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Article ; Online: A SPRY1 domain cardiac ryanodine receptor variant associated with short-coupled torsade de pointes.

Touat-Hamici, Zahia / Blancard, Malorie / Ma, Ruifang / Lin, Lianyun / Iddir, Yasmine / Denjoy, Isabelle / Leenhardt, Antoine / Yuchi, Zhiguang / Guicheney, Pascale

Scientific reports

2021 Volume 11, Issue 1, Page(s) 5243

Abstract: Idiopathic ventricular fibrillation (IVF) causes sudden death in young adult patients without structural or ischemic heart disease. Most IVF cases are sporadic and some patients present with short-coupled torsade de pointes, the genetics of which are ... ...

Abstract	Idiopathic ventricular fibrillation (IVF) causes sudden death in young adult patients without structural or ischemic heart disease. Most IVF cases are sporadic and some patients present with short-coupled torsade de pointes, the genetics of which are poorly understood. A man who had a first syncope at the age of 35 presented with frequent short-coupled premature ventricular beats with bursts of polymorphic ventricular tachycardia and then died suddenly. By exome sequencing, we identified three rare variants: p.I784F in the SPRY1 of the ryanodine receptor 2 (RyR2), p.A96S in connexin 40 (Cx40), reported to affect electrical coupling and cardiac conduction, and a nonsense p.R244X in the cardiac-specific troponin I-interacting kinase (TNNI3K). We assessed intracellular Ca
MeSH term(s)	Adult ; Aged ; Aged, 80 and over ; Calcium Signaling/genetics ; Connexins/genetics ; Death, Sudden/epidemiology ; Female ; HEK293 Cells ; Humans ; Male ; Membrane Proteins/genetics ; Middle Aged ; Myocardial Ischemia/genetics ; Myocardial Ischemia/pathology ; Phosphoproteins/genetics ; Protein Domains/genetics ; Protein Serine-Threonine Kinases/genetics ; Ryanodine Receptor Calcium Release Channel/genetics ; Torsades de Pointes/complications ; Torsades de Pointes/genetics ; Torsades de Pointes/pathology ; Ventricular Fibrillation/genetics ; Ventricular Fibrillation/pathology ; Exome Sequencing ; Gap Junction alpha-5 Protein
Chemical Substances	Connexins ; Membrane Proteins ; Phosphoproteins ; RyR2 protein, human ; Ryanodine Receptor Calcium Release Channel ; SPRY1 protein, human ; Protein Serine-Threonine Kinases (EC 2.7.11.1) ; TNNI3K protein, human (EC 2.7.11.1)
Language	English
Publishing date	2021-03-04
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/s41598-021-84373-9
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Article: Cell-Free DNA Extracted from CSF for the Molecular Diagnosis of Pediatric Embryonal Brain Tumors.

Chicard, Mathieu / Iddir, Yasmine / Masliah Planchon, Julien / Combaret, Valérie / Attignon, Valéry / Saint-Charles, Alexandra / Frappaz, Didier / Faure-Conter, Cécile / Beccaria, Kévin / Varlet, Pascale / Geoerger, Birgit / Baulande, Sylvain / Pierron, Gaelle / Bouchoucha, Yassine / Doz, François / Delattre, Olivier / Waterfall, Joshua J / Bourdeaut, Franck / Schleiermacher, Gudrun

Cancers

2023 Volume 15, Issue 13

Abstract: Background: Liquid biopsies are revolutionary tools used to detect tumor-specific genetic alterations in body fluids, including the use of cell-free DNA (cfDNA) for molecular diagnosis in cancer patients. In brain tumors, cerebrospinal fluid (CSF) cfDNA ...

Abstract	Background: Liquid biopsies are revolutionary tools used to detect tumor-specific genetic alterations in body fluids, including the use of cell-free DNA (cfDNA) for molecular diagnosis in cancer patients. In brain tumors, cerebrospinal fluid (CSF) cfDNA might be more informative than plasma cfDNA. Here, we assess the use of CSF cfDNA in pediatric embryonal brain tumors (EBT) for molecular diagnosis. Methods: The CSF cfDNA of pediatric patients with medulloblastoma ( Results: 15/25 CSF cfDNA samples yielded informative results, with informative CNA and SNVs in 11 and 15 cases, respectively. For cases with paired tumor and CSF cfDNA WES ( Conclusion: CSF cfDNA sequencing yielded informative results in 60% (15/25) of all cases, with informative results in 83% (15/18) of all cases analyzed by WES. These results pave the way for the implementation of these novel approaches for molecular diagnosis and minimal residual disease monitoring.
Language	English
Publishing date	2023-07-07
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2527080-1
ISSN	2072-6694
ISSN	2072-6694
DOI	10.3390/cancers15133532
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Article ; Online: Cell-Free DNA as a Diagnostic and Prognostic Biomarker in Pediatric Rhabdomyosarcoma.

