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1. Oral etoposide in heavily pre-treated metastatic breast cancer: results from the ESME cohort and comparison with other chemotherapy regimens

Author

Jean-Marc Ferrero, Jean-Yves Pierga, Marc Debled, Luc Cabel, Florence Dalenc, Irwin Piot, Bianca Cheaib, Isabelle Desmoulins, Christelle Levy, David Pérol, Anthony Gonçalves, Audrey Mailliez, Marie-Ange Mouret-Reynier, Matthieu Carton, Florence Lerebours, Gaëtane Simon, Claudia Lefeuvre, Jean-Christophe Eymard, Thierry Petit, Marianne Leheurteur, William Jacot, Geneviève Perrocheau, Lionel Uwer, Institut Curie [Saint-Cloud], Pathologie mammaire, Département de médecine oncologique [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), Centre de Recherches en Cancérologie de Toulouse (CRCT), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), CRLCC Institut Claudius Regaud, CRLCC Oscar Lambret, Centre Régional de Lutte contre le Cancer François Baclesse (CRLC François Baclesse ), Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN), Institut de Recherche en Cancérologie de Montpellier (IRCM - U1194 Inserm - UM), CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Institut Bergonié - Département de médecine, Université Bordeaux Segalen - Bordeaux 2-Centre régional de lutte contre le cancer [CRLCC], Centre de Lutte Contre le Cancer Henri Becquerel Normandie Rouen (CLCC Henri Becquerel), Département d'oncologie médicale [Centre Georges-François Leclerc], Centre Régional de Lutte contre le cancer - Centre Georges-François Leclerc (CRLCC - CGFL), CRLCC Eugène Marquis (CRLCC), Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), Institut de Cancérologie de Lorraine - Alexis Vautrin (ICL), Centre Antoine Lacassagne, CRLCC Antoine Lacassagne, Institut Jean Godinot, CRLCC Jean Godinot, CRLCC Paul Strauss, CRLCC Jean Perrin, Institut de cancérologie de l'Ouest - Nantes (ICO Nantes), CRLCC Paul Papin-CRLCC René Gauducheau, UNICANCER - Institut régional du Cancer [Montpellier] (ICM), CRLCC Val d'Aurelle - Paul Lamarque, Centre Léon Bérard [Lyon], Institut Claudius Regaud, Centre Régional de Lutte contre le Cancer Oscar Lambret [Lille] (UNICANCER/Lille), Université Lille Nord de France (COMUE)-UNICANCER, Centre Régional de Lutte contre le Cancer François Baclesse [Caen] (UNICANCER/CRLC), UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU), Institut Bergonié [Bordeaux], UNICANCER, Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER-UNICANCER, Institut de Cancérologie de Lorraine - Alexis Vautrin [Nancy] (UNICANCER/ICL), Centre de Lutte contre le Cancer Antoine Lacassagne [Nice] (UNICANCER/CAL), UNICANCER-Université Côte d'Azur (UCA), Institut Jean Godinot [Reims], Centre Jean Perrin [Clermont-Ferrand] (UNICANCER/CJP), Institut de Cancérologie de l'Ouest [Angers/Nantes] (UNICANCER/ICO), UNICANCER - Institut régional du Cancer Montpellier Val d'Aurelle (ICM), Institut Curie - Saint Cloud (ICSC), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université de Lille-UNICANCER, and Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)

Subjects
0301 basic medicine, Oncology, Cancer Research, medicine.medical_specialty, Receptor, ErbB-2, medicine.medical_treatment, Administration, Oral, [SDV.CAN]Life Sciences [q-bio]/Cancer, Breast Neoplasms, 03 medical and health sciences, 0302 clinical medicine, Breast cancer, Oral administration, Internal medicine, Antineoplastic Combined Chemotherapy Protocols, Medicine, Humans, Topoisomerase II Inhibitors, skin and connective tissue diseases, Etoposide, Retrospective Studies, Chemotherapy, business.industry, Proportional hazards model, Middle Aged, medicine.disease, Metastatic breast cancer, Progression-Free Survival, 3. Good health, 030104 developmental biology, 030220 oncology & carcinogenesis, Propensity score matching, Cohort, Oral drug, Female, business, medicine.drug, Follow-Up Studies
Abstract

HER2-negative metastatic breast cancer (MBC) is a common setting in which chemotherapy could be effective even in later lines of treatment. Oral etoposide has demonstrated clinical activity in this setting in small-scale studies, but its efficacy has not been compared to that of other chemotherapy regimens. We used the ESME database (Epidemiological Strategy and Medical Economics), a real-life national French multicentre cohort of MBC patients initiating therapy between 1 January 2008 to 31 December 2014. HER2-negative MBC patients who received oral etoposide as > 3rd chemotherapy line and for more than 14 days were included. Primary objective was progression-free survival (PFS); secondary objectives were overall survival (OS), and propensity-score matched Cox models including comparison with other therapies in the same setting. Three hundred forty-five out of 16,702 patients received oral etoposide and 222 were eligible. Median PFS was 3.2 months [95% CI 2.8–4] and median OS 7.3 months [95% CI 5.7–10.3]. Median PFS did not significantly differ according to the therapeutic line. The only prognostic factor for both PFS and OS was the MBC phenotype (hormone receptor-positive versus triple-negative, HR = 0.71 [95% CI 0.52–0.97], p = 0.028 for PFS and HR = 0.65 [0.46–0.92], p = 0.014 for OS). After matching for the propensity score, no differential effect on PFS or OS was observed between oral etoposide and other chemotherapy regimens administered in the same setting (HR = 0.94 [95% CI 0.77–1.15], p = 0.55 for PFS and HR = 1.10 [95% CI 0.88–1.37], p = 0.40 for OS). Oral etoposide retains some efficacy in selected heavily pre-treated patients with HER2-negative MBC, with the advantages of oral administration.

