA Repair, 0303 health sciences, 030302 biochemistry & molecular biology, MESH: Transcription Factors, Telomere, MESH: Hydroxyurea, Chromatin, DNA-Binding Proteins, MESH: Schizosaccharomyces, MESH: Cell Survival, MESH: Centromere, Saccharomyces cerevisiae Proteins, DNA repair, DNA damage, Cell Survival, Ultraviolet Rays, Centromere, Antineoplastic Agents, Biology, MESH: Checkpoint Kinase 2, Methylation, MESH: Methylation, 03 medical and health sciences, Histone H3, MESH: Cell Cycle Proteins, MESH: Methyltransferases, Schizosaccharomyces, Humans, CHEK1, Gene Silencing, Molecular Biology, MESH: Protein Kinases, 030304 developmental biology, MESH: DNA Damage, MESH: Humans, MESH: Histone-Lysine N-Methyltransferase, MESH: Schizosaccharomyces pombe Proteins, Histone-Lysine N-Methyltransferase, Methyltransferases, G2-M DNA damage checkpoint, biology.organism_classification, Molecular biology, Genes, cdc, Checkpoint Kinase 2, MESH: Genes, cdc, Schizosaccharomyces pombe, MESH: Antineoplastic Agents, MESH: Ultraviolet Rays, Schizosaccharomyces pombe Proteins, MESH: Telomere, Protein Kinases, MESH: DNA-Binding Proteins, DNA Damage, Transcription Factors
Abstract: International audience; We have characterized spSet1p, the Schizosaccharomyces pombe ortholog of the budding yeast histone H3 methyltransferase Set1p. SpSet1p catalyzes methylation of H3 at K4, in vivo and in vitro. Deleting spset1 partially affects telomeric and centromeric silencing. Strikingly, lack of spSet1p causes elongation of telomeres in wild-type cells and in most DNA damage checkpoint rad mutant cells, but not in cells lacking the ATM kinase Rad3 or its associated protein Rad26. Interestingly, spset1 deletion specifically causes a reduction in sensitivity to ultraviolet radiation of the PCNA-like checkpoint mutants hus1 and rad1, but not of cells devoid of Rad3. This partial suppression was not due to restoration of checkpoint function or to transcriptional induction of DNA repair genes. Moreover, spset1 allows recovery specifically of the crb2 checkpoint mutant upon treatment with the replication inhibitor hydroxyurea but not upon UV irradiation. Nevertheless, the pathway induced in spset1 cells cannot substitute for the Mus81/Rqh1 DNA damage tolerance pathway. Our results suggest that SpSet1p and the ATM kinase Rad3 function in a common genetic pathway linking chromatin to telomere length regulation and DNA repair.
Published: 2003

31. Mutation d’HSP110 dans les cancers colorectaux

Author: Anaïs Lagrange, Alex Duval, Kevin Berthenet, Ada Collura, and Carmen Garrido
Subjects: General Medicine, Biology, General Biochemistry, Genetics and Molecular Biology
Published: 2012

32. Microsatellite Instability in Colorectal Cancer: Time to Stop Hiding!

Author: Ada Collura, Carmen Garrido, Anaïs Lagrange, Alex Duval, and Kevin Berthenet
Subjects: Pathology, medicine.medical_specialty, Chemotherapy, Colorectal cancer, medicine.medical_treatment, Microsatellite instability, Disease, Biology, medicine.disease, digestive system diseases, Therapeutic approach, Oncology, Chromosome instability, Cancer research, medicine, Microsatellite, Animals, Humans, In patient, Microsatellite Instability, HSP110 Heat-Shock Proteins, Colorectal Neoplasms, neoplasms, Editorial Comments
Abstract: Colorectal cancer (CRC) is the second cause of cancer-related death worldwide. Surgery constitutes the primary therapy for these tumors, together with chemotherapy that is usually recommended in patients with metastatic primary CRC. Although molecularly distinct entities arising from different physiopathogenic mechanisms - microsatellite (MSI) and chromosomal instability (also called microsatellite stable, MSS) - have been characterized in CRC, there is still no specific therapeutic approach that takes into account disease’s molecular heterogeneity [1]. MSI is observed in 1015% of sporadic CRCs. MSI CRCs displayed particular morphologic features, with greater predilection for the right colon, mucinous histology, low metastatic power, poorer differentiation and higher numbers of tumorinfiltrating lymphocytes. They have been consistently reported to show an improved prognosis and a different response to chemotherapeutic agents. In a recent article in Nature Medicine, we have reported the specific mutation of the molecular chaperone HSP110 in MSI CRCs and how the presence of this mutant may constitute a first step towards the understanding of their particular clinical characteristics [2].
Published: 2011

