Oncogenetics Program


Board

Pr. Pierre Laurent-Puig
Physician
Pr. Eric Pasmant
Biologist


Steering Committee

Dr. Géraldine Perkins - Physician
Dr. Marion Dhooge - Physician
Dr. Khadija Lanhou-Laforêt - Psychiatrist
Dr. Camille Tlemsani - Physician
Dr. Nadim Hamzaoui - Biologist
Dr. Nelly Burnichon - Biologist
Pr. Hélène Blons - Biologist
Pr. Karen Leroy - Biologist
Dr. Judith Favier - Scientist
Dr. Virginie Verkarre - Pathologist
Dr. Audrey Lupo Mansuet - Pathologist
Anne-Marie Birot - Genetic Councellor

The Paris Cancer Institute CARPEM institute oncogenetics program is run by a multidisciplinary team composed by geneticists, genetic counsellors, psychologists and/or psychiatrist, gastroenterologists, oncologists, endocrinologists, dermatologists, molecular geneticists and pathologists.

Major objectives are :

1) to inform patients affected by frequent or rare tumors and to propose genetic testing when appropriate;

2) to identify constitutional pathogenic variants;

3) to propose recommendations for specific management and surveillance in accordance with specialists of the main organs involved (see screening program);

4) to offer predictive genetic counselling to the relatives of patients with a hereditary predisposition.

To be easily accessible to patients of both sites, the oncogenetics program is taking place into two oncogenetics clinics located at HEGP and CCH.

ONCOGENETIC CLINICS

This clinic, labeled by the French National Cancer Institute (INCa) from 2002, performed 2353 consultations in 2018. Taking account of the incidence of different cancers, a broad offer of genetic counselling is proposed to at-risk patients and their relatives, managed at hEGP or CCH, with a suspicion of hereditary breast and ovarian or prostatic cancers as well as for those with a suspicion to a genetic predisposition to colorectal cancers on both sites. In total four different physicians (1 geneticist: P. Laurent-Puig; 3 gastroenterologists: G. Perkins, A. Zaanan, M. Dhooge) and three genetic counsellors are involved (D. Molière A-M. Birot, S Farelly). Regarding rare cancers and/or rare tumors, a dedicated geneticist and a genetic counsellor (A-P. Gimenez Roqueplo, A-M. Birot) are available in the genetic consultation of HEGP whereas different specialists, but graduates in oncogenetics, are available at CCH in Endocrinology department (for neuroendocrine tumors, A Jouinot, G Assié, J Bertherat), in Oncology department (for sarcomas, C Tlemsani) and in Dermatology department (for melanomas and other skin tumors, JC Chanal and S Guegan).  Psychiatrist (K. Lahlou-Laforet) or psychologist (I. Molley-Massol) is available on both sites.

For frequent cancers, our oncogenetics physicians are part of regional support network helping patients with hereditary predisposition to frequent cancer to improve their follow-up: the PRED-IdF[1] network, for patients with predisposition to digestive tract cancer, and the SAR network[2], for patients with predisposition to breast and ovarian cancer.

We are also part of a regional committee of digestive oncogenetics, for the collegial discussion of difficult cases of suspicion of predisposition to digestive tracts cancer syndroms , gathering genetics counsellors and oncogeneticists from Ile de France (CODIF : Comité d’Oncogénétique Digestive d’Ile de France).

 

[1] https://www.pred-idf.com/ Network supported by National Cancer Institute led by Pr Cellier

[2] http://seinarisque.aphp.fr/ Network supported by National Cancer Institute led by Nathalie Chabbert-Buffet

 

ONCOGENETIC BIOLOGY

Genetic tests are carried out in the molecular genetic laboratories of both sites that analyzed 2062 patients at germline level in 2018. Constitutional tests are mainly based on next generation sequencing with dedicated panels developed by a unique laboratory. We have implemented at Cochin laboratory (N. Hamzaoui, E. Pasmant) the NGS analysis of consensus panels of cancer genes with clear clinical utility for hereditary colorectal cancer syndromes (APC, BMPR1A, CDH1, EPCAM, MLH1, MSH2, MSH6, MUTYH, PMS2, POLD1, POLE, PTEN, SMAD4 and STK11) and hereditary breast and ovarian cancer syndromes (BRCA1, BRCA2, PALB2, TP53, CDH1, PTEN, RAD51C, RAD51D, MLH1, MSH2, MSH6, PMS2 and EPCAM) that have been recommended by the GGC-Unicancer group. Cochin laboratory (N. Hamzaoui, E. Pasmant) has also developed specific multigene panels for hereditary pancreatic cancer and hereditary prostate cancer. Cochin and HEGP laboratories developed specific NGS panels dedicated to rare tumor predisposition syndromes including neuroendocrine tumors (N. Burnichon, A. Buffet, MO. North), renal cancers (N. Burnichon), neurofibromatosis type 1 (D. Vidaud, E. Pasmant), and neurofibromatosis type 2 and schwannomatosis (B. Parfait).