Published
2018

2. Time trends of overall survival among metastatic breast cancer patients in the real-life ESME cohort

Author

Laurence Vanlemmens, Marc Debled, Christian Cailliot, Elisa Gobbini, Thomas Bachelot, Monia Ezzalfani, Christelle Jouannaud, Suzette Delaloge, Magali Lacroix-Triki, Anne Patsouris, Thierry Petit, Simone Mathoulin-Pélissier, Veronique Lorgis, William Jacot, Marie Ange Mouret-Reynier, Mathieu Robain, C. Lefeuvre-Plesse, Florence Dalenc, Audrey Lardy Cleaud, Etienne Brain, Christelle Levy, David Pérol, C. Courtinard, Véronique Diéras, Marianne Leheurteur, Lionel Uwer, Anthony Gonçalves, Jean Marc Ferrero, Département de médecine oncologique [Gustave Roussy], Institut Gustave Roussy (IGR), Cancer et génome: Bioinformatique, biostatistiques et épidémiologie d'un système complexe, Institut Curie [Paris]-MINES ParisTech - École nationale supérieure des mines de Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institute Curie, Centre Léon Bérard [Lyon], Institut Curie [Saint-Cloud], Service d'Oncologie Médicale, CRLCC Haute Normandie-Centre de Lutte Contre le Cancer Henri Becquerel Normandie Rouen (CLCC Henri Becquerel), CRLC Val d'Aurelle-Paul Lamarque, CRLCC Val d'Aurelle - Paul Lamarque, Institut de Recherche en Cancérologie de Montpellier (IRCM - U1194 Inserm - UM), CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Imagerie Moléculaire et Stratégies Théranostiques (IMoST), Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Institut National de la Santé et de la Recherche Médicale (INSERM), École nationale supérieure d'architecture de Toulouse (ENSA Toulouse), Centre de Recherches en Cancérologie de Toulouse (CRCT), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut de Cancérologie de l'Ouest [Angers/Nantes] (UNICANCER/ICO), UNICANCER, Service d'Oncologie médicale [CHU Caen], CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN), Service d'Oncologie Médicale [CHRU Besançon], 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), Centre Régional de Lutte contre le Cancer Oscar Lambret [Lille] (UNICANCER/Lille), Université Lille Nord de France (COMUE)-UNICANCER, Department of Medical Oncology, CRLCC Eugène Marquis (CRLCC), Centre d'Investigation Clinique - Epidemiologie Clinique / Essais Cliniques Bordeaux, Institut National de la Santé et de la Recherche Médicale (INSERM), Bordeaux population health (BPH), Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), CRLCC Jean Godinot, Institut de Cancérologie de Lorraine - Alexis Vautrin [Nancy] (UNICANCER/ICL), Département de biologie et pathologie médicales [Gustave Roussy], Cancer et génôme: Bioinformatique, biostatistiques et épidémiologie d'un système complexe, MINES ParisTech - École nationale supérieure des mines de Paris-Institut Curie-Institut National de la Santé et de la Recherche Médicale (INSERM), CRLCC Haute Normandie-CRLCC Henri Becquerel, CRLCC Val d'Aurelle - Paul Lamarque-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Imagerie Moléculaire et Stratégies Théranostiques - Clermont Auvergne (IMoST), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne (UCA), Institut de cancérologie de l'Ouest - Paul Papin (ICO - Paul Papin), Service d'oncologie Médicale, Centre Hospitalier Régional Universitaire [Besançon] (CHRU Besançon)-Hôpital Jean Minjoz, Center Oscar Lambret, CRLCC Oscar Lambret, Institut de Cancérologie de Lorraine - Alexis Vautrin (ICL), Mines Paris - PSL (École nationale supérieure des mines de Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Curie - Saint Cloud (ICSC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and Université de Lille-UNICANCER

Subjects
Adult, Cancer Research, medicine.medical_specialty, Multivariate analysis, Time Factors, Receptor, ErbB-2, [SDV.CAN]Life Sciences [q-bio]/Cancer, Breast Neoplasms, Triple Negative Breast Neoplasms, 03 medical and health sciences, Young Adult, 0302 clinical medicine, Cancer Survivors, Risk Factors, HER2, Internal medicine, polycyclic compounds, Overall survival, Biomarkers, Tumor, Medicine, Humans, 030212 general & internal medicine, Neoplasm Metastasis, skin and connective tissue diseases, Aged, Retrospective Studies, Subtypes, Aged, 80 and over, business.industry, Time trends, Hazard ratio, Middle Aged, Metastatic breast cancer, medicine.disease, Confidence interval, 3. Good health, Treatment Outcome, Oncology, Receptors, Estrogen, 030220 oncology & carcinogenesis, Cohort, Observational study, Female, France, business, Receptors, Progesterone
Abstract

Real-life analysis of overall survival (OS) trends among metastatic breast cancer (MBC) patients may help define medical needs and evaluate the impact of public health investments. The present study aimed to evaluate the independent impact of the year of MBC diagnosis on OS in the Epidemio-Strategy-Medical-Economical (ESME)-MBC cohort.ESME-MBC (NCT03275311) is a French, national, multicentre, observational cohort including 16,702 consecutive newly diagnosed MBC patients (01 January 2008-31 December 2014). Of 16,680 eligible patients, 15,085 had full immunohistochemistry data, allowing classification as hormone receptor-positive and HER2-negative (HR+/HER2-, N = 9907), HER2-positive (HER2+, N = 2861) or triple-negative (HR-/HER2-, N = 2317) subcohorts. Multivariate analyses of OS were conducted among the full ESME cohort and subcohorts.Median OS of the whole cohort was 37.22 months (95% confidence interval [CI], 36.3-38.04). Year of diagnosis was an independent predictor of OS (hazard ratio 0.98 [95% CI, 0.97-1.00], P = .01) together with age, subtype, disease-free interval, visceral metastases and number of organs involved. Median OS of HR+/HER2-, HER2+ and HR-/HER2- subcohorts was, respectively, 42.12 (95% CI, 40.90-43.10), 44.91 (95% CI, 42.51-47.90) and 14.52 (95% CI, 13.70-15.24) months. Year of diagnosis was a strong independent predictor of OS in HER2+ subcohort (hazard ratio 0.91 [95% CI, 0.88-0.94], P .001), but not in HR+/HER2- nor HR-/HER2- subcohorts (hazard ratio 1.00 [95% CI, 0.98-1.01], P = .80 and 1.00 [95% CI, 0.97-1.02], P = .90, respectively).The OS of MBC patients has slightly improved over the past decade. However, this effect is confined to HER2+ cases, highlighting the need of new strategies in the other subtypes.

