Molecular biology
Human and Social Sciences
- SEQUAPRE : Preferences and representations of patients faced with the arrival of next generation sequencing in car. Project of the Rare Diseases Foundation 2014. Principal investigator: Pr Laurence Faivre.
Next generation sequencing is transforming the field of development, diseases and notably the diagnosis of patients, too often confronted with a diagnostic odyssey. Before doctors can use NGS in routine practice, it is necessary to anticipate the information to communicate to patients and to parents so that will consent to this new type of examination.
This project was initiated by two CLAD (Dijon and Lyon), supported by teams in the field of human and social sciences, and a group of associations. The aims are: 1/ to evaluate the wishes of parents of patients with development anomalies with regard to the nature of results and their announcement (survey among parents of approximately 500 patients, potential candidates for NGS in the centers of Dijon and Lyon over 9 months), and 2/ to describe, analyze and understand, after the use of NGS for diagnostic purposes, the experiences, expectations and reactions of families and geneticists vis-à-vis the diagnostic trajectory and the announcement of the results (30 interviews conducted with the parents and 10 with geneticists).
The nature of the results from NGS and the possibility to re-analyze them were considered important attributes by the 513 respondents. This survey also showed that the respondents expressed clear preferences for the communication of uncertain results and the automatic re-analysis of examination results. 58 interviews were conducted with parents and medical geneticists. Whatever the result of NGS, it was regarded as a step and not an end in itself. Even when a diagnosis was made, the trajectory continued and a feeling of helplessness may persist, as families experience a displacement of boundaries between disease and handicap. NGS therefore represents a passage from odyssey to trajectory.
- DISSEQ : Medico-economic evaluation of different next generation sequencing strategies in the diagnosis of patients with intellectual deficiency. PRME 2015. Principal investigator: Pr Christel Thauvin-Robinet.
Currently, in France, the diagnosis of Intellectual deficiency (ID) is based on clinical expertise, CGH-Array, screening for fragile-X syndrome and, if necessary the study of targeted genes, sometimes at the price of numerous repeated, long and costly biological examinations.
Two types of targeted gene panels have been developed in France, for intellectual deficiency: DI44 (small panel of 44 genes with a diagnostic yield of 10% and a low cost) and DI459 (large panel of 459 genes with diagnostic yield of 25% and a high cost). In parallel, there is WES with a higher diagnostic yield and higher cost, but it may avoid other costly para-clinical investigations, and allows the re-analysis of genomic data over time as new medical and scientific knowledge comes to light.
With the arrival of these new sequencing techniques for diagnosis, it seems essential to compare the cost-effectiveness of three possible strategies to determine which would be most suitable for deployment in France.
330 patients must be included by the 10 inclusion centers in France. This project is funded for an amount of 1,700,000 euros. It will benefit from the methodological support of several health economists (Dr C. Lejeune, AC. Bertaux and Pr S. Bejean) and the CIC-EC of Dijon (Pr C. Binquet) and Nancy (Pr F. Guillemin).
- FIND: Incidental findings resulting from NGS for diagnostic purposes: from the needs of patients to organizational modalities. PREPS 2016. Principal investigator: Pr Laurence Faivre.
The fact of proposing a part or all of the incidental findings to patients is a matter of debate in France and elsewhere. This question raises new issues and generates new needs to which professionals must respond by appropriate management and new skills. It gives rise to specific ethical questions, which require a clear understanding of expectations and the experience of patients. The evolution of care trajectories must also meet criteria of efficacy and financial and organizational sustainability for healthcare establishments and, beyond that, for the healthcare system as a whole. This project aims to evaluate the expectations of patients/parents with regard to this opportunity, and to identify the modalities concerning the information provided to patients and their accompaniment to ensure they are appropriate and efficient. This project, conceived in 2016, will start in 2017. 250 patients or parents are necessary for this research.
- PADAP: Possibility of Access to Incidental Findings: Psychological Approach
The objective is to gather the experiences and the opinions of patients with regard to the possibility of gaining access to incidental findings from exome sequencing. Interviews in open focus groups have been organized with associations of patients affected by diseases involving the list of 59 genes of the ACMG on the one hand, and patients without a diagnosis on the other. These focus group meetings led by psychologists will be recorded, and will be anonymized before transcription. The analysis will be done using anchored instruction theory, a method that reveals the variety of topics raised by the participants. The results could help advance reflection in France with regard to national recommendations on incidental findings from NGS.