 

MOLECULAR TUMOR BOARD

The geneticists involved in this program participate to the CARPEM Institute multidisciplinary molecular tumor board, reassembling physicians with varying expertise, organized twice by month. Results from NGS panel tests or exome and /or RNA sequencing are discussed. The incidental germline variations are evaluated and discussed, and patients are then quickly referred to a genetics consultation. Germline results are explained to the patients by geneticists.

Three members of our board (Anne-Paule Gimenez-Roqueplo, Eric Pasmant, Pierre Laurent-Puig) are directors of different INSERM research teams, located at the PARCC, the Cochin Institute, and the Cordeliers research centers, that tackle both basic and translational science in oncology with human genetics, biomarker identification, and innovative therapeutic proof-of-concept in using cutting-edge technologies. This proximity between basic and clinical research grandly helps the prompt transfer of innovations from bench to beside and the development of translational research projects which are promptly endorsed by all the oncogenetics team.

Clinical research
  • Clinical research in oncogenetics of rare tumors

Our clinical research programs are mainly based on collections or registries developed on site. For instance, rare adrenal tumors are the main focus of the French COMETE network funded in 1993 and currently led by AP Gimenez-Roqueplo. This network, firstly centred at HEGP and Cochin, organizes clinical and biological sample collection at national level and was the support of numerous research studies (3 PHRC, 1 PRTK). Thanks to this invaluable collection of such rare cancers considerable progresses were made. Notably, the APGR’s team demonstrated that pheochromocytoma and paraganglioma (PPGL) are the cancers the most impacted by the genetics (78% of the PPGL COMETE collection was explained by germline or somatic genetic alterations) and led a gene discovery program allowing the identification of three different PPGL susceptibility genes in patients enrolled in the COMETE collection, the last one is SLC25A11(Buffet, Cancer Res, 2018). A custom PPGL multi-gene panel for NGS assay for both germline and tumor DNA screening has been developed at HEGP and validated retrospectively and prospectively with 824 DNAs of the collection. This NGS assay was certified by the French Committee for Accreditation (standard EN ISO 15189: 2012) and used in routine practice (Benaim, J Med Genet, 2019). Recently, we demonstrated with a national retrospective multicentre clinical study that the knowledge of the germline SDHx or VHL mutation status at the time of diagnosis has a positive impact in the management and outcome of patients and definitely sustained the US and EU recommendations which stated that all patients with PPGL should benefit from a genetic counselling and a genetic test by NGS (Buffet, J Clin Endocrinol Metab, 2019). The French registry for SDHx-related PPGL (PGL.R), which is managed at HEGP, is currently the support of a clinical study dedicated to test the hypothesis that environmental factors, such as succinate dehydrogenase inhibitors widely used as pesticides, may trigger tumor development in SDHx mutation carriers. PGL.R is also the support of clinical research studies dedicated to establish screening protocols in mutation carriers (Gravel, Eur Radiol, 2016).

Another clinical research program is dedicated to neurofibromatosis type 1 and type 2 (NF1 and NF2), two complex tumor-predisposition disorders showing inter-individual variations in the timing of the clinical manifestations and the severity of features. Thanks to 3 consecutive national funding (PHRC: 2002, 2005, and 2010), a large NF1 cohort (>1,500 NF1 patients) was built in France in collaboration with Pr. Wolkenstein (Paris Est Créteil University). Based on the NF-France cohort analysis, we provided evidence that genetic modifiers, unlinked to the NF1 locus, contributed to NF1 variable expressivity. Taking advantage of the NF France cohort, we are conducting an association study at the genome wide level (E. Pasmant). For each NF1 patient, the phenotype was recorded using a standardized questionnaire (eCRF) and the NF1 genotype was determined using a dedicated NGS panel developed at the Cochin hospital (Pasmant, Eur J Hum Genet, 2015). This GWAS project is carried out in collaboration with the French National Genotyping Center (director: Jean-François Deleuze).

