The Paris Cancer Institute CARPEM have strong dual routine and research activities in the genomics of solid tumors (mainly endocrine, gastro-intestinal, hepatic, thoracic, gynecological dermatological, urological tumors and sarcomas), and hematological malignancies. Altogether, biologist and pathologist analyzed samples of more than 3000 patients with cancer each years for the main genomic alterations and contributed therefore to a precision care of the patients. They have a strong activity in translational research, and they facilitated the rapid adoption of new tests in daily clinical practices

All these activities are structured around cancer multidisciplinary team meetings both for solid tumors (one in Cochin – Pr. E. Pasmant and one in HEGP – Pr H. Blons) and for hematological malignancies one on lymphoid diseases (Necker – Pr V.Asnafi), one on myeloid malignancies (Cochin – Pr. M. Fontenay) including members of the genomics of tumors program per organ as well as pathologist radiologist. These meetings follow the INCA national guidelines, and ESMO guidelines. These platforms are INCa-labelled since 2008 and somatic testing has been COFRAC-labelled for the subset of tests used in clinical settings.

Bioinformatics is organized around senior researchers (G. Assié, H. Blons, O. Kosmider, P. Laurent-Puig, E. Letouzé) with help of MOABI department in the SeQoia Platform led by Pr. M. Vidaud for whole genome and whole exome sequencing. The SIRIC CARPEM currently support two bioinformaticians to develop new pipelines.

Furthermore, since end of 2014 for solid tumors APHP tumor board was led by P. Laurent-Puig who set-up a program of exome and RNA sequencing for selected patients with colon, lung or rare cancers. This program is the forerunner of the “Tumor Board” France Genomic Medicine 2025 Plan, which set out the indications of whole genome sequencing, whole exome sequencing and RNA-sequencing for patients in therapeutic failure and rare cancers. These National programs are led by P. Laurent-Puig and Anne-Paule Gimenez-Roqueplo respectively. In Onco-hematology, the indications validated by the France genomic Medicine 2025 plan involving patients with acute leukemia in relapse and aggressive lymphomas

Remarkable features of this program:

The teams largely contribute to the molecular classification of their tumor of interest and discovered biomarkers or composite biomarkers for diagnosis and prognosis (Molecular classification of colon, renal, mesothelioma, hepatocellular carcinoma, T-acute lymphoblastic leukemia and myelodysplastic syndromes). They have made major contributions in the genomic field of solid and hematological cancers. They have strong activities in the translational research and the CARPEM research program facilitated the transfer into daily practice. They developed specific methods for detecting circulating tumor DNA in solid tumors by sequencing and implemented this in routine tests for lung and colon cancer.

Physicians, biologists and scientists involved in this program interacted strongly with in-site physicians highly renowned in the diagnosis of solid and hematological. They are involved in numerous national and international programs in their fields of expertise. They are also strongly involved in clinical and translational research of different programs of the SIRIC Carpem. Their activities encompass a wide variety of tumor types which included frequent and rare tumors. This research activity is either part of ancillary research within the framework of therapeutic trials, or of research further upstream, enabling the identification of new biomarkers.It benefits from national and European academic (Europe program H2020, INCA, PHRC, ANR), non-academic charities (ARC, Ligue) and industry funding. In particular, several teams coordinate or participate in major networks of research in France (Plan-cancer, 4 PRT-K programs, …) and in Europe (COMETE, FP7 TRIAGE, MDS-RIGHT, ICGC FR-Liver, Mantle Lymphoma Network).