33. Étude des conséquences génomiques et fonctionnelles de l'instabilité des microsatellites dans le cancer colorectal

Author: Greene, Malorie, Centre de Recherche Saint-Antoine (CR Saint-Antoine), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Université Pierre et Marie Curie - Paris VI, Ada Collura, STAR, ABES, Centre de Recherche Saint-Antoine (CRSA), and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)
Subjects: Cancer colorectal, Déficience du MMR, [SDV.CAN] Life Sciences [q-bio]/Cancer, Instabilité des microsatellites et séquences non répétées, Instabilité génétique, [SDV.CAN]Life Sciences [q-bio]/Cancer, MMR deficiency, Microsatellite instability and non-repeated sequences, Pressions de sélection, Validation fonctionnelle, Colorectal cancer
Abstract: Since the discovery of a link between mismatch repair (MMR) deficiency and cancer, microsatellite instability (MSI) is thought as a process underlying cell transformation and tumour progression and invasion. MSI tumours are a subset of frequent human neoplasms, both inherited and sporadic, associated with several primary locations (colon, stomach, endometrium…). In MMR-deficient cells, MSI generates hundreds of frameshift mutations in genes (MSI Target Genes, MSI-TGs) containing coding microsatellite sequences (e.g. -1/+1 bp, insertions/deletions, i.e. indels). Some of these mutations affect genes with a role in human carcinogenesis and are thus expected to promote the MSI-driven tumorigenic process. During my PhD, I aimed to decipher the role of MSI in colon tumorigenesis. I exploited exome-sequencing data available in my lab that were generated from the analysis of a series of 47 human MSI primary colorectal cancer (CRC). Through biostatistics analysis and mathematical models that we designed to interpret mutation rates in the context of the high background for instability characterizing MSI in CRC, we identified a few microsatellites containing genes coding mutations that were negatively selected in MSI colon tumours (N=13). Under the hypothesis that these events may have a negative impact in colon tumorigenesis, I demonstrated that the silencing of these MSI target genes (siRNA/shRNA) was deleterious for MSI cancer cells using in vitro and in vivo models (impairment of proliferation and/or migration and/or response to chemotherapy and/or tumour growth) (Jonchère*, Marisa*, Greene* et al., submitted)., L’instabilité des séquences répétées microsatellites du génome (courtes répétitions en tandem d’un à cinq nucléotides) est une conséquence de l’inactivation du système MMR (MisMatch Repair), en charge de la réparation des erreurs produites au cours de la réplication de l’ADN. Cette instabilité est associée à un processus de transformation cellulaire original, observé chez l’homme dans des pathologies tumorales fréquentes, nommées MSI (pour Microsatellite Instability). Les localisations primaires les plus fréquentes de ces tumeurs sont le côlon, l’endomètre et l’estomac. Elles peuvent avoir une origine héréditaire (prédisposition familiale ; syndrome de Lynch et apparentés), mais sont dans la majorité des cas de survenue sporadique. La transformation des cellules MMR-déficientes s’observe dans le contexte de l’accumulation de nombreuses mutations somatiques dans l’ADN tumoral. Certaines ont un caractère oncogénique en favorisant la troncature et la perte de fonction de gènes suppresseurs de tumeur ou apparentés, impliqués dans des voies de signalisations diverses et qui contiennent des microsatellites codants (mutations indels d’une à deux paires de base, décalant le cadre de lecture, fréquemment rapportées dans ces tumeurs). Les travaux présentés dans le cadre de mon doctorat visent à mieux comprendre le rôle de l’instabilité microsatellitaire dans la tumorigenèse MSI. Ils s’inscrivent dans le contexte du décryptage et de l’analyse des données de séquençage d’exome de 47 cancers colorectaux primitifs MSI. Dans le contexte d’un niveau élevé d’instabilité génomique caractérisant ces tumeurs, la mise au point par mon laboratoire d’accueil de modèles probabilistes a permis de dresser une liste restreinte de gènes, remarquables par le fait qu’ils sont affectés par des mutations somatiques dont les fréquences sont exceptionnellement élevées ou basses dans l’ADN tumoral. Sous l’hypothèse que de tels évènements somatiques affectent des gènes clés de la tumorigenèse MSI colique, j’ai focalisé mes recherches sur les gènes dont les altérations sont peu fréquentes. Brièvement, j’ai pu démontrer le caractère délétère d’un petit nombre d’altérations microsatellitaires codantes dont la survenue semble soumise à une pression de sélection négative (N=13). Mes résultats indiquent que ces mutations semblent fragiliser le phénotype tumoral des cellules dans lesquelles elles surviennent, la perte de fonction des gènes qu’elles affectent conduisant à diverses conséquences délétères en fonction du gène candidat (e.g. sensibilisation à la mort cellulaire, perte des capacités proliférative et migratoire, ralentissement de la croissance tumorale). Ces résultats rapportent pour la première fois et à grande échelle, la sélection négative de mutations dans des tumeurs à forte instabilité génomique MSI. Ils ouvrent de nouvelles voies pour la compréhension de ce mode particulier de transformation cellulaire, et sont potentiellement d’intérêt pour la mise au point de thérapies personnalisées pour les patients.
Published: 2017