  • Clinical research in oncogenetics of frequent tumors

We developed 2 types of clinical research in frequent tumors: interventional and observational.

We participate to the conception of a trial testing the effect of chemoprevention by low-dose aspirin of new or recurrent colorectal adenomas in patients with Lynch syndrome (AAS Lynch trial) which evaluate the effect of aspirin in Lynch syndrome patients (NCT02813824). The main hypothesis to be tested is that aspirin could decrease colorectal adenoma recurrence evaluated during high quality follow-up by colonic chromo-endoscopy in Lynch syndrome patients. Two hundred eighty-eight patients out of the 850 were included and our center included 29 patients in the first year leading it to the top 3 participating centers.

We recently conducted a study (NCT02570516) comparing two techniques of colonoscopy in Lynch syndrome patients: the indigo carmin chromoendoscopy (ICC) and the narrow-band imaging (NBI), a virtual chromoendoscopy technique. These two technics were compared in a multicenter trial for detecting colonic adenomas in patients with LS.  We were unable to demonstrate the noninferiority assumption of NBI compared with combined NBI and ICC. Although less time consuming, colonoscopy using the third-generation NBI cannot be recommended to replace ICC in patients with LS (Cellier et al.  Am J Gastroenterol2019).

Compared to sporadic colorectal cancer, only very few studies have assessed nutritional habits of patients with Lynch Syndrome, and the influence of these nutritional factors on familial colorectal cancer: except for smoking habits and adiposity, which both seem to increase the risk of colorectal tumors in Lynch syndrome, other lifestyle factors, such as physical activity, alcohol or diet have not or only scarcely been studied. To better inform subjects with Lynch Syndrome on factors that could effectively reduce their risk of developing colorectal cancer, there is a need to closely evaluate their dietary behavior and to understand the role of lifestyle behaviors, especially dietary factors. We invite patients with LS to participate to the The NutriNet-Santé program a web-based cohort launched in 2009 in France with the objective of studying the associations between nutrition and health, as well as the determinants of dietary behaviors and nutritional status. This will allow us to determine which are the dietary behaviors adopted by lynch syndrome patients.

We included all the families and individuals identified with a Lynch syndrome in our institution into the French Observatory for the Lynch Syndrome, OFELy, a national clinical and biological base dedicated to research on Lynch syndrome.

Translational research
  • Translational research in oncogenetics of rare tumors and cancers

The first integrative multi-omics analysis in PPGL has classified this tumor into 5 different molecular entities mainly driven by distinct germline and/or somatic mutations in cancer susceptibility genes. This analysis has revealed the importance of driver mutations in the molecular signature and the biomarkers newly identified have been transferred for routine diagnosis (Castro-Vega, Nat Commun 2015). These data have paved the way towards the establishment of precision medicine strategies for PPGL patients reinforced by set-up a translational research program entitled “The COMETE-network, towards an easy-to use adrenal cancer/tumor identity card” funded by the INCa. New biomarkers able to predict tumor aggressiveness, including lncRNAs (Job, Endocr Rel Cancer, 2019), miR signature (Calsina, Theranostics, 2019) and tumoral SDHB-independent risk factors for malignancy (Job, Clin Can Res, 2019), were validated. All those new biomarkers have demonstrated their prognostic value and are ready to be measured in routine practice. The next step will be to evaluate whether the analysis of tumor biomarkers can be complemented by analyses of liquid biopsies for the diagnosis, prognosis and follow-up of patients.

Main of the tumorigenic effects related to SDHx mutations are linked to the succinate accumulation which acts as an oncometabolite. A method of noninvasive detection of succinate by in vivo 1H-MRS was developed as specific biomarker of SDHx mutation in mouse model of Sdhb-deficient tumours. The sequence was then successively transferred into the radiology department of HEGP to prospectively assess its diagnostic performances of the sequence for the identification of SDH deficiency in PPGL. Sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of 1H-MRS SUCCES were respectively assessed to 87%, 100%, 100%, 90%, and 94% allowing to conclude that detection of succinate using 1H-MRS is a highly specific and sensitive hallmark of SDH-deficiency in PPGL (Lussey-Lepoutre, Eur J Nucl Med Mol Imaging, 2019)