Clinical Research

• Lung Cancer: D. Damotte, & H. Blons are involved at national level in national clinical research groups mainly in the “Intergroupe Français de Chirurgie Thoracique”-IFCT- with the following clinical trials: TASTE, SHIVA, BioClinALK)
• Gynecological cancers: PA Just, J Alexandre & H Blons are involved at the national level in the “Association de Recherche cancers Gynécologiques” – ARCAGY group and investigators of several clinical trials in gynecaelogical malignancies. The pathology and tumor genomics platforms of Cochin and HEGP have been involved in PAOLA-1 trial now characterize the methylation of BRCA1 and RAD51C and currently leading together with the Centre F Baclesse in Caen the pathology and molecular characterization of endometrial cancers included in UTOLA (NCT03745950).
• Colon Cancer (CC) P.Laurent-Puig & J. Taieb are strongly involved in the different national network of clinical research in digestive cancer (Fédération Francophone de Cancérologie Digestive, GERCOR, PRODIGE groups) they led large national and international cohorts of patient with CC (IDEA NCT00958737 and PETACC08 NCT00265811) and develop program for translational research for the genomic characterization of these tumors, and set-up new ongoing trial based for example on the presence of circulating tumor DNA after surgery in CC patients (CIRCULATE NCT04120701)
• Urothelial cancer H Blons is leading the biological studies of the NEMIO clinical trial (NCT03549715), a phase I/II Neoadjuvant dose-dense MVAC in cOmbination with durvalumab and tremelimumab in muscle-invasive urothelial carcinoma.
• Acute lymphoblastic leukemias (ALL) V Asnafi, L Lhermitte, E Macintyre are involved in clinical trials on ALL (GRAALL-2003 NCT00222027, GRAALL-2005 NCT00327678).
• Myelodysplastic syndromes (MDS) O Kosmider, M Fontenay are conducted the biological studies of clinical trials on MDS treatment by erythropoiesis-stimulating agents (NCT03598582, NCT03223961) or erythropoiesis-maturating agents (LUSPLUS, COMBOLA) within EMSCO associating the German and French cooperative groups, the molecular classification of MDS in FP7-TRIAGE, IWG-PM and the multi-omics classification of MDS in MDS-RIGHT (H2020).

Translational research

Translational research involves 10 teams, 5 of wich are Inserm research teams, located to the PARCC, INEM, Imagine, Institut Cochin and the Cordeliers research centers.

The research teams led by Jérôme Bertherat (IC), Isabelle Cremer (CRC), Anne-Paule Gimenez-Roqueplo (PARCC), Pierre Laurent-Puig (CRC), Eric Pasmant (IC) and J. Zucman-Rossi (CRC) have main translational research fields about the genomics of solid tumors including rare endocrine tumors, lung cancer, sarcoma, paraganglioma, colon cancer, neurofibromatosis, mesothelioma, hepatocarcinoma and renal cancer in order to find prognostic and predictive markers of therapeutic responses.  

J. Zucman-Rossi team by developing whole genome and exome sequencing together with RNAseq, identified several new oncogenes and tumor suppressors genes in human hepatocellular carcinoma (HCC). Translation to diagnostic, prognostic and identification of therapeutic targets is progressively performed for HCC and adenoma (Nault et al, 2017, Rebouissou et al, 2016). This team also contributes to decipher the molecular classification of clear-cell renal cell carcinomas (Verbiest et al, 2019). Furthermore Didier Jean in J Zucman-Rossi’s team has developed a molecular classification of mesothelioma and by using a deconvolution approach, refine the classification by considering the epithelioid-like and sarcomatoid-like components of the tumor (Tranchant et al, 2017; Blum et al, 2019).

AP Gimenez-Roqueplo and J Favier team performed an extensive genetic and genomic characterization of the largest international cohort of Pheochromocytomas and Paragangliomas (PPGL) patients and identified molecular signatures and oncogenic pathways associated with driver mutations (Fishbein et al, 2017 ; Ben Aim et al, 2019). Focusing on succinate dehydrogenase genes (SDH)-mutated tumors has revealed mechanisms explaining the metastatic phenotype. The development of a magnetic resonance spectroscopy imaging method for succinate detection allows exploring tumor masses before surgery (Lussey-Lepoutre et al, 2016).