34. Etude de la mutation de la chaperonne HSP110 dans les cancers gastro-intestinaux MSI : conséquences fonctionnelles et cliniques

Author: Bokhari, A'Dem, Centre de Recherche Saint-Antoine (UMRS893), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Pierre et Marie Curie - Paris VI, Ada Collura, Alex Duval, and STAR, ABES
Subjects: Cancer colorectal, [SDV.GEN]Life Sciences [q-bio]/Genetics, Cancer gastrique, Approche thérapeutique, Microsatellite instability, NMD, [SDV.GEN] Life Sciences [q-bio]/Genetics, Instabilité microsatellitaire, digestive system diseases, HSP110
Abstract: Microsatellite instability (MSI) results from impaired DNA mismatch repair, being observed in 10-15% of frequent tumors in human, e.g. Colorectal (CRC), Gastric Cancers (GC) and others. In 2011, frequent somatic mutations of the HSP110 chaperone have been reported in MSI CRC by my lab, affecting a T17 intronic DNA repeat located in intron 8. Large (≥ 5 base pairs) bi-allelic somatic deletions of this DNA repeat in tumor DNAs, as observed in about 25% of MSI CRC, lead to complete inactivation of HSP110 by exon 9 skipping and sensitization of tumor cells to chemotherapy. These large deletions are predictive of improved response to adjuvant chemotherapy in CRC patients. During my PhD thesis, I further investigated the role of HSP110 in MSI tumors. My results demonstrate that HSP110 mutation leads to cell proliferation decrease through the reduction of STAT3 transcription factor phosphorylation in CRC tumors (Berthenet*, Bokhari*, et al., Oncogene 2016). Furthermore, I showed that HSP110 mutation is also frequently observed in MSI gastric cancer, leading to very similar pathophysiological consequences during tumor progression and improved patient’s survival independently from tumor stage (Cervera*, Lagrange*, Bokhari* et al., submitted). Finally, I worked on an innovative therapeutic approach that consisted in inhibiting the NMD (Nonsense-Mediated mRNA Decay) system, an ubiquitous process recognizing and degrading mRNAs containing premature termination codons (PTC). The inhibition of NMD leads to the expression of deleterious MSI-driven mutant transcripts such as the HSP110DE9, coding for a dominant negative mutant, derived from HSP110 mutation in MSI cancer cells., L'instabilité microsatellitaire (MSI) résulte d'une déficience du système de réparation des mésappariements de l'ADN. Cette instabilité est observée dans 10-15% des tumeurs chez l'Homme, incluant les cancers colorectaux (CCR) et de l'estomac (CG). En 2011, notre laboratoire a rapporté la mutation de la chaperonne HSP110 dans les CCR MSI. Cette mutation affecte un microsatellite intronique de 17 thymidines (T17), localisé au niveau de l'intron 8. Les grandes délétions somatiques du T17 (? 5 paires de bases), représentant 25% des CCR MSI, conduisent à l'inactivation complète de la chaperonne HSP110 dans les CCR MSI. De manière remarquable, ces grandes délétions sont prédictives chez les patients d'une excellente réponse à la chimiothérapie adjuvante. Au cours de ma thèse, mes travaux ont visé à étudier l'impact de la mutation d'HSP110 dans les tumeurs gastro-intestinales MSI. Mes résultats démontrent que la mutation du microsatellite T17 d'HSP110 a pour conséquence une diminution de la prolifération cellulaire en partie lié à la diminution de la phosphorylation du facteur de transcription STAT3. En outre, mes résultats suggèrent que cette mutation serait un facteur prédictif de survie chez les patients atteint de CG, indiquant le potentiel théranostique d'HSP110. Enfin, je propose une approche thérapeutique innovante pour les patients atteints de CCR MSI, basée sur la potentialisation de l'expression de transcrits mutants, codant pour des protéines délétères pour la cellule tumorale, à l'instar du dominant négatif HSP110DE9 résultant de la mutation d'HSP110 dont l'ARN semble être régulé par le système NMD (Nonsense-Mediated mRNA Decay).
Published: 2017