Patients affected by neurofibromatosis type 1 have an increased risk for malignant and non-malignant tumors compared with the general population. Neurofibromas are one of the major clinical features of NF1. They are benign peripheral nerve sheath tumors which consist in a proliferation of Schwann cells showing somatic inactivation of the NF1 WT allele. The malignant transformation of neurofibromas into MPNSTs (Malignant Peripheral Nerve Sheath Tumors) is the leading cause of death in NF1 patients. In 2014, we demonstrated for the first time that PRC2 (Polycomb Repressive Complex 2) played a key role in the development of NF1-associated MPNSTs, in an international collaborative study (De Readt, Nature, 2014). PRC2 is involved in maintaining transcriptional repression. EZH1/2, the catalytic PRC2 components, function as histone methyltransferase that di- and tri-methylates lysine 27 on histone 3. Recently, we investigated whether the absence of EZH2 mutations in MPNST is due to a PRC2 noncanonical function of the enzyme or to redundancy with EZH1. Through genetic and pharmacological analyses, we showed that EZH2 has no PRC2-independent function and we provided evidence that the compensatory function of EZH1 explained the tumor-type specific mutation patterns of PRC2 in MPNSTs (Wassef, Proc Natl Acad Sci U S A, 2019). We now aim to identify vulnerabilities associated with PRC2 mutations with two approaches: chemical and genetic screen.

NF1 somatic alterations are also found in sporadic cancers. Several studies showed that NF1 somatic mutations are found with a frequency at around 5% considering all subtypes of cancers. Lung cancers belong to cancers with frequent NF1 somatic mutations according TCGA data. We confirmed that 18% of lung adenocarcinoma samples harbored NF1 somatic mutations in a cohort of 154 patients from HEGP using targeted NGS. We were also able to establish a genotype-phenotype correlation (Tlemsani Cancer Med2019). This work has been done thanks to a SIRIC CARPEM funding. Following these results, we developed cell models of NF1 mutated using the CRISPR-Cas9 system. We showed that NF1 loss-of-function triggered RAS-MAPK pathway activation. Homozygous NF1 mutated cells seemed to be more aggressive in vitrocompared to heterozygous and wild type mutated cells. In vitro pharmacological screens showed that only homozygous NF1 mutated cells are sensitive to MEK inhibitors. In order to identify synthetic lethal targets in NF1-mutant cells, we aim to carry out a genome-wide genetic screen using the CRISPR/CAS9 technology. Such screens aim at identifying sgRNAs that are lost over time, to infer genes that are essential for survival or proliferation. This will narrow-down a list of potential targets to the most promising candidates. The next steps of this project will be to establish if the model of carcinogenesis and epigenetic alterations we found in MPNST are identical in case of sporadic NF1 mutated tumors in lung cancers but also in other NF1 mutated sporadic cancers.

  • Translational research in oncogenetics of frequent tumors

POLE 3’-5’  exonuclease domain contributes to DNA replication fidelity. Germline missense mutations in POLE exonuclease domain cause polymerase proofreading-associated polyposis (PPAP) syndrome. Defective polymerase proofreading contributes to human malignancy by promoting genomic instability. Highly penetrant germline heterozygous mutations in the proofreading domains of the POLE gene predispose to colorectal cancer and other malignancies. This tumour predisposition condition is now known as polymerase proofreading-associated polyposis syndrome. The germline variant alleles have been shown to reduce proofreading activity and cause a mutator phenotype in yeast. Assessing pathogenicity of POLE missense mutations is a challenge Our ability to predict the phenotypic consequences of a genetic variant in the human genome remains poor. Individual in vitro assays have shown that several cancer-associated pathogenic POLE variants have reduced exonuclease activity and fidelity. As the exonuclease function of POLE is key for replication fidelity, one commonly used assay measures whether expression of a POLE variant can induce hypermutability. Recently using yeast functional assays, we created nine POLE missense variants with directed mutagenesis and showed they were associated with a hypermutator phenotype in yeast fluctuation assays. However, experimental assessments of POLE single variants have been limited in several ways. First, they are typically performed post hoc and have not kept pace with the discovery of VUS. Second, assays expressing variants are laborious and need “one by one” assays. Recent genome editing approaches and next generation sequencing technologies provide a potential means to overcome these challenges but has yet to be applied to characterize any appreciable number of variants in POLE. 

We are developing a functional genomic test in Cochin Hospital to provide a comprehensive analysis of all possible missense mutations in the POLE proofreading domain with saturation genome editing in the cognate yeast gene.