J Bertherat and G Assié team performed the first integrated genomics study of Adrenocortical tumors (Zheng et al, 2016). Molecular classification revealed 2 major groups of cancers with specific gene expression profiles: one C1B group with good outcome and one C1A group with poor outcome. The C1B group can further be divided into 3 subgroups according to methylation and driver gene status (Jouinot et al, 2017). These results have allowed to develop molecular markers based on targeted methylation assay for ACC prognostication (Assié et al, 2019).

Laurent-Puig and V. Taly team has developed new technologies to characterize circulating tumor DNA (ctDNA), that can change clinical practices: (1) NGS routine test enables to detect alterations as low as 0.1% in plasma (Pécuchet et al, 2016a) (2) Detection of hypermethylation of WIF1 and NPY genes by ddPCR was developed as a universal ctDNA marker in colon cancer (Garrigou et al, 2016). These methods were validated in 3 prospective studies showing that the initial ctDNA concentration and its decrease during treatment is a prognostic marker in pancreatic (Pietrasz et al, 2017), lung (Pécuchet et al, 2016b) and colon cancer (Garlan et al, 2017,).

Finally, at the instigation of SIRIC CARPEM, several collaborative projects between the teams have been set up P Laurent-Puig H. Blons, K. Leroy and E. Pasmant have developed novel panel of genes for diagnosis in clinical setting of non-small cell lung cancer, colon cancer, and sarcoma (Legras et al, 2018; Tlemsani et al, 2018; 2019). In collaboration with I Cremer’s team, H Blons and D. Damotte developed a combined histomolecular algorithm to distinguish multiple primary tumors from metastasis in lung adenocarcinomas (Mansuet-Lupo et al, 2019). A strong interaction between tumor genomics and immunotherapy programs has to be highlighted. D. Damotte and K Leroy established the association of the tumor inflammation signature and clinical benefit of anti-PD1 treatment in a multi-cancer cohort and specifically in NSCLC (Damotte J Transl Med. 2019). A program analyzing the different biomarkers (T resident memory cells, gene expression signature, T-cell clonality) associated with ICI sensitivity is coordinated by Pr Eric Tartour, in collaboration with P Laurent-Puig and I Cremer teams (SIGN’IT grant from ARC 2018). In gynaecological cancers, J Alexandre, PA Just, and K Leroy set-up the molecular classification for prognosis of endometrial cancers based on TCGA datasets and reported the low expression of NRF2 target, NQO1 in TP53-mutated tumors (Beinse et al, 2019).

Three research teams have developed a translational research in the field of the genomics of hematological malignancies.

V Asnafi & E Macintyre (INEM) research team essentially involves analysis of the mechanisms controlling human T lymphoid ontogeny and oncogenic transformation in immature T lymphoid malignancies, particularly T-cell lymphoblastic acute leukemias/lymphomas (Trinquand et al Cancer Discovery 2016, Bond et al JCO 2017, Petit et al Blood 2018, Touzart et al CCR 2019). This allowed identification a molecular « classifier » based on mutational status of NOTCH1/FBXW7/RAS/PTEN, which predicts outcome in T-ALL and is currently used in GRAALL2014 trial for T-ALL stratification treatment. These studies are possible due to close collaboration with the adult (GRAALL and LYSA) and pediatric (SFCE Leukemia and Lymphoma committees) clinical cooperative groups, and European networks.

M Fontenay D Bouscary team is involved in the genomic characterization and pronostication of MDS and acute myeloid leukemias based on national cohorts (Bondu et al, 2019) and in the context of international initiatives for prognostication of genetic alterations in myelodysplastic syndromes: IWG-PM (PI: MSKCC, NYC), FP7 TRIAGE (PI Nijmegen, The Netherlands), MDS-RIGHT/H2020 (PI: Nijmegen, The Netherlands) (Haase et al, 2019). This team also participates in the identification of gene signature and genetic biomarkers of response to treatments (Chesnais et al, 2016; Kerdivel et al, 2018; Mondesir et al, 2019; European program HARMONY, PI G Sanz, Spain).