Published
2018

3. Overexpression of MBNL1 fetal isoforms and modified splicing of Tau in the DM1 brain: Two individual consequences of CUG trinucleotide repeats

Author

V. Vingtdeux, O. Leroy, H. Gruffat, N. Sergeant, Luc Buée, M.L. Caillet-Boudin, E. Vanbrussel, Bernard Sablonnière, C.A. Maurage, A. Delacourte, Shoichi Ishiura, S. Schraen-Maschke, D. Ghanem, Claire-Marie Dhaenens, Helene Tran, J. Delplanque, M.S. Mahadevan, N. Charlet-Berguerand, A. Sergeant, P. Vermersch, Thomas A. Cooper, Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer (JPArc - U837 Inserm), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Université Lille 2 - Faculté de Médecine, Institut de médecine predictive et de recherche thérapeutique (IMPRT), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-CRLCC Oscar Lambret-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Droit et Santé-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Neuroendocrinologie et physiopathologie neuronale, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Droit et Santé, Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de génétique et biologie moléculaire et cellulaire (IGBMC), Université Louis Pasteur - Strasbourg I-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U837 (JPArc), Université Lille Nord de France (COMUE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Centre Régional de Lutte contre le Cancer Oscar Lambret [Lille] (UNICANCER/Lille), Université de Lille-UNICANCER-Université de Lille-UNICANCER-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Droit et Santé-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U1172 Inserm - U837 (JPArc), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Lille Nord de France (COMUE)-Université de Lille, Université Lille Nord de France (COMUE)-UNICANCER-Université Lille Nord de France (COMUE)-UNICANCER-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Droit et Santé-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), and Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Louis Pasteur - Strasbourg I

Subjects
Adult, Gene isoform, Untranslated region, congenital, hereditary, and neonatal diseases and abnormalities, Green Fluorescent Proteins, Tau protein, Exonic splicing enhancer, tau Proteins, Transfection, Myotonic dystrophy, 03 medical and health sciences, Exon, chemistry.chemical_compound, Fetus, 0302 clinical medicine, Trinucleotide Repeats, Developmental Neuroscience, Chlorocebus aethiops, medicine, Animals, Humans, Myotonic Dystrophy, Protein Isoforms, MBNL1, Cloning, Molecular, 030304 developmental biology, Genetics, 0303 health sciences, biology, Brain, RNA-Binding Proteins, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Middle Aged, medicine.disease, Cell biology, Alternative Splicing, Gene Expression Regulation, Neurology, chemistry, COS Cells, RNA splicing, biology.protein, 030217 neurology & neurosurgery, HeLa Cells
Abstract

Neurofibrillary degeneration is often observed in the brain of patients with type 1 myotonic dystrophy (DM1). It consists principally of the aggregation of Tau isoforms that lack exon 2/3 encoded sequences, and is the consequence of the modified splicing of Tau pre-mRNA. In experimental models of DM1, the splicing of several transcripts is modified due to the loss of Muscleblind-like 1 (MBNL1) function. In the present study, we demonstrate that the MBNL1 protein is also present in the human brain, and consists of several isoforms, as shown by RT-PCR and sequencing. In comparison with controls, we show that the adult DM1 brain exhibits modifications in the splicing of MBNL1, with the preferential expression of long MBNL1 isoforms — a splicing pattern similar to that seen in the fetal human brain. In cultured HeLa cells, the presence of long CUG repeats, such as those found in the DM1 mutation, leads to similar changes in the splicing pattern of MBNL1, and the localization of MBNL1 in nuclear RNA foci. Long CUG repeats also reproduce the repression of Tau exon 2/3 inclusion, as in the human disease, suggesting that their effect on MBNL1 expression may lead to changes in Tau splicing. However, while an overall reduction in the expression of MBNL1 mimics the effect of the DM1 mutation, none of the MBNL1 isoforms tested so far modulates the endogenous splicing of Tau. The modified splicing of Tau thus results from a possibly CUG-mediated loss of function of MBNL1, but not from changes in the MBNL1 expression pattern.

Published
2008

4. Plasma ceramide, a real-time predictive marker of pulmonary and hepatic metastases response to stereotactic body radiation therapy combined with irinotecan

Author

Marie-Hélène Gaugler, Emmanuel Rio, Natacha Ripoche, Christian Carrie, François Paris, Nolwenn Dubois, Marc Mahe, Loïc Campion, Xavier Mirabel, Michel Krempf, Véronique Ferchaud-Roucher, Institut de Cancérologie de l'Ouest [Angers/Nantes] (UNICANCER/ICO), UNICANCER, Centre de Recherche en Cancérologie Nantes-Angers (CRCNA), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM)-Hôtel-Dieu de Nantes-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital Laennec-Centre National de la Recherche Scientifique (CNRS)-Faculté de Médecine d'Angers-Centre hospitalier universitaire de Nantes (CHU Nantes), Université de Nantes (UN), INRA: UMR1280 Physiologie des adaptations (UMR1280), Institut National de la Recherche Agronomique (INRA), Centre Léon Bérard [Lyon], Centre Régional de Lutte contre le Cancer Oscar Lambret [Lille] (UNICANCER/Lille), Université Lille Nord de France (COMUE)-UNICANCER, The work was funded by the Institut National Du Cancer (INCA),la Ligue Nationale Contre le Cancer and Electricité de France (EDF)., Bernardo, Elizabeth, Physiopathologie des Adaptations Nutritionnelles (PhAN), Institut National de la Recherche Agronomique (INRA)-Université de Nantes (UN), Université de Lille-UNICANCER, Institut de cancérologie de l'Ouest - Nantes (ICO Nantes), CRLCC Paul Papin-CRLCC René Gauducheau, Centre de Recherche en Cancérologie / Nantes - Angers (CRCNA), Centre hospitalier universitaire de Nantes (CHU Nantes)-Faculté de Médecine d'Angers-Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM)-Centre National de la Recherche Scientifique (CNRS)-Hôpital Laennec-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôtel-Dieu de Nantes, Center Oscar Lambret, and CRLCC Oscar Lambret

Subjects
0301 basic medicine, Oncology, Male, Pathology, Radiation-Sensitizing Agents, Lung Neoplasms, Colorectal cancer, medicine.medical_treatment, Kaplan-Meier Estimate, Metastases, Ceramide, chemistry.chemical_compound, 0302 clinical medicine, Stereotactic radiotherapy, Predictive marker, Liver Neoplasms, Hematology, Middle Aged, Combined Modality Therapy, 3. Good health, Treatment Outcome, Radiology Nuclear Medicine and imaging, 030220 oncology & carcinogenesis, Female, medicine.drug, Adult, medicine.medical_specialty, [SDV.CAN]Life Sciences [q-bio]/Cancer, Ceramides, Irinotecan, Radiosurgery, 03 medical and health sciences, [SDV.CAN] Life Sciences [q-bio]/Cancer, Internal medicine, medicine, Humans, Radiology, Nuclear Medicine and imaging, Aged, Chemotherapy, business.industry, Biomarker, medicine.disease, Sphingolipid, Radiation therapy, 030104 developmental biology, chemistry, Camptothecin, business, Biomarkers
Abstract

Background and purposesEarly biomarkers of tumour response are needed to discriminate between responders and non-responders to radiotherapy. We evaluated the ability of ceramide, a bioactive sphingolipid, to predict tumour sensitivity in patients treated by hypofractionated stereotactic body radiation therapy (SBRT) combined with irinotecan chemotherapy.Materials and methodsPlasma levels of total ceramide and of its subspecies were measured before and during treatment in 35 patients with liver and lung oligometastases of colorectal cancer included in a phase II trial. Cer levels were quantified by LC–ESI-MS/MS and compared to tumour volume response evaluated one year later by CT-scan.ResultsPretreatment plasma ceramide levels were not indicative of tumour response. Nevertheless, the levels of total ceramide and of its 4 main subspecies were significantly higher at days 3 and 10 of treatment in objective responders than in non-responders. According to Kaplan–Meier curves, almost complete tumour control was achieved at 1year in patients with increased total ceramide levels whereas 50% of patients with decreased levels experienced an increase in tumour volume.ConclusionsTotal plasma ceramide is a promising biomarker of tumour response to SBRT combined with irinotecan that should enable to segregate patients with high risk of tumour escape.