Lak, Nathalie S M / van Zogchel, Lieke M J / Zappeij-Kannegieter, Lily / Javadi, Ahmad / van Paemel, Ruben / Vandeputte, Charlotte / De Preter, Katleen / De Wilde, Bram / Chicard, Mathieu / Iddir, Yasmine / Schleiermacher, Gudrun / Ruhen, Olivia / Shipley, Janet / Fiocco, Marta / Merks, Johannes H M / van Noesel, Max M / van der Schoot, C Ellen / Tytgat, Godelieve A M / Stutterheim, Janine

JCO precision oncology

2023 Volume 7, Page(s) e2200113

Abstract: Purpose: Total cell-free DNA (cfDNA) and tumor-derived cfDNA (ctDNA) can be used to study tumor-derived genetic aberrations. We analyzed the diagnostic and prognostic potential of cfDNA and ctDNA, obtained from pediatric patients with rhabdomyosarcoma.!# ...

Abstract	Purpose: Total cell-free DNA (cfDNA) and tumor-derived cfDNA (ctDNA) can be used to study tumor-derived genetic aberrations. We analyzed the diagnostic and prognostic potential of cfDNA and ctDNA, obtained from pediatric patients with rhabdomyosarcoma. Methods: cfDNA was isolated from diagnostic plasma samples from 57 patients enrolled in the EpSSG RMS2005 study. To study the diagnostic potential, shallow whole genome sequencing (shWGS) and cell-free reduced representation bisulphite sequencing (cfRRBS) were performed in a subset of samples and all samples were tested using droplet digital polymerase chain reaction to detect methylated Results: At diagnosis, ctDNA was detected in 16 of 30 and 24 of 26 patients using shallow whole genome sequencing and cfRRBS, respectively. Furthermore, 21 of 25 samples were correctly classified as embryonal by cfRRBS. Conclusion: Analyzing ctDNA at diagnosis using various techniques is feasible in pediatric rhabdomyosarcoma and has potential for clinical use. Measuring
MeSH term(s)	Humans ; Child ; Cell-Free Nucleic Acids/genetics ; Prognosis ; Rhabdomyosarcoma/diagnosis ; Rhabdomyosarcoma/genetics ; RNA ; Biomarkers
Chemical Substances	Cell-Free Nucleic Acids ; RNA (63231-63-0) ; Biomarkers
Language	English
Publishing date	2023-01-18
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	2473-4284
ISSN (online)	2473-4284
DOI	10.1200/PO.22.00113
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Article ; Online: Molecular Characterization of Circulating Tumor DNA in Pediatric Rhabdomyosarcoma: A Feasibility Study.

Ruhen, Olivia / Lak, Nathalie S M / Stutterheim, Janine / Danielli, Sara G / Chicard, Mathieu / Iddir, Yasmine / Saint-Charles, Alexandra / Di Paolo, Virginia / Tombolan, Lucia / Gatz, Susanne A / Aladowicz, Ewa / Proszek, Paula / Jamal, Sabri / Stankunaite, Reda / Hughes, Deborah / Carter, Paul / Izquierdo, Elisa / Wasti, Ajla / Chisholm, Julia C /

George, Sally L / Pace, Erika / Chesler, Louis / Aerts, Isabelle / Pierron, Gaelle / Zaidi, Sakina / Delattre, Olivier / Surdez, Didier / Kelsey, Anna / Hubank, Michael / Bonvini, Paolo / Bisogno, Gianni / Di Giannatale, Angela / Schleiermacher, Gudrun / Schäfer, Beat W / Tytgat, Godelieve A M / Shipley, Janet

JCO precision oncology

2022 Volume 6, Page(s) e2100534

Abstract: Purpose: Rhabdomyosarcomas (RMS) are rare neoplasms affecting children and young adults. Efforts to improve patient survival have been undermined by a lack of suitable disease markers. Plasma circulating tumor DNA (ctDNA) has shown promise as a ... ...