EXOMA Project, NCT02840604 (Investigator coordinator : Pr F Ghiringhelli, CGFL)
The management of cancers and the therapeutic orientation were until recently principally based on the histopathological features of the tumor. The development of targeted therapies is a turning point in oncological management and the number of new therapies is increasing steadily. These molecules target a specific molecular defect in the tumor, which makes the treatment more effective and more specific. These treatments, however, are only effective if the tumor has a specific molecular anomaly that is known and has been characterized. In recent years, the widespread use of next generation sequencing has given rise to a new era in cancer research, and in molecular diagnosis. Indeed, the enormous sequencing capability afforded by next generation sequencing technologies has made it possible to analyze the whole coding sequence of the genome (exome), or even the whole genome of a tumor (whole genome sequencing) in a short time. The evolution and the development of bioinformatics tools associated with genomic techniques now make it possible to establish the genetic profile of a tumor. The targeted diagnosis of molecular anomalies has made it possible to propose targeted treatments and to discover genetic predispositions to cancer.
The principal objective of this study is to evaluate the clinical benefits in terms of therapeutic proposals following somatic and constitutional exome analysis carried out in routine practice. The analysis is done by quantifying the number of patients obtaining a therapeutic proposal according to the results of the tumor profile analysis. This also allow us to define the number of patients with changes in their treatments following the analysis and to determine the number of patients reoriented towards a targeted therapy trial following the analysis. We could also determine the incidence of genetic predispositions discovered incidentally by this type of analysis. The analyses are delivered in the form of 2 lists of variants: the first one contains variants for which there is a targeted therapy (this list comes from merging the list of the English 100,000 genome project and the Target list of the Broad institute). We can subsequently apply a proposal from the Broad institute or a proposal for an open therapeutic trial in France. A therapeutic recommendation with a bibliographic reference or the proposal for inclusion in a therapeutic trial targeting this mutation and open in France using the INCA database of clinical trials is provided. The second one is completed by an analysis of a list of genes related to cancer (list of the English 100,000 genome project). For each list, the type of mutation is specified and the function of the mutation (activating, inhibiting, neutral or unknown) is indicated. For antioncogenes, a study of loss of heterozygosity is done. In cases of mutant genes carrying a predisposition to cancer, a second oncogenetics consultation is programed.
MEDICOLON project (investigator coordinator: Pr F Ghiringhelli)
Phase II study in digestive cancerology, focused on the role of exoma analysis to predict the response to immunotherapy including 52 patients (Astra Zeneca (700KE)) funding).
Projet IMMUNOGLIO (Investigator coordinator : Pr F Ghiringhelli)
This project aims, through high-throughput sequencing approaches and immune system technical analysis, to determine how glioblastoma tumoral genetics influences in situ immune response.
It will be the biggest glioblatoma prospective cohort characterized on genetics and immune aspects. (ERA-NET TRANSCAN JTC 2015 (INCa) funding)
Project “study for the research of genetic and immunological biomarkers of nivolumab response in bronchial cancer” (Investigateur principal : Pr F Ghiringhelli)
The main goal is a correlation study between nivolumab response and tumoral genetics (trancriptome and exoma). This project aims at evaluating prognosis models which integrate high throughput data analysis for biomarkers identification in cancerology, with an application to the nivolumab response in non-small cell bronchial cancers. (Ligue Nationale contre le Cancer 2016 funding).
The OncoSNIPE® Project (associated investigators: Pr F. Ghiringhelli, Pr P. Fumoleau)
The aim of the OncoSNIPE® project is the development and the implementation of bioinformatics approaches that make use of methodologies based on, among other things, artificial intelligence, statistical learning and semantic enrichment, which must allow the identification and characterization of patients who are resistant to anti-cancer treatments and thus to orient research to the development of specific therapeutic solutions through the identification of new targets.
The project, lasting 4 years, is piloted and coordinated by Oncodesign, and combines the skills of 4 industrial partners with complementary and synergistic expertise and know-how: Expert System (Modene, Italie), Sword (Lyon), Acobiom (Montpellier) and Oncodesign (Dijon) and 3 academic institutions: the University Hospital of Strasbourg, the Centre George François Leclerc (Dijon) and the Institut Paoli Calmettes (Marseille), the latter two are anti-cancer centers.
Precision medicine is centered on knowledge of the patient’s disease.
The OncoSNIPE® project is a research and development project conducted in an environment where precision medicine is considered a major opportunity for the management of patients. In oncology, the development of resistance and insensitivity to treatments lies at the origin of relapses, leading to the death of huge numbers of patients every year (8.2 million deaths in 2012).