Physicians of the oncogenetic clinics are involved in the formation of students of the French oncogenetics degree (DIU d’oncogénétique). They also took part in the redaction of national recommendations and expertise for the screening and the follow up of patients with genetic predisposition to frequent and rare cancers:

  • National recommendations of the French Genetics Cancer Group – Unicancer on the modalities of multi-gene panel analyses in hereditary predispositions to tumors of the digestive tract (2019);
  • La polypose associée à MUTYH : synthèse et actualisation des recommandations françaises établies en 2012 sous l’égide de l’Institut National du Cancer (INCa) (2020);
  • Expertise INCa MUTYH 2012; PPGL NGS Consensus, Nature Rev Endocrinol, 2017).

Biologists of the oncogenetics laboratory are involved in the formation of students in genetics and oncogenetics. They are implicated in teaching and training at different levels :

  • They participate to the Genetic research initiation course (Parcours d’initiation à la recherche mention Génétique, M1; coordinators: Eric Pasmant and Julie Steffann) of the Université de Paris.
  • They participate in the Genetic Master (M2, UE « Molecular Genetic of Human Diseases ») of Université de Paris and Ecole Universitaire de Recherche Génétique et Epigénétique Nouvelle Ecole (E.U.R. G.E.N.E.).
  • They are involved in the Diplôme Universitaire (DU, university diploma) “NGS-based approaches and applications to genetic diagnosis and therapeutic stratification ” (coordinators: Eric Pasmant and Yves Rozhenholc) and Diplôme Inter-Universitaire de Médecine Moléculaire en Cancérologie Université Paris Sud.

 

With a view to the development of the Genomic France 2025 plan, we would like to offer patients included in this program of exhaustive characterization of the genetic alterations of their tumors a coordinated management of the incident discoveries within this framework.

We plan to develop consultations dedicated to this indication and provide educational information of the patients involved in this program.

We will continue our clinical and translational research efforts in our areas of expertise (rare and frequent tumours) in order to promote the transfer of advances in translational research to the clinic.

Name SurnameTitle/PositionSpecialityResearch UnitResarch Team
Anne-Paule GIMENEZ-ROQUEPLOPrOncogeneticsPARCC UMR970Genetics and metabolism of rare cancers
Eric PASMANTDrMolecular oncogeneticsInstitut CochinGenetics and epigenetics of rare tumors
Pierre LAURENT-PUIGPrOncogeneticsUMRS 1138 Centre de recherche des CordeliersPersonalized medicine, pharmacogenomics, therapeutic optimization
Nadim HAMZAOUIMD PhDMolecular oncogeneticsInstitut CochinGenomics and epigenetics of rare tumors
Virginie VERKARREMD, PhDPathologistPARCC UMR970Genetics and metabolism of rare cancers
Geraldine PERKINSMDGastroenterologistUMRS 1138 Centre de recherche des CordeliersPersonalized medicine, pharmacogenomics, therapeutic optimization
Marion DHOOGEMDGastroenterologistInstitut CochinGenetics and epigenetics of rare tumors
Khadija LAHLOU-LAFORETMDPsychiatrist
Camille TLEMSANIMD, PhDMedical oncologyInstitut CochinGenomics and epigenetics of rare tumors
Nelly BURNICHONPrMolecular OncogeneticsPARCC UMR970Genetics and metabolism of rare cancers
Helène BLONSPrMolecular OncogeneticsUMRS 1138 Centre de recherche des CordeliersPersonalized medicine, pharmacogenomics, therapeutic optimization
Karen LEROYPrOncology (molecular biology)UMRS 1138 Centre de recherche des CordeliersInflammation, complement and cancer
Judith FAVIERPhDResearch directorPARCC UMR970Genetics and metabolism of rare cancers
Audrey LUPO MANSUETMD, PhDPathologistUMRS 1138 Centre de recherche des CordeliersCancer, immune control and escape
Anne-Marie BIROT Genetic counsellor
Isabelle MOLLEY MASSOL Psychologist

The selected following publications highlight the strength of clinical and translational research developed in the oncogenetics program:

Clinical research:
  1. Ben Aim L, Pigny P, Castro-Vega LJ, Buffet A, Amar L, Bertherat J, Drui D, Guilhem I, Baudin E, Lussey-Lepoutre C, Corsini C, Chabrier G, Briet C, Faivre L, Cardot-Bauters C, Favier J, Gimenez-Roqueplo AP, Burnichon N. Targeted next-generation sequencing detects rare genetic events in pheochromocytoma and paraganglioma. J Med Genet. 2019 Aug;56(8):513-520
  2. Gaujoux S, Pasmant E, Silve C, Mehsen-Cetre N, Coriat R, Rouquette A, Dousset B, Prat F, Leroy K. McCune Albright syndrome is a genetic predisposition to intraductal papillary and mucinous neoplasms of the pancreas associated pancreatic cancer in relation with GNAS somatic mutation – a case report. Medicine (Baltimore) 2019;98(50):e18102.
  3. Pacot L, Burin des Roziers C, Laurendeau I, Briand-Suleau A, Coustier A, Mayard T, Tlemsani C, Faivre L, Thomas Q, Rodriguez D, Blesson S, Dollfus H, Muller YG, Parfait B, Vidaud M, Gilbert-Dussardier B, Yardin C, Dauriat B, Derancourt C, Vidaud D, Pasmant E. One NF1 Mutation may Conceal Another. Genes (Basel) 2019;10(9).
  4. Romanet P, Odou MF, North MO, Saveanu A, Coppin L, Pasmant E, Mohamed A, Goudet P, Borson-Chazot F, Calender A, Béroud C, Lévy N, Giraud S, Barlier A; TENGEN group. Proposition of adjustments to the ACMG-AMP framework for the interpretation of MEN1 missense variants. Hum Mutat. 2019;40(6):661-674
  5. Buffet A, Ben Aim L, Leboulleux S, Drui D, Vezzosi D, Libé R, Ajzenberg C, Bernardeschi D, Cariou B, Chabolle F, Chabre O, Darrouzet V, Delemer B, Desailloud R, Goichot B, Esvant A, Offredo L, Herman P, Laboureau S, Lefebvre H, Pierre P, Raingeard I, Reznik Y, Sadoul JL, Hadoux J, Tabarin A, Tauveron I, Zenaty D, Favier J, Bertherat J, Baudin E, Amar L, Gimenez-Roqueplo AP; French Group of Endocrine Tumors (GTE) and COMETE Network. Positive Impact of Genetic Test on the Management and Outcome of Patients With Paraganglioma and/or Pheochromocytoma. J Clin Endocrinol Metab. 2019 Apr 1;104(4):1109-1118
  6. Romanet P, Mohamed A, Giraud S, Odou MF, North MO, Pertuit M, Pasmant E, Coppin L, Guien C, Calender A, Borson-Chazot F, Béroud C, Goudet P, Barlier A. UMD-MEN1 database: an overview of the 370 MEN1 variants present in 1,676 patients from the French population. J Clin Endocrinol Metab. 2019;104(3):753-764
  7. Cellier C, Perrod G, Colas C, Dhooge M, Saurin JC, Lecomte T, Coron E, Rahmi G, Savale C, Chaussade S, Bellanger J, Dray X, Benech N, Le Rhun M, Barbieux JP, Pereira H, Chatellier G, Samaha E. Back-to-Back Comparison of Colonoscopy With Virtual Chromoendoscopy Using a Third-Generation Narrow-Band Imaging System to Chromoendoscopy With Indigo Carmine in Patients With Lynch Syndrome. Am J Gastroenterol. 2019 Oct;114(10):1665-1670.
  8. Tlemsani C, Pasmant E, Boudou-Rouquette P, Bellesoeur A, Even J, Larousserie F, Reyes C, Gentien D, Alexandre J, Vidaud M,Anract P, Leroy K, Goldwasser F. BRCA2 Loss-of-Function and High Sensitivity to Cisplatin-Based Chemotherapy in a Patient With a Pleomorphic Soft Tissue Sarcoma: Effect of Genomic Medicine. Am J Med Sci. 2018;356(4):404-407
  9. Buffet A, Morin A, Castro-Vega LJ, Habarou F, Lussey-Lepoutre C, Letouzé E, Lefebvre H, Guilhem I, Haissaguerre M, Raingeard I, Padilla-Girola M, Tran T, Tchara L, Bertherat J, Amar L, Ottolenghi C, Burnichon N, Gimenez-Roqueplo AP, Favier J. Germline Mutations in the Mitochondrial 2-Oxoglutarate/Malate Carrier SLC25A11 Gene Confer a Predisposition to Metastatic Paragangliomas. Cancer Res. 2018 Apr 15;78(8):1914-1922.