Hermine team has main a translational research program dedicated to the genomic characterization and monitoring of virus-induced lymphoproliferative disorders (Kataoka et al, 2019; Marcais et al, 2016; Artesi et al, 2017; Sarkozy et al, 2017).

These research areas are developed in the program 1 and 2 of the SIRIC CARPEM.

COMING SOON

Interactions between medical tumor boards and research team meetings allow bidirectional translational research for care to research and from research to care. Interactions with the SeQOIA platform will facilitate the integration of whole genome, whole exome and RNA-sequencing package to patient care in specific indications including acute lymphoid and myeloid leukemia at high risk of relapse, aggressive lymphomas and patients with solid tumor of less than 40 years old in therapeutic failure. The Paris Cancer Institute: CARPEM will help the translation of discoveries to the clinics and reinforce the integration of immune microenvironment analyses into composite biomarkers for the diagnosis, prognosis and prediction of response to treatments.

The selected following publications highlighted the strength clinical and translational research developed in genomics of tumors program:

1. 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 Jul 11. doi: 10.1001/jamaoncol.2019.1558

2. 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.

3. Biton J, Mansuet-Lupo A, Pécuchet N, Alifano M, Ouakrim H, Arrondeau J, Boudou-Rouquette P, Goldwasser F, Leroy K, Goc J, Wislez M, Germain C, Laurent-Puig P, Dieu-Nosjean MC, Cremer I, Herbst R, Blons H, Damotte D.TP53, STK11, and EGFR Mutations Predict Tumor Immune Profile and the Response to Anti-PD-1 in Lung Adenocarcinoma. Clin Cancer Res. 2018 Nov 15;24(22):5710-5723

4. Blum Y, Meiller C, Quetel L, Elarouci N, Ayadi M, Tashtanbaeva D, Armenoult L, Montagne F, Tranchant R, Renier A, de Koning L, Copin MC, Hofman P, Hofman V, Porte H, Le Pimpec-Barthes F, Zucman-Rossi J, Jaurand MC, de Reyniès A, Jean D. Dissecting heterogeneity in malignant pleural mesothelioma through histo-molecular gradients for clinical applications. Nat Commun. 2019 Mar 22;10(1):1333.

5. Bond J, Graux C, Lhermitte L, Lara D, Cluzeau T, Leguay T, Cieslak A, Trinquand A, Pastoret C, Belhocine M, Spicuglia S, Lheritier V, Leprêtre S, Thomas X, Huguet F, Ifrah N, Dombret H, Macintyre E, Boissel N, Asnafi V. Early Response-Based Therapy Stratification Improves Survival in Adult Early Thymic Precursor Acute Lymphoblastic Leukemia: A Group for Research on Adult Acute Lymphoblastic Leukemia Study. J Clin Oncol. 2017 Aug 10;35(23):2683-2691.

6. Bondu S, Alary AS, Lefèvre C, Houy A, Jung G, Lefebvre T, Rombaut D, Boussaid I, Bousta A, Guillonneau F, Perrier P, Alsafadi S, Wassef M, Margueron R, Rousseau A, Droin N, Cagnard N, Kaltenbach S, Winter S, Kubasch AS, Bouscary D, Santini V, Toma A, Hunault M, Stamatoullas A, Gyan E, Cluzeau T, Platzbecker U, Adès L, Puy H, Stern MH, Karim Z, Mayeux P, Nemeth E, Park S, Ganz T, Kautz L, Kosmider O, Fontenay M. A variant erythroferrone disrupts iron homeostasis in SF3B1-mutated myelodysplastic syndrome. Sci Transl Med. 2019 Jul 10;11(500). pii: eaav5467.

7. 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.