Published
2015

5. Phase II randomised trial of chemoradiotherapy with FOLFOX4 or cisplatin plus fluorouracil in oesophageal cancer

Author

Emmanuel Rio, Y. Yataghene, Pierre-Luc Etienne, Xavier Mirabel, M. Rives, Didier Peiffert, Pierre Michel, B. Lamezec, Jean-Luc Raoul, L. Mineur, E. Le Prisé, Antoine Adenis, Hélène Senellart, Thierry Conroy, Centre Alexis Vautrin (CAV), Maladies chroniques, santé perçue, et processus d'adaptation (APEMAC), Université Paris Descartes - Paris 5 (UPD5)-Université de Lorraine (UL), Quality of Life in oncology platform, Canceropole Grand-Est, Sanofi-Aventis R&D, SANOFI Recherche, Centre René Gauducheau, CRLCC René Gauducheau, Foie, métabolismes et cancer, Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Institut Sainte Catherine [Avignon], Institut Claudius Regaud, Centre Régional de Lutte contre le Cancer Oscar Lambret [Lille] (UNICANCER/Lille), Université de Lille-UNICANCER, Service de radiothérapie, CRLCC Eugène Marquis (CRLCC), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Institut Sainte Catherine, CRLCC Institut Claudius Regaud, Center Oscar Lambret, CRLCC Oscar Lambret, Université Lille Nord de France (COMUE)-UNICANCER, Centre Alexis Vautrin ( CAV ), Maladies chroniques, santé perçue, et processus d'adaptation ( APEMAC ), Université Paris Descartes - Paris 5 ( UPD5 ) -Université de Lorraine ( UL ), Université de Rennes 1 ( UR1 ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), and CRLCC Eugène Marquis ( CRLCC )

Subjects
Adult, Male, Cancer Research, medicine.medical_specialty, oesophageal cancer, Esophageal Neoplasms, Organoplatinum Compounds, medicine.drug_class, Leucovorin, [SDV.CAN]Life Sciences [q-bio]/Cancer, Gastroenterology, Antimetabolite, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, law.invention, chemoradiotherapy, 03 medical and health sciences, 0302 clinical medicine, Randomized controlled trial, law, Internal medicine, Antineoplastic Combined Chemotherapy Protocols, medicine, Combined Modality Therapy, Humans, Aged, Cisplatin, Aged, 80 and over, business.industry, oxaliplatin, Middle Aged, 3. Good health, Oxaliplatin, Surgery, Oncology, Fluorouracil, 030220 oncology & carcinogenesis, Concomitant, Clinical Study, 030211 gastroenterology & hepatology, Female, business, Chemoradiotherapy, medicine.drug
Abstract

International audience; Background: Concurrent chemoradiotherapy is a valuable treatment option for localised oesophageal cancer (EC), but improvement is still needed. A randomised phase II trial was initiated to assess the feasibility and efficacy in terms of the endoscopic complete response rate (ECRR) of radiotherapy with oxaliplatin, leucovorin and fluorouracil (FOLFOX4) or cisplatin/fluorouracil. Methods: Patients with unresectable EC (any T, any N, M0 or M1a), or medically unfit for surgery, were randomly assigned to receive either six cycles (three concomitant and three post-radiotherapy) of FOLFOX4 (arm A) or four cycles (two concomitant and two post-radiotherapy) of cisplatin/fluorouracil (arm B) along with radiotherapy 50 Gy in both arms. Responses were reviewed by independent experts. Results: A total of 97 patients were randomised (arm A/B, 53/44) and 95 were assessable. The majority had squamous cell carcinoma (82%; arm A/B, 42/38). Chemoradiotherapy was completed in 74 and 66%. The ECRR was 45 and 29% in arms A and B, respectively. Median times to progression were 15.2 and 9.2 months and the median overall survival was 22.7 and 15.1 months in arms A and B, respectively. Conclusion: Chemoradiotherapy with FOLFOX4, a well-tolerated and convenient combination with promising efficacy, is now being tested in a phase III trial.

Published
2010

6. SMARCA4 inactivation defines a group of undifferentiated thoracic malignancies transcriptionally related to BAF-deficient sarcomas