  10. Gravel G, Niccoli P, Rohmer V, Moulin G, Borson-Chazot F, Rousset P, Pasco-Papon A, Marcus C, Dubrulle F, Gouya H, Bidault F, Dupas B, Gabrillargues J, Caumont-Prim A, Hernigou A, Gimenez-Roqueplo AP, Halimi P. The value of a rapid contrast-enhanced angio-MRI protocol in the detection of head and neck paragangliomas in SDHx mutations carriers: a retrospective study on behalf of the PGL.EVA investigators. Eur Radiol. 2016 Jun;26(6):1696-704.
Translational research
  1. Lussey-Lepoutre C, Bellucci A, Burnichon N, Amar L, Buffet A, Drossart T, Fontaine S, Clement O, Benit P, Rustin P, Groussin L, Meatchi T, Gimenez-Roqueplo AP, Tavitian B, Favier J. Succinate detection using in vivo 1H-MR spectroscopy identifies germline and somatic SDHx mutations in paragangliomas. Eur J Nucl Med Mol Imaging. 2019 Dec 13.
  2. Job S, Georges A, Burnichon N, Buffet A, Amar L, Bertherat J, Bouatia-Naji N, de Reyniès A, Drui D, Lussey-Lepoutre C, Favier J, Gimenez-Roqueplo AP, Castro-Vega LJ. Transcriptome analysis of lncRNAs in pheochromocytomas and paragangliomas. J Clin Endocrinol Metab. 2019. Nov 2
  3. Assié G, Jouinot A, Fassnacht M, Libé R, Garinet S, Jacob L, Hamzaoui N, Neou M, Sakat J, de La Villéon B, Perlemoine K, Ragazzon B, Sibony M, Tissier F, Gaujoux S, Dousset B, Sbiera S, Ronchi CL, Kroiss M, Korpershoek E, De Krijger R, Waldmann J, Quinkler M, Haissaguerre M, Tabarin A, Chabre O, Luconi M, Mannelli M, Groussin L, Bertagna X, Baudin E, Amar L, Coste J, Beuschlein F, Bertherat J.Value of Molecular Classification for Prognostic Assessment of Adrenocortical Carcinoma. JAMA Oncol. 2019
  4. Wassef M, Luscan A, Aflaki S, Zielinski D, Jansen PWTC, Baymaz HI, Battistella A, Kersouani C, Servant N, Wallace MR, Romero P, Kosmider O, Just PA, Hivelin M, Jacques S, Vincent-Salomon A, Vermeulen M, Vidaud M, Pasmant E, Margueron R. EZH1/2 function mostly within canonical PRC2 and exhibit proliferation-dependent redundancy that shapes mutational signatures in cancer. Proc Natl Acad Sci U S A 2019;116:6075-6080
  5. Calsina B, Castro-Vega LJ, Torres-Pérez R, Inglada-Pérez L, Currás-Freixes M, Roldán-Romero JM, Mancikova V, Letón R, Remacha L, Santos M, Burnichon N, Lussey-Lepoutre C, Rapizzi E, Graña O, Álvarez-Escolá C, de Cubas AA, Lanillos J, Cordero-Barreal A, Martínez-Montes ÁM, Bellucci A, Amar L, Fernandes-Rosa FL, Calatayud M, Aller J, Lamas C, Sastre-Marcos J, Canu L, Korpershoek E, Timmers HJ, Lenders JW, Beuschlein F, Fassnacht-Capeller M, Eisenhofer G, Mannelli M, Al-Shahrour F, Favier J, Rodríguez-Antona C, Cascón A, Montero-Conde C, Gimenez-Roqueplo AP, Robledo M. Integrative multi-omics analysis identifies a prognostic miRNA signature and a targetable miR-21-3p/TSC2/mTOR axis in metastatic pheochromocytoma/paraganglioma. Theranostics. 2019 Jul 9;9(17):4946-4958.
  6. Job S, Draskovic I, Burnichon N, Buffet A, Cros J, Lépine C, Venisse A, Robidel E, Verkarre V, Meatchi T, Sibony M, Amar L, Bertherat J, de Reyniès A, Londoño-Vallejo A, Favier J, Castro-Vega LJ, Gimenez-Roqueplo AP. Telomerase Activation and ATRX Mutations Are Independent Risk Factors for Metastatic Pheochromocytoma and Paraganglioma. Clin Cancer Res. 2019 Jan 15;25(2):760-770.