OncoSNIPE® will target three types of cancer: breast, pancreas and lung. These three cancers, which present circumstances for the onset of resistance mechanisms in oncology, lend to the project the diversity necessary for the implementation of diagnostic and therapeutic tools.
Accredited by the Cap Digital competitiveness pole, OncoSNIPE® won an award from the Programme d’Investissements d’Avenir « Structuring research and development projects for Competitiveness (PSPC) ». Thanks to this, the project could obtain, following a final contractual agreement with Bpifrance, public funding amounting to 7.7 million euros in the form of reimbursable advances and grants divided among the academic institutions and industrial partners. The overall estimated budget for OncoSNIPE®, including private investments, is 12 million euros and the project will eventually generate more than 43 direct jobs over the period 2021-2025.
During these 4 years, more than 800 patients will be managed by the academic partners and 600 will benefit from an original longitudinal follow-up during which, they will have not only a classical clinical follow-up, but also a genomic follow-up with NGS of their tumor (Exom-seq and RNA-seq) and their blood markers (RNA-seq) done at the diagnosis, at the time of the best therapeutic response, and at the onset of the first signs of resistance. All of this information, contextualized using semantic enrichment approaches, will serve as a basis to model resistance mechanisms, to identify biomarkers, to discover new therapeutic targets and to generate the knowledge necessary for the implementation of a precision medicine trajectory dedicated to patients who are resistant to anti-cancer treatments.
Bpifrance is the operator for the management of Structuring of research and development Projects for Competitiveness (PSPC) of the Programme d’investissements d’avenir, piloted by the Commissariat Général à l’investissement (CGI). The aim of these projects is to structure industrial networks or to promote the emergence of new companies. Through the financial support of ambitious program, they aim to strengthen the positions of French companies on lead markets and more generally the economic position of networks of companies, by strengthening or constructing durable collaborative relationships between companies, services and research organizations.
The Improving immunotherapy of solid tumors by targeting the immunosuppressive tumor microenvironment project: from pre-clinical "proof-of-concept" to the development of phase Ibstudy (Microther) (associated investigator: François Ghiringhelli)
Funding: ERA-NET TRANSCAN JTC 2015 (INCa) Aligning national/regional translational cancer research programmes and activities TRANSCAN2017--371. Principal investigator Massimo Di Nicola, MD, Immunotherapy and Anticancer Innovative Therapeutics, Unit Dept. Medical Oncology Fondazione IRCCS Istituto Nazionale Tumori, 20133 Milan, Italy
This project aims to characterize the influence of the tumor microenvironment on the antitumor immune response on the effect of immunotherapies
The Mutational landscape of HER2+ and triple-negative breast cancer and its Evolution during neoadjuvant chemotherapy (associated investigator: François Ghiringhelli)
AAP: NPRQ Qatar. Principal coordinator: Lotfi Chouchane, Qatar
This project aims to determine whether chemotherapy affects the mutational status of HER2+ and triple-negative breast tumors. The tumors will be characterized before and during treatment to determine whether the chemotherapy induces an accumulation of mutations and whether this affects the efficacy of the treatment. 60 tumors will be sequenced before treatment, after 1 course and after 6 courses of chemotherapy.
The ALCAPONE project (associated investigator: François Ghiringhelli)
This project aims to study the molecular characteristics of non-small cell lung cancer before the initiation of treatment and at relapse using NGS techniques (exome or gene panel). The aim is to characterize the evolution of mutations on treatment and to search for markers of resistance.
The « EXOCare-search by exome sequencing for new genes carrying a predisposition for rare cancers in children (EXOme Cancers Rares of the Enfant) » project (associated investigator: Pr L Faivre, project sponsored by the Groupe Inter-regional Grand Ouest Cancers of the Enfant - GOCE)
The aim of this study is to identify genes carrying a predisposition to pediatric cancers by exome sequencing in a selected population of children presenting cancer associated with a development anomaly. This project makes use of the « TED » registry (Tumors And Development) and includes the constitutional and somatic exome sequencing of 100 patients presenting development delay using a trio strategy: 300 persons and 100 tumors.
The clinicians of the institution develop collaborations in most french research groups in cancerology and the clinical research studies of the french cooperative groups are systematically open to the CGFL. The institution is also part of the EORTC (European Organisation for Research and Treatment of Cancer) and studies of this group are regularly open. We can also mentioned a participation in research groups involved in cancer biology, such as the GPCO (Clinical Pharmacology in Oncology group), and in the immunology – immunotherapy reflexion working group within the SiRICs network, which wanted the participation of the Center's teams (S Ladoire and F Ghiringhelli).