Author

Franck Tirode, Françoise Galateau-Sallé, Jean-Yves Blay, Stelly Ballet, Wilfrid Richer, Alexandra Leary, Aurélie Auguste, Marie Brevet, Sarah Watson, Gaëlle Pierron, Sandrine Boyault, Olivier Delattre, Benjamin Besse, Gérard Zalcman, Mojgan Devouassoux-Shisheboran, Nelly Firmin, Yves Allory, Julien Masliah-Planchon, Jean Michel Coindre, Dominique Ranchère-Vince, Vincent Thomas de Montpréville, Sylvie Lantuejoul, Nicolas Girard, Françoise Thivolet-Béjui, Elie Fadel, François Le Loarer, Daniel Pissaloux, Jean Michel Vignaud, Franck Bourdeaut, Isabelle Treilleux, Pierre Joseph Dechelotte, Sandrine Paindavoine, Centre de Recherche en Cancérologie de Lyon ( CRCL ), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Service de Pathologie [Centre Leon Berard], Centre Léon Bérard [Lyon], Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon, Unité de génétique et biologie des cancers ( U830 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut Curie-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Unité de Génétique Somatique, INSTITUT CURIE, Service de pathologie [Hôptital Marie Lannelongue], Hôpital Marie Lannelongue, Institut de recherche en cancérologie de Montpellier ( IRCM ), Université Montpellier 1 ( UM1 ) -CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université de Montpellier ( UM ), Biomarqueurs prédictifs et nouvelles stratégies moléculaires en thérapeutique anticancéreuse ( U981 ), Université Paris-Sud - Paris 11 ( UP11 ) -Institut Gustave Roussy ( IGR ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Service de Génétique [Centre Leon Berard], Service de Pathologie [CHU Clermont Ferrand], CHU Clermont-Ferrand, Département de médecine oncologique [Gustave Roussy], Institut Gustave Roussy ( IGR ), Université Paris-Sud - Paris 11 ( UP11 ), Service de Pathologie [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy ( CHRU Nancy ), Centre de Pathologie Est, Lyon, Service de Chirurgie Thoracique et Vasculaire [Centre Chirurgical Marie Lannelongue], Centre chirurgical Marie Lannelongue, Site de Recherche Intégrée en Cancérologie ( SIRIC-ONCOLille ), Université de Lille, Sciences et Technologies-Université de Lille, Sciences Humaines et Sociales-CRLCC Oscar Lambret-Cancéropole Nord-Ouest-Université de Lille, Droit et Santé-Centre Hospitalier Régional Universitaire [Lille] ( CHRU Lille ), Service d'Anatomo-Pathologie [Hôpital de la Croix-Rousse - HCL], Hôpital de la Croix-Rousse [CHU - HCL], Hospices Civils de Lyon ( HCL ) -Hospices Civils de Lyon ( HCL ), Service de pneumologie [Caen], CHU Caen-Université de Caen Normandie ( UNICAEN ), Normandie Université ( NU ) -Normandie Université ( NU ), Plateforme de Ressources Biologiques, Département de pathologie, Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 ( UPEC UP12 ), Université Paris-Est Créteil Val-de-Marne - Paris 12 ( UPEC UP12 ), Biomécanique cellulaire et respiratoire ( BCR ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Paris-Est Créteil Val-de-Marne - Paris 12 ( UPEC UP12 ) -Centre National de la Recherche Scientifique ( CNRS ), Département d'oncologie pédiatrique [Institut Curie, Paris], Service de pneumologie [Centre Hospitalier Lyon Sud - HCL], Centre Hospitalier Lyon Sud [CHU - HCL] ( CHLS ), Service de Pathologie [Grenoble], Centre Hospitalier Universitaire [Grenoble] ( CHU ), Unité de recherche interdisciplinaire pour la prévention et le traitement des cancers ( ANTICIPE ), Normandie Université ( NU ) -Normandie Université ( NU ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre Régional de Lutte contre le Cancer François Baclesse ( CRLC François Baclesse ), Département de Pathologie [Caen], Université de Caen Normandie ( UNICAEN ), Normandie Université ( NU ) -Normandie Université ( NU ) -CHU Caen, Institut Bergonié - CRLCC Bordeaux, Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Claude Bernard Lyon 1 (UCBL), Unité de génétique et biologie des cancers (U830), Université Paris Descartes - Paris 5 (UPD5)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Curie [Paris], Institut de Recherche en Cancérologie de Montpellier (IRCM - U1194 Inserm - UM), CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Biomarqueurs prédictifs et nouvelles stratégies moléculaires en thérapeutique anticancéreuse (U981), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Gustave Roussy (IGR), Université Paris-Sud - Paris 11 (UP11), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Centre Chirurgical Marie Lannelongue (CCML), Site de Recherche Intégrée en Cancérologie (SIRIC-ONCOLille), Université de Lille, Sciences et Technologies-Université de Lille, Sciences Humaines et Sociales-Centre Régional de Lutte contre le Cancer Oscar Lambret [Lille] (UNICANCER/Lille), Université Lille Nord de France (COMUE)-UNICANCER-Université Lille Nord de France (COMUE)-UNICANCER-Cancéropole Nord-Ouest-Université de Lille, Droit et Santé-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Service de pneumologie [CHU Caen], Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN), Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Biomécanique cellulaire et respiratoire (BCR), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Centre National de la Recherche Scientifique (CNRS), Hôpital Henri Mondor, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Centre Hospitalier Universitaire [Grenoble] (CHU), Université Joseph Fourier - Grenoble 1 (UJF), Unité de recherche interdisciplinaire pour la prévention et le traitement des cancers (ANTICIPE), Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN)-Centre Régional de Lutte contre le Cancer François Baclesse [Caen] (UNICANCER/CRLC), UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-UNICANCER-Institut National de la Santé et de la Recherche Médicale (INSERM), Département de Pathologie [CHU Caen], Institut Bergonié [Bordeaux], UNICANCER, Université de Lille-UNICANCER-Université de Lille-UNICANCER-Cancéropole Nord-Ouest-Université de Lille, Droit et Santé-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), and Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-UNICANCER-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
Adult, Transcription, Genetic, [SDV]Life Sciences [q-bio], Biology, Bioinformatics, Transcriptome, SOX2, Genetics, medicine, Humans, Thoracic Neoplasm, Lung, [ SDV ] Life Sciences [q-bio], DNA Helicases, Nuclear Proteins, Sarcoma, Thoracic Neoplasms, medicine.disease, 3. Good health, DNA-Binding Proteins, medicine.anatomical_structure, SMARCA4, Cancer research, Immunohistochemistry, Differential diagnosis, Transcription Factors
Abstract

International audience; While investigating cohorts of unclassified sarcomas by RNA sequencing, we identified 19 cases with inactivation of SMARCA4, which encodes an ATPase subunit of BAF chromatin-remodeling complexes. Clinically, the cases were all strikingly similar, presenting as compressive mediastino-pulmonary masses in 30- to 35-year-old adults with a median survival time of 7 months. To help define the nosological relationships of these tumors, we compared their transcriptomic profiles with those of SMARCA4-mutated small-cell carcinomas of the ovary, hypercalcemic type (SCCOHTs), SMARCB1-inactivated malignant rhabdoid tumors (MRTs) and lung carcinomas (of which 10% display SMARCA4 mutations). Gene profiling analyses demonstrated that these tumors were distinct from lung carcinomas but related to MRTs and SCCOHTs. Transcriptome analyses, further validated by immunohistochemistry, highlighted strong expression of SOX2, a marker that supports the differential diagnosis of these tumors from SMARCA4-deficient lung carcinomas. The prospective recruitment of cases confirmed this new category of 'SMARCA4-deficient thoracic sarcomas' as readily recognizable in clinical practice, providing opportunities to tailor their therapeutic management.