Abstract	Purpose: Rhabdomyosarcomas (RMS) are rare neoplasms affecting children and young adults. Efforts to improve patient survival have been undermined by a lack of suitable disease markers. Plasma circulating tumor DNA (ctDNA) has shown promise as a potential minimally invasive biomarker and monitoring tool in other cancers; however, it remains underexplored in RMS. We aimed to determine the feasibility of identifying and quantifying ctDNA in plasma as a marker of disease burden and/or treatment response using blood samples from RMS mouse models and patients. Methods: We established mouse models of RMS and applied quantitative polymerase chain reaction (PCR) and droplet digital PCR (ddPCR) to detect ctDNA within the mouse plasma. Potential driver mutations, copy-number alterations, and DNA breakpoints associated with Results: Human tumor-derived DNA was detectable in plasma samples from mouse models of RMS and correlated with tumor burden. In patients, ctDNA was detected in 14/18 pretreatment plasma samples with ddPCR and 7/7 cases assessed by sequencing. Levels of ctDNA at diagnosis were significantly higher in patients with unfavorable tumor sites, positive nodal status, and metastasis. In patients with serial plasma samples (n = 18), fluctuations in ctDNA levels corresponded to treatment response. Conclusion: Comprehensive ctDNA analysis combining high sensitivity and throughput can identify key molecular drivers in RMS models and patients, suggesting potential as a minimally invasive biomarker. Preclinical assessment of treatments using mouse models and further patient testing through prospective clinical trials are now warranted.
MeSH term(s)	Humans ; Child ; Mice ; Animals ; Circulating Tumor DNA/genetics ; Feasibility Studies ; Prospective Studies ; Biomarkers, Tumor/genetics ; Mutation ; Neoplasms ; Rhabdomyosarcoma, Embryonal
Chemical Substances	Circulating Tumor DNA ; Biomarkers, Tumor
Language	English
Publishing date	2022-10-20
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	2473-4284
ISSN (online)	2473-4284
DOI	10.1200/PO.21.00534
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Article ; Online: The European MAPPYACTS Trial: Precision Medicine Program in Pediatric and Adolescent Patients with Recurrent Malignancies.

Berlanga, Pablo / Pierron, Gaelle / Lacroix, Ludovic / Chicard, Mathieu / Adam de Beaumais, Tiphaine / Marchais, Antonin / Harttrampf, Anne C / Iddir, Yasmine / Larive, Alicia / Soriano Fernandez, Aroa / Hezam, Imene / Chevassus, Cecile / Bernard, Virginie / Cotteret, Sophie / Scoazec, Jean-Yves / Gauthier, Arnaud / Abbou, Samuel / Corradini, Nadege / André, Nicolas /

Aerts, Isabelle / Thebaud, Estelle / Casanova, Michela / Owens, Cormac / Hladun-Alvaro, Raquel / Michiels, Stefan / Delattre, Olivier / Vassal, Gilles / Schleiermacher, Gudrun / Geoerger, Birgit

Cancer discovery

2022 Volume 12, Issue 5, Page(s) 1266–1281

Abstract: Abstract: MAPPYACTS (NCT02613962) is an international prospective precision medicine trial aiming to define tumor molecular profiles in pediatric patients with recurrent/refractory malignancies in order to suggest the most adapted salvage treatment. ... ...

Abstract	Abstract: MAPPYACTS (NCT02613962) is an international prospective precision medicine trial aiming to define tumor molecular profiles in pediatric patients with recurrent/refractory malignancies in order to suggest the most adapted salvage treatment. From February 2016 to July 2020, 787 patients were included in France, Italy, Ireland, and Spain. At least one genetic alteration leading to a targeted treatment suggestion was identified in 436 patients (69%) with successful sequencing; 10% of these alterations were considered "ready for routine use." Of 356 patients with follow-up beyond 12 months, 107 (30%) received one or more matched targeted therapies-56% of them within early clinical trials-mainly in the AcSé-ESMART platform trial (NCT02813135). Overall, matched treatment resulted in a 17% objective response rate, and of those patients with ready for routine use alterations, it was 38%. In patients with extracerebral tumors, 76% of actionable alterations detected in tumor tissue were also identified in circulating cell-free DNA (cfDNA). Significance: MAPPYACTS underlines the feasibility of molecular profiling at cancer recurrence in children on a multicenter, international level and demonstrates benefit for patients with selected key drivers. The use of cfDNA deserves validation in prospective studies. Our study highlights the need for innovative therapeutic proof-of-concept trials that address the underlying cancer complexity. This article is highlighted in the In This Issue feature, p. 1171.
MeSH term(s)	Adolescent ; Biomarkers, Tumor/genetics ; Carcinoma ; Cell-Free Nucleic Acids ; Child ; High-Throughput Nucleotide Sequencing/methods ; Humans ; Mutation ; Neoplasm Recurrence, Local/drug therapy ; Neoplasm Recurrence, Local/genetics ; Precision Medicine/methods ; Prospective Studies
Chemical Substances	Biomarkers, Tumor ; Cell-Free Nucleic Acids
Language	English
Publishing date	2022-03-12
Publishing country	United States
Document type	Journal Article ; Multicenter Study ; Research Support, Non-U.S. Gov't
ZDB-ID	2625242-9
ISSN	2159-8290 ; 2159-8274
ISSN (online)	2159-8290
ISSN	2159-8274
DOI	10.1158/2159-8290.CD-21-1136
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Article ; Online: Combination Therapies Targeting ALK-aberrant Neuroblastoma in Preclinical Models.