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34 results on '"Ada Collura"'

1. Microsatellite instability at U2AF-binding polypyrimidic tract sites perturbs alternative splicing during colorectal cancer initiation

2. Identification of Positively and Negatively Selected Driver Gene Mutations Associated With Colorectal Cancer With Microsatellite InstabilitySummary

3. Prediction of Response to Immune Checkpoint Blockade in Patients with Metastatic Colorectal Cancer with Microsatellite Instability

4. The HIF1α/JMY pathway promotes glioblastoma stem-like cell invasiveness after irradiation

5. Consequences of the Hsp110DE9 mutation in tumorigenesis and the 5-fluorouracil-based chemotherapy response in Msh2-deficient mice

6. Performance of Next-Generation Sequencing for the Detection of Microsatellite Instability in Colorectal Cancer With Deficient DNA Mismatch Repair

7. Instabilité des microsatellites et cancer

8. Targeting nonsense-mediated mRNA decay in colorectal cancers with microsatellite instability

9. Identification of Positively and Negatively Selected Driver Gene Mutations Associated With Colorectal Cancer With Microsatellite Instability

10. [Microsatellite instability and cancer: from genomic instability to personalized medicine]

11. MSI/MMR-deficient tumor diagnosis: Which standard for screening and for diagnosis? Diagnostic modalities for the colon and other sites: Differences between tumors

12. METHODS AND PHARMACEUTICAL COMPOSITIONS FOR TREATING CANCER

13. Major improvement in the detection of microsatellite instability in colorectal cancer using HSP110 T17 E-ice-COLD-PCR

14. Prevalence of Microsatellite Instability in Intraductal Papillary Mucinous Neoplasms of the Pancreas

15. HSP110 promotes colorectal cancer growth through STAT3 activation

16. The Balance Between Cytotoxic T-cell Lymphocytes and Immune Checkpoint Expression in the Prognosis of Colon Tumors

17. The HSP90 inhibitor, 17AAG, protects the intestinal stem cell niche and inhibits graft versus host disease development

18. HSP110 T17 simplifies and improves the microsatellite instability testing in patients with colorectal cancer

19. Extracellular HSP110 skews macrophage polarization in colorectal cancer

20. Tumours with loss of MSH6 expression are MSI-H when screened with a pentaplex of five mononucleotide repeats

21. Azathioprine induction of tumors with microsatellite instability: risk evaluation using a mouse model

22. Patients with colorectal tumors with microsatellite instability and large deletions in HSP110 T17 have improved response to 5-fluorouracil–based chemotherapy

23. Extensive characterization of sphere models established from colorectal cancer cell lines

24. Lynch or not Lynch? Is that always a question?

25. Lynch or Not Lynch? Is that Always a Question?

26. Expression of a mutant HSP110 sensitizes colorectal cancer cells to chemotherapy and improves disease prognosis

27. Abasic sites linked to dUTP incorporation in DNA are a major cause of spontaneous mutations in absence of base excision repair and Rad17-Mec3-Ddc1 (9-1-1) DNA damage checkpoint clamp in Saccharomyces cerevisiae

28. Methylation tolerance due to an O6-methylguanine DNA methyltransferase (MGMT) field defect in the colonic mucosa: an initiating step in the development of mismatch repair-deficient colorectal cancers

29. The Fission Yeast Crb2/Chk1 Pathway Coordinates the DNA Damage and Spindle Checkpoint in Response to Replication Stress Induced by Topoisomerase I Inhibitor

30. The fission yeast spSet1p is a histone H3-K4 methyltransferase that functions in telomere maintenance and DNA repair in an ATM kinase Rad3-dependent pathway

31. Mutation d’HSP110 dans les cancers colorectaux

32. Microsatellite Instability in Colorectal Cancer: Time to Stop Hiding!

33. Étude des conséquences génomiques et fonctionnelles de l'instabilité des microsatellites dans le cancer colorectal

34. Etude de la mutation de la chaperonne HSP110 dans les cancers gastro-intestinaux MSI : conséquences fonctionnelles et cliniques

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