7. Exploring the link between MORF4L1 and risk of breast cancer

Author

Martrat, G., Maxwell, C.A., Tominaga, E., Porta-de-la-Riva, M., Bonifaci, N., Gomez-Baldo, L., Bogliolo, M., Lazaro, C., Blanco, I., Brunet, J., Aguilar, H., Fernandez-Rodriguez, J., Seal, S., Renwick, A., Rahman, N., Kuhl, J., Neveling, K., Schindler, D., Ramirez, M.J., Castella, M., Hernandez, G., Easton, D.F., Peock, S., Cook, M., Oliver, C.T., Frost, D., Platte, R., Evans, D.G., Lalloo, F., Eeles, R., Izatt, L., Chu, C., Davidson, R., Ong, K.R., Cook, J., Douglas, F., Hodgson, S., Brewer, C., Morrison, P.J., Porteous, M., Peterlongo, P., Manoukian, S., Peissel, B., Zaffaroni, D., Roversi, G., Barile, M., Viel, A., Pasini, B., Ottini, L., Putignano, A.L., Savarese, A., Bernard, L., Radice, P., Healey, S., Spurdle, A., Chen, X.Q., Beesley, J., Rookus, M.A., Verhoef, S., Tilanus-Linthorst, M.A., Vreeswijk, M.P., Asperen, C.J., Bodmer, D., Ausems, M.G.E.M., Os, T.A. van, Blok, M.J., Meijers-Heijboer, H.E.J., Hogervorst, F.B.L., Goldgar, D.E., Buys, S., John, E.M., Miron, A., Southey, M., Daly, M.B., Harbst, K., Borg, A., Rantala, J., Barbany-Bustinza, G., Ehrencrona, H., Stenmark-Askmalm, M., Kaufman, B., Laitman, Y., Milgrom, R., Friedman, E., Domchek, S.M., Nathanson, K.L., Rebbeck, T.R., Oskar, T., Couch, F.J., Wang, X.S., Fredericksen, Z., Cuadras, D., Moreno, V., Pientka, F.K., Depping, R., Caldes, T., Osorio, A., Benitez, J., Bueren, J., Heikkinen, T., Nevanlinna, H., Hamann, U., Torres, D., Caligo, M.A., Godwin, A.K., Imyanitov, E.N., Janavicius, R., Sinilnikova, O.M., Stoppa-Lyonnet, D., Mazoyer, S., Verny-Pierre, C., Castera, L., Pauw, A. de, Bignon, Y.J., Uhrhammer, N., Peyrat, J.P., Vennin, P., Ferrer, S.F., Collonge-Rame, M.A., Mortemousque, I., McGuffog, L., Chenevix-Trench, G., Pereira-Smith, O.M., Antoniou, A.C., Ceron, J., Tominaga, K., Surralles, J., Pujana, M.A., EMBRACE, kConFab, HEBON, BCFR, SWE-BRCA, GEMO Study Collaborators, Human Genetics, BMC, Ed., Translational Research Laboratory, Catalan Institute of Oncology-Bellvitge Institute for Biomedical Research, Biomedical Research Centre Network for Epidemiology and Public Health (CIBERESP), Catalan Institute of Oncology, Department of Cellular and Structural Biology, The University of Texas Health Science Center at Houston (UTHealth)-Sam and Ann Barshop Institute for Longevity and Aging Studies, Chemoresistance and Predictive Factors of Tumor Response and Stromal Microenvironment, Institut d'Investigació Biomèdica de Bellvitge [Barcelone] (IDIBELL), Biomarkers and Susceptibility Unit, Department of Genetics and Microbiology, Universitat Autònoma de Barcelona (UAB), Biomedical Research Centre Network for Rare Diseases (CIBERER), Genetic Counseling and Hereditary Cancer Programme, Section of Cancer Genetics, Institute of cancer research, Department of Human Genetics, Julius-Maximilians-Universität Würzburg (JMU), Strangeways Research Laboratory, University of Cambridge [UK] (CAM)-Department of Public Health and Primary Care-Centre for Cancer Genetic Epidemiology, Centre for Cancer Genetic Epidemiology [Cambridge], University of Cambridge [UK] (CAM)-Department of Oncology, Genetic Medicine, St Mary's Hospital-NHS Foundation Trust-Manchester Academic Health Sciences Centre-Central Manchester University Hospitals, Oncogenetics Team, The Institute of Cancer Research and Royal Marsden NHS Foundation Trust, Clinical Genetics Department, Guy's and St Thomas NHS Foundation Trust, Yorkshire Regional Genetics Service, St James's hospital, Ferguson-Smith Centre for Clinical Genetics, West Midlands Regional Genetics Service, Birmingham Women's and Children's NHS Foundation Trust, Sheffield Clinical Genetics Service, Sheffield Children's NHS Foundation Trust, Institute of Human Genetics, Newcastle Upon Tyne Hospitals NHS Foundation Trust, Queen Mary University of London (QMUL)-St George's Hospital, Department of Clinical Genetics, Royal Devon & Exeter Hospital, Northern Ireland Regional Genetics Centre, Belfast City Hospital, South East of Scotland Regional Genetics Service, Western General Hospital, Unit of Molecular Bases of Genetic Risk and Genetic Testing, Department of Preventive and Predictive Medicine-Fondazione IRCCS Istituto Nazionale Tumori (INT), Department of Preventive and Predictive Medicine, IFOM, Istituto FIRC di Oncologia Molecolare (IFOM), Unit of Medical Genetics, Fondazione IRCCS INT, Division of Cancer Prevention and Genetics, Istituto Europeo di Oncologia (IEO), Division of Experimental Oncology 1, Centro di Riferimento Oncologico (CRO), Department of Genetics, Biology and Biochemistry, Università degli studi di Torino = University of Turin (UNITO), Department of Molecular Medicine, Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome] (UNIROMA), Università degli Studi di Firenze = University of Florence (UniFI), Fiorgen Foundation for Pharmacogenomics, Division of Medical Oncology, Regina Elena Cancer Institute, Department of Experimental Oncology, IEO, Division of Genetics and Population Health, Queensland Institute of Medical Research, Department of Epidemiology, The Netherlands Cancer Institute, Family Cancer Clinic, Department of Surgical Oncology, Erasmus University Medical Center [Rotterdam] (Erasmus MC)-Family Cancer Clinic, Center for Human and Clinical Genetics, Leiden University Medical Center (LUMC), DNA Diagnostics, Radboud University Medical Center [Nijmegen], Department of Medical Genetics, University Medical Center [Utrecht], Academic Medical Center - Academisch Medisch Centrum [Amsterdam] (AMC), University of Amsterdam [Amsterdam] (UvA)-University of Amsterdam [Amsterdam] (UvA), University Hospital Maastricht, VU Medical Center, Department of Dermatology, University of Utah School of Medicine [Salt Lake City], Department of Internal Medicine, Huntsman Cancer Institute, Cancer Prevention Institute of California, Department of Cancer Biology, Dana-Farber Cancer Institute [Boston], Department of Surgery, Harvard Medical School [Boston] (HMS), Centre for Molecular, Environmental, Genetic and Analytic Epidemiology (MEGA), University of Melbourne-Melbourne School of Population Health, Division of Population Science, Fox Chase Cancer Center, Department of Oncology, Clinical Sciences, Lund University [Lund]-Skåne University Hospital, Karolinska University Hospital [Stockholm], Department of Genetics and Pathology, Uppsala University, Department of Oncology, University Hospital-Hälsouniversitetet Universitetssjukhuset, The Institute of Oncology, Chaim Sheba Medical Center, The Susanne Levy Gertner Oncogenetics Unit, Sackler Faculty of Medicine, Tel Aviv University (TAU), Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania-University of Pennsylvania, Department of Medicine, Medical Genetics, Abramson Cancer Center-Perelman School of Medicine, Center for Clinical Epidemiology and Biostatistics, Faculty of Medicine, University of Iceland [Reykjavik], Department of Laboratory Medicine and Pathology, Mayo Clinic, Department of Health Sciences Research, Statistical Assessment Service, Department of Physiology, Universität zu Lübeck = University of Lübeck [Lübeck]-Center for Structural and Cell Biology in