Tucker, Elizabeth R / Jiménez, Irene / Chen, Lindi / Bellini, Angela / Gorrini, Chiara / Calton, Elizabeth / Gao, Qiong / Che, Harvey / Poon, Evon / Jamin, Yann / Martins Da Costa, Barbara / Barker, Karen / Shrestha, Sumana / Hutchinson, J Ciaran / Dhariwal, Simran / Goodman, Angharad / Del Nery, Elaine / Gestraud, Pierre / Bhalshankar, Jaydutt /

Iddir, Yasmine / Saberi-Ansari, Elnaz / Saint-Charles, Alexandra / Geoerger, Birgit / Marques Da Costa, Maria Eugénia / Pierre-Eugène, Cécile / Janoueix-Lerosey, Isabelle / Decaudin, Didier / Nemati, Fariba / Carcaboso, Angel M / Surdez, Didier / Delattre, Olivier / George, Sally L / Chesler, Louis / Tweddle, Deborah A / Schleiermacher, Gudrun

Clinical cancer research : an official journal of the American Association for Cancer Research

2023 Volume 29, Issue 7, Page(s) 1317–1331

Abstract: Purpose: ALK-activating mutations are identified in approximately 10% of newly diagnosed neuroblastomas and ALK amplifications in a further 1%-2% of cases. Lorlatinib, a third-generation anaplastic lymphoma kinase (ALK) inhibitor, will soon be given ... ...

Abstract	Purpose: ALK-activating mutations are identified in approximately 10% of newly diagnosed neuroblastomas and ALK amplifications in a further 1%-2% of cases. Lorlatinib, a third-generation anaplastic lymphoma kinase (ALK) inhibitor, will soon be given alongside induction chemotherapy for children with ALK-aberrant neuroblastoma. However, resistance to single-agent treatment has been reported and therapies that improve the response duration are urgently required. We studied the preclinical combination of lorlatinib with chemotherapy, or with the MDM2 inhibitor, idasanutlin, as recent data have suggested that ALK inhibitor resistance can be overcome through activation of the p53-MDM2 pathway. Experimental design: We compared different ALK inhibitors in preclinical models prior to evaluating lorlatinib in combination with chemotherapy or idasanutlin. We developed a triple chemotherapy (CAV: cyclophosphamide, doxorubicin, and vincristine) in vivo dosing schedule and applied this to both neuroblastoma genetically engineered mouse models (GEMM) and patient-derived xenografts (PDX). Results: Lorlatinib in combination with chemotherapy was synergistic in immunocompetent neuroblastoma GEMM. Significant growth inhibition in response to lorlatinib was only observed in the ALK-amplified PDX model with high ALK expression. In this PDX, lorlatinib combined with idasanutlin resulted in complete tumor regression and significantly delayed tumor regrowth. Conclusions: In our preclinical neuroblastoma models, high ALK expression was associated with lorlatinib response alone or in combination with either chemotherapy or idasanutlin. The synergy between MDM2 and ALK inhibition warrants further evaluation of this combination as a potential clinical approach for children with neuroblastoma.
MeSH term(s)	Mice ; Animals ; Humans ; Anaplastic Lymphoma Kinase/genetics ; Aminopyridines/therapeutic use ; Lactams, Macrocyclic/pharmacology ; Lactams, Macrocyclic/therapeutic use ; Neuroblastoma/drug therapy ; Neuroblastoma/genetics ; Neuroblastoma/metabolism ; Protein Kinase Inhibitors/pharmacology ; Protein Kinase Inhibitors/therapeutic use ; Lung Neoplasms/drug therapy
Chemical Substances	lorlatinib (OSP71S83EU) ; RG7388 ; Anaplastic Lymphoma Kinase (EC 2.7.10.1) ; Aminopyridines ; Lactams, Macrocyclic ; Protein Kinase Inhibitors
Language	English
Publishing date	2023-01-15
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1225457-5
ISSN	1557-3265 ; 1078-0432
ISSN (online)	1557-3265
ISSN	1078-0432
DOI	10.1158/1078-0432.CCR-22-2274
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Article ; Online: The feasibility of using liquid biopsies as a complementary assay for copy number aberration profiling in routinely collected paediatric cancer patient samples.