  7. Tlemsani C, Pécuchet N, Gruber A, Laurendeau I, Danel C, Riquet M, Le Pimpec-Barthes F, Fabre E, Mansuet-Lupo A, Damotte D, Alifano M, Luscan A, Rousseau B, Vidaud D, Varin J, Parfait B, Bieche I, Leroy K, Laurent-Puig P, Terris B, Blons H, Vidaud M, Pasmant E. NF1 mutations identify molecular and clinical subtypes of lung adenocarcinomas. Cancer Med. 2019;8(9):4330-4337
  8. Tlemsani C, Leroy K, Gimenez-Roqueplo AP, Mansuet-Lupo A, Pasmant E, Larousserie F, Boudou-Rouquette P, Vidaud M, Cadranel J, Blons H, Goldwasser F, Laurent-Puig P. Chemoresistant pleomorphic rhabdomyosarcoma: whole exome sequencing reveals underlying cancer predisposition and therapeutic options. J Med Genet. 2018
  9. Garinet S, Nectoux J, Neou M, Pasmant E, Jouinot A, Sibony M, Orhant L, Pipoli da Fonseca J, Hecale-Perlemoine K, Bricaire L, Groussin L, Soubrane O, Dousset B, Libé R, Letourneur F, Bertherat J, Assié G. Detection and monitoring of circulating tumor DNA in adrenocortical carcinoma. Endocr Relat Cancer. 2018;25(3):L13-L17
  10. Shackleford G, Sampathkumar NK, Hichor M, Weill L, Meffre D, Juricek L, Laurendeau I, Chevallier A, Ortonne N, Larousserie F, Herbin M, Bièche I, Coumoul X, Beraneck M, Baulieu EE, Charbonnier F, Pasmant E, Massaad C. Involvement of Aryl hydrocarbon receptor in myelination and in human nerve sheath tumorigenesis. Proc Natl Acad Sci U S A. 2018;115:E1319-E1328
  11. Louvrier C, Pasmant E, Briand-Suleau A, Cohen J, Nitschké P, Nectoux J, Orhant L, Zordan C, Goizet C, Goutagny S, Lallemand D, Vidaud M, Vidaud D, Kalamarides M, Parfait B. Targeted next-generation sequencing for differential diagnosis of neurofibromatosis type 2, schwannomatosis, and meningiomatosis. Neuro Oncol. 2018;20(7):917-929.
  12. Leclerc J, Flament C, Lovecchio T, Delattre L, Ait Yahya E, Baert-Desurmont S, Burnichon N, Bronner M, Cabaret O, Lejeune S, Guimbaud R, Morin G, Mauillon J, Jonveaux P, Laurent-Puig P, Frébourg T, Porchet N, Buisine MP.Diversity of genetic events associated with MLH1 promoter methylation in Lynch syndrome families with heritable constitutional epimutation. Genet Med. 2018 Dec;20(12):1589-1599.
  13. Garinet S, Néou M, de La Villéon B, Faillot S, Sakat J, Da Fonseca JP, Jouinot A, Le Tourneau C, Kamal M, Luscap-Rondof W, Boeva V, Gaujoux S, Vidaud M, Pasmant E, Letourneur F, Bertherat J, Assié G. Calling Chromosome Alterations, DNA Methylation Statuses, and Mutations in Tumors by Simple Targeted Next-Generation Sequencing: A Solution for Transferring Integrated Pangenomic Studies into Routine Practice? J Mol Diagn. 2017;19:776-787.

Annex 1:  Main indicators of clinical activities

 
Year201620172018
Number of oncogenetic consultations210023532239

Annex 2:  Ongoing Clinical Trials

Sponsor Title Phase NCT number Coordinator/investigator
Effect of Chemoprevention by Low-dose Aspirin of New or Recurrent Colorectal Adenomas in Patients With Lynch Syndrome Etude AAS-Lynch – III NCT02813824 Robert Benhamouzing / Geraldine Perkins
If you are interested by this program and want to candidate to a PhD, post doctoral position, contact the leader
Pr. Anne-Paule Gimenez-Roqueplo

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Carina Binet : Secrétaire Général du CARPEM
Tél. : 01 76 53 43 85 – carina.binet@carpem.fr

Aurore Hattabi, PhD : Coordinatrice Scientifique du CARPEM
Tél : 01 76 53 43 85 – aurore.hattabi@carpem.fr

contact@carpem.fr