Medicine, Medical Oncology Branch, Hospital Clínico San Carlos, Human Cancer Genetics Programme, CIBER de Enfermedades Raras (CIBERER)-Spanish National Cancer Research Centre, Division of Hematopoiesis and Gene Therapy, Centro de Investigaciones Energéticas Medioambientales y Tecnológicas [Madrid] (CIEMAT), Department of Obstetrics and Gynecology, Helsinki University Central Hospital, Molecular Genetics of Breast Cancer, German Cancer Research Center - Deutsches Krebsforschungszentrum [Heidelberg] (DKFZ), Instituto de Genética Humana, Pontificia Universidad Javeriana (PUJ), Section of Genetic Oncology, University of Pisa - Università di Pisa, Department of Pathology and Laboratory Medicine, University of Kansas Medical Center [Kansas City, KS, USA], Laboratory of Molecular Oncology, N.N. Petrov Institute of Oncology, Department of Molecular and Regenerative Medicine, Hematology, Oncology and Transfusion, Vilnius University [Vilnius]-Hospital Santariskiu Clinics, Unité Mixte de Génétique Constitutionnelle des Cancers Fréquents, Centre Léon Bérard [Lyon]-Hospices Civils de Lyon (HCL), Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service de Génétique Oncologique, Institut Curie [Paris], Unité de génétique et biologie des cancers (U830), Université Paris Descartes - Paris 5 (UPD5)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Département d'Oncogénétique, Centre Jean Perrin [Clermont-Ferrand] (UNICANCER/CJP), UNICANCER-UNICANCER, Laboratoire d'Oncologie Moléculaire Humaine, Centre Régional de Lutte contre le Cancer Oscar Lambret [Lille] (UNICANCER/Lille), Université de Lille-UNICANCER-Université de Lille-UNICANCER, Consultation d'Oncogénétique, Laboratoire de Génétique Chromosomique, CH Chambéry, Département de Génétique et Reproduction, Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon)-Hôpital Saint-Jacques, Service de génétique [Tours], Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Hôpital Bretonneau, The CIMBA data management is supported by Cancer Research - UK., kConFab, HEBON, BCFR, SWE-BRCA, GEMO Study Collaborators, Autonomous University of Barcelona, Julius-Maximilians-Universität Würzburg [Wurtzbourg, Allemagne] (JMU), Department of Oncology-University of Cambridge [UK] (CAM), University of Turin, Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome], Università degli Studi di Firenze = University of Florence [Firenze] (UNIFI), Departament of Genetics and Pathology, Uppsala University-Rudbeck Laboratory, Tel Aviv University [Tel Aviv], University of Pennsylvania [Philadelphia]-University of Pennsylvania [Philadelphia], Universität zu Lübeck [Lübeck]-Center for Structural and Cell Biology in Medicine, University of Kansas Medical Center [Lawrence], Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5), Université Lille Nord de France (COMUE)-UNICANCER-Université Lille Nord de France (COMUE)-UNICANCER, Universiteit Leiden-Universiteit Leiden, Skåne University Hospital-Lund University [Lund], University of Pennsylvania [Philadelphia]-University of Pennsylvania [Philadelphia]-Abramson Cancer Center, Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Bretonneau-Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Clinical Genetics, Faculteit der Geneeskunde, Klinische Genetica, RS: GROW - School for Oncology and Reproduction, Genetica & Celbiologie, Easton, Douglas [0000-0003-2444-3247], Antoniou, Antonis [0000-0001-9223-3116], Apollo - University of Cambridge Repository, Martrat, G, Maxwell, C, Tominaga, E, Porta de la Riva, M, Bonifaci, N, Gómez Baldó, L, Bogliolo, M, Lázaro, C, Blanco, I, Brunet, J, Aguilar, H, Fernández Rodríguez, J, Seal, S, Renwick, A, Rahman, N, Kühl, J, Neveling, K, Schindler, D, Ramírez, M, Castellà, M, Hernández, G, Embrace, Easton, D, Peock, S, Cook, M, Oliver, C, Frost, D, Platte, R, Evans, D, Lalloo, F, Eeles, R, Izatt, L, Chu, C, Davidson, R, Ong, K, Cook, J, Douglas, F, Hodgson, S, Brewer, C, Morrison, P, Porteous, M, Peterlongo, P, Manoukian, S, Peissel, B, Zaffaroni, D, Roversi, G, Barile, M, Viel, A, Pasini, B, Ottini, L, Putignano, A, Savarese, A, Bernard, L, Radice, P, Healey, S, Spurdle, A, Chen, X, Beesley, J, Rookus, M, Verhoef, S, Tilanus Linthorst, M, Vreeswijk, M, Asperen, C, Bodmer, D, Ausems, M, van Os, T, Blok, M, Meijers Heijboer, H, Hogervorst, F, Goldgar, D, Buys, S, John, E, Miron, A, Southey, M, Daly, M, Harbst, K, Borg, A, Rantala, J, Barbany Bustinza, G, Ehrencrona, H, Stenmark Askmalm, M, Kaufman, B, Laitman, Y, Milgrom, R, Friedman, E, Domchek, S, Nathanson, K, Rebbeck, T, Johannsson, O, Couch, F, Wang, X, Fredericksen, Z, Cuadras, D, Moreno, V, Pientka, F, Depping, R, Caldés, T, Osorio, A, Benítez, J, Bueren, J, Heikkinen, T, Nevanlinna, H, Hamann, U, Torres, D, Caligo, M, Godwin, A, Imyanitov, E, Janavicius, R, Sinilnikova, O, Stoppa Lyonnet, D, Mazoyer, S, Verny Pierre, C, Castera, L, de Pauw, A, Bignon, Y, Uhrhammer, N, Peyrat, J, Vennin, P, Ferrer, S, Collonge Rame, M, Mortemousque, I, Mcguffog, L, Chenevix Trench, G, Pereira Smith, O, Antoniou, A, Cerón, J, Tominaga, K, Surrallés, J, Pujana, M, Human genetics, CCA - Oncogenesis, Biomedical Research Centre Network for Epidemiology and Public Health ( CIBERESP ), The University of Texas Health Science Center at San Antonio-Sam and Ann Barshop Institute for Longevity and Aging Studies, Institut d'Investigació Biomèdica de Bellvitge [Barcelone] ( IDIBELL ), Biomedical Research Centre Network for Rare Diseases ( CIBERER ), University of Würzburg, University of Cambridge [UK] ( CAM ) -Department of Public Health and Primary Care-Centre for Cancer Genetic Epidemiology, University of Cambridge [UK] ( CAM ) -Department of Oncology, Birmingham Women's Hospital Healthcare NHS Trust, Sheffield Children's Hospital, Newcastle Upon Tyne Hospitals NHS Trust, Queen Mary University of London ( QMUL ) -St George's Hospital, IFOM, Istituto FIRC di Oncologia Molecolare ( IFOM ), Università degli Studi di Roma 'La Sapienza' [Rome], University of Florence, Erasmus MC-Daniel den Hoed Cancer Center-Family Cancer Clinic, University Medical Center Utrecht, Academic Medical Center [Amsterdam] ( AMC ), University of Amsterdam [Amsterdam] ( UvA ) -University of Amsterdam [Amsterdam] ( UvA ), Harvard Medical School [Boston] ( HMS ), Centre for Molecular, Environmental, Genetic and Analytic Epidemiology ( MEGA ), University of Pennsylvania School of Medicine, University of Pennsylvania School of Medicine-Abramson Cancer Center, Centro de Investigaciones Energéticas, Deutsches Krebsforschungszentrum ( DKFZ ), Pontificia Universidad Javeriana, University of Pisa [Pisa], University of Kansas Medical Center, Centre Léon Bérard [Lyon]-Hospices Civils de Lyon ( HCL ), Centre de Recherche en Cancérologie de Lyon ( CRCL ), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), INSTITUT CURIE, Unité de génétique et biologie des cancers ( U830 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut Curie-Institut National de la Santé et de la Recherche Médicale ( INSERM ), CRLCC Jean Perrin, CRLCC Oscar Lambret, Centre Hospitalier Régional Universitaire [Besançon] ( CHRU Besançon ) -Hôpital Saint-Jacques, Hôpital Bretonneau-CHRU Tours, and Universitat de Barcelona