8. Garlan F, Laurent-Puig P, Sefrioui D, Siauve N, Didelot A, Sarafan-Vasseur N, Michel P, Perkins G, Mulot C, Blons H, Taieb J, Di Fiore F, Taly V, Zaanan A. Early Evaluation of Circulating Tumor DNA as Marker of Therapeutic Efficacy in Metastatic Colorectal Cancer Patients (PLACOL Study). Clin Cancer Res. 2017 Sep 15;23(18):5416-5425.

9. Garrigou S, Perkins G, Garlan F, Normand C, Didelot A, Le Corre D, Peyvandi S, Mulot C, Niarra R, Aucouturier P, Chatellier G, Nizard P, Perez-Toralla K, Zonta E, Charpy C, Pujals A, Barau C, Bouché O, Emile JF, Pezet D, Bibeau F, Hutchison JB, Link DR, Zaanan A, Laurent-Puig P, Sobhani I, Taly V. A Study of Hypermethylated Circulating Tumor DNA as a Universal Colorectal Cancer Biomarker. Clin Chem. 2016 Aug;62(8):1129-39.

10. Kataoka K, Miyoshi H, Sakata S, Dobashi A, Couronné L, Kogure Y, Sato Y, Nishida K, Gion Y, Shiraishi Y, Tanaka H, Chiba K, Watatani Y, Kakiuchi N, Shiozawa Y, Yoshizato T, Yoshida K, Makishima H, Sanada M, Onozawa M, Teshima T, Yoshiki Y, Ishida T, Suzuki K, Shimada K, Tomita A, Kato M, Ota Y, Izutsu K, Demachi-Okamura A, Akatsuka Y, Miyano S, Yoshino T, Gaulard P, Hermine O, Takeuchi K, Ohshima K, Ogawa S. Frequent structural variations involving programmed death ligands in Epstein-Barr virus-associated lymphomas. 2019 Jul;33(7):1687-1699.

11. Letouzé E, Shinde J, Renault V, Couchy G, Blanc JF, Tubacher E, Bayard Q, Bacq D, Meyer V, Semhoun J, Bioulac-Sage P, Prévôt S, Azoulay D, Paradis V, Imbeaud S, Deleuze JF, Zucman-Rossi J. Mutational signatures reveal the dynamic interplay of risk factors and cellular processes during liver tumorigenesis. Nat Commun. 2017 Nov 3;8(1):1315.

12. Pécuchet N, Zonta E, Didelot A, Combe P, Thibault C, Gibault L, Lours C, Rozenholc Y, Taly V, Laurent-Puig P, Blons H, Fabre E. Base-Position Error Rate Analysis of Next-Generation Sequencing Applied to Circulating Tumor DNA in Non-Small Cell Lung Cancer: A Prospective Study. PLoS Med. 2016b Dec 27;13(12):e1002199.

13. Pietrasz D, Pécuchet N, Garlan F, Didelot A, Dubreuil O, Doat S, Imbert-Bismut F, Karoui M, Vaillant JC, Taly V, Laurent-Puig P, Bachet JB. Plasma Circulating Tumor DNA in Pancreatic Cancer Patients Is a Prognostic Marker. Clin Cancer Res. 2017 Jan 1;23(1):116-123.

14. Taieb J, Zaanan A, Le Malicot K, Julié C, Blons H, Mineur L, Bennouna J, Tabernero J, Mini E, Folprecht G, Van Laethem JL, Lepage C, Emile JF, Laurent-Puig P. Prognostic Effect of BRAF and KRAS Mutations in Patients With Stage III Colon Cancer Treated With Leucovorin, Fluorouracil, and Oxaliplatin With or Without Cetuximab: A Post Hoc Analysis of the PETACC-8 Trial.JAMA Oncol. 2016 May 1;2(5):643-653.

Annex 1:  Main indicators of translational research

Annex 2:  Ongoing Translational Research

Annex 3:  Ongoing Clinical  Trials

If you are interested by this program and want to candidate to a PhD, post doctoral position, contact the leader

Pr. Michaela Fontenay