Van Paemel, Ruben / Vandeputte, Charlotte / Raman, Lennart / Van Thorre, Jolien / Willems, Leen / Van Dorpe, Jo / Van Der Linden, Malaïka / De Wilde, Jilke / De Koker, Andries / Menten, Björn / Devalck, Christine / Vicha, Ales / Grega, Marek / Schleiermacher, Gudrun / Iddir, Yasmine / Chicard, Mathieu / van Zogchel, Lieke / Stutterheim, Janine / Lak, Nathalie S M /

Tytgat, G A M / Laureys, Geneviève / Speleman, Frank / De Wilde, Bram / Lammens, Tim / De Preter, Katleen / Van Roy, Nadine

European journal of cancer (Oxford, England : 1990)

2021 Volume 160, Page(s) 12–23

Abstract: Background: Paediatric tumours are often characterised by the presence of recurrent DNA copy number alterations (CNAs). These DNA copy number profiles, obtained from a tissue biopsy, can aid in the correct prognostic classification and therapeutic ... ...

Abstract	Background: Paediatric tumours are often characterised by the presence of recurrent DNA copy number alterations (CNAs). These DNA copy number profiles, obtained from a tissue biopsy, can aid in the correct prognostic classification and therapeutic stratification of several paediatric cancer entities (e.g. MYCN amplification in neuroblastoma) and are part of the routine diagnostic practice. Liquid biopsies (LQBs) offer a potentially safer alternative for such invasive tumour tissue biopsies and can provide deeper insight into tumour heterogeneity. Procedure: The robustness and reliability of LQB CNA analyses was evaluated. We performed retrospective CNA profiling using shallow whole-genome sequencing (sWGS) on paired plasma circulating cell-free DNA (cfDNA) and tissue DNA samples from routinely collected samples from paediatric patients (n = 128) representing different tumour entities, including osteosarcoma, Ewing sarcoma, rhabdomyosarcoma, Wilms tumour, brain tumours and neuroblastoma. Results: Overall, we observed a good concordance between CNAs in tissue DNA and cfDNA. The main cause of CNA discordance was found to be low cfDNA sample quality (i.e. the ratio of cfDNA (<700 bp) and high molecular weight DNA (>700 bp)). Furthermore, CNAs were observed that were present in cfDNA and not in tissue DNA, or vice-versa. In neuroblastoma samples, no false-positives or false-negatives were identified for the detection of the prognostic marker MYCN amplification. Conclusion: In future prospective studies, CNA analysis on LQBs that are of sufficient quality can serve as a complementary assay for CNA analysis on tissue biopsies, as either cfDNA or tissue DNA can contain CNAs that cannot be identified in the other biomaterial.
MeSH term(s)	Adolescent ; Biomarkers, Tumor/genetics ; Cell-Free Nucleic Acids/genetics ; Child ; Child, Preschool ; DNA Copy Number Variations/genetics ; Feasibility Studies ; Female ; Humans ; Liquid Biopsy/methods ; Male ; Prospective Studies ; Retrospective Studies
Chemical Substances	Biomarkers, Tumor ; Cell-Free Nucleic Acids
Language	English
Publishing date	2021-11-16
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	82061-1
ISSN	1879-0852 ; 0277-5379 ; 0959-8049 ; 0964-1947
ISSN (online)	1879-0852
ISSN	0277-5379 ; 0959-8049 ; 0964-1947
DOI	10.1016/j.ejca.2021.09.022
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Article ; Online: A SPRY1 domain cardiac ryanodine receptor variant associated with short-coupled torsade de pointes.

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Article: Cell-Free DNA Extracted from CSF for the Molecular Diagnosis of Pediatric Embryonal Brain Tumors.

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Article ; Online: Cell-Free DNA as a Diagnostic and Prognostic Biomarker in Pediatric Rhabdomyosarcoma.

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Article ; Online: Molecular Characterization of Circulating Tumor DNA in Pediatric Rhabdomyosarcoma: A Feasibility Study.

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Article ; Online: The European MAPPYACTS Trial: Precision Medicine Program in Pediatric and Adolescent Patients with Recurrent Malignancies.

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Article ; Online: Combination Therapies Targeting ALK-aberrant Neuroblastoma in Preclinical Models.

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Article ; Online: The feasibility of using liquid biopsies as a complementary assay for copy number aberration profiling in routinely collected paediatric cancer patient samples.

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