Subjects
DNA Repair, Genes, BRCA2, RAD51, Genes, BRCA1, Germ-Cell, Helicase Brip1, medicine.disease_cause, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, Mice, 0302 clinical medicine, Breast cancer, Fanconi anemia, Risk Factors, Replication Protein A, Teknik och teknologier, Homologous Recombination, skin and connective tissue diseases, C-Elegans, Genetics, Medicine(all), ddc:616, 0303 health sciences, Mutation, Fanconi Anemia Complementation Group D2 Protein, Nuclear Proteins, Anèmia aplàstica, 3. Good health, 030220 oncology & carcinogenesis, Chromodomain Protein, Engineering and Technology, Female, RNA Interference, Fanconi Anemia Complementation Group N Protein, Aplastic anemia, Research Article, BRCA2 Mutation Carrier, DNA repair, PALB2, Breast Neoplasms, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, Cell Line, Càncer de mama, Genomic disorders and inherited multi-system disorders [IGMD 3], 03 medical and health sciences, SDG 3 - Good Health and Well-being, [SDV.CAN] Life Sciences [q-bio]/Cancer, Two-Hybrid System Techniques, medicine, Genetic predisposition, Animals, Humans, Genetic Predisposition to Disease, Caenorhabditis elegans, Gene, 030304 developmental biology, Phenocopy, Caenorhabditis-Elegan, Tumor Suppressor Proteins, medicine.disease, BRCA1, BRCA2, Pancreatic-Cancer, Fanconi Anemia, Genes, Cancer and Oncology, Fanconi-Anemia, Cancer research, Rad51 Recombinase, Susceptibility Gene, DNA Damage, Transcription Factors
Abstract

Introduction Proteins encoded by Fanconi anemia (FA) and/or breast cancer (BrCa) susceptibility genes cooperate in a common DNA damage repair signaling pathway. To gain deeper insight into this pathway and its influence on cancer risk, we searched for novel components through protein physical interaction screens. Methods Protein physical interactions were screened using the yeast two-hybrid system. Co-affinity purifications and endogenous co-immunoprecipitation assays were performed to corroborate interactions. Biochemical and functional assays in human, mouse and Caenorhabditis elegans models were carried out to characterize pathway components. Thirteen FANCD2-monoubiquitinylation-positive FA cell lines excluded for genetic defects in the downstream pathway components and 300 familial BrCa patients negative for BRCA1/2 mutations were analyzed for genetic mutations. Common genetic variants were genotyped in 9,573 BRCA1/2 mutation carriers for associations with BrCa risk. Results A previously identified co-purifying protein with PALB2 was identified, MRG15 (MORF4L1 gene). Results in human, mouse and C. elegans models delineate molecular and functional relationships with BRCA2, PALB2, RAD51 and RPA1 that suggest a role for MRG15 in the repair of DNA double-strand breaks. Mrg15-deficient murine embryonic fibroblasts showed moderate sensitivity to γ-irradiation relative to controls and reduced formation of Rad51 nuclear foci. Examination of mutants of MRG15 and BRCA2 C. elegans orthologs revealed phenocopy by accumulation of RPA-1 (human RPA1) nuclear foci and aberrant chromosomal compactions in meiotic cells. However, no alterations or mutations were identified for MRG15/MORF4L1 in unclassified FA patients and BrCa familial cases. Finally, no significant associations between common MORF4L1 variants and BrCa risk for BRCA1 or BRCA2 mutation carriers were identified: rs7164529, Ptrend = 0.45 and 0.05, P2df = 0.51 and 0.14, respectively; and rs10519219, Ptrend = 0.92 and 0.72, P2df = 0.76 and 0.07, respectively. Conclusions While the present study expands on the role of MRG15 in the control of genomic stability, weak associations cannot be ruled out for potential low-penetrance variants at MORF4L1 and BrCa risk among BRCA2 mutation carriers.

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