Génétique et biologie des tumeurs pédiatriques

Publications de l’équipe

Année de publication : 2018

Mitchell J Machiela, Thomas G P Grünewald, Didier Surdez, Stephanie Reynaud, Olivier Mirabeau, Eric Karlins, Rebeca Alba Rubio, Sakina Zaidi, Sandrine Grossetete-Lalami, Stelly Ballet, Eve Lapouble, Valérie Laurence, Jean Michon, Gaelle Pierron, Heinrich Kovar, Nathalie Gaspar, Udo Kontny, Anna González-Neira, Piero Picci, Javier Alonso, Ana Patino-Garcia, Nadège Corradini, Perrine Marec Bérard, Neal D Freedman, Nathaniel Rothman, Casey L Dagnall, Laurie Burdett, Kristine Jones, Michelle Manning, Kathleen Wyatt, Weiyin Zhou, Meredith Yeager, David G Cox, Robert N Hoover, Javed Khan, Gregory T Armstrong, Wendy M Leisenring, Smita Bhatia, Leslie L Robison, Andreas E Kulozik, Jennifer Kriebel, Thomas Meitinger, Markus Metzler, Wolfgang Hartmann, Konstantin Strauch, Thomas Kirchner, Uta Dirksen, Lindsay M Morton, Lisa Mirabello, Margaret A Tucker, Franck Tirode, Stephen J Chanock, Olivier Delattre (2018 Aug 11)

Genome-wide association study identifies multiple new loci associated with Ewing sarcoma susceptibility.

Nature communications : 3184 : DOI : 10.1038/s41467-018-05537-2 En savoir plus

Ewing sarcoma (EWS) is a pediatric cancer characterized by the EWSR1-FLI1 fusion. We performed a genome-wide association study of 733 EWS cases and 1346 unaffected individuals of European ancestry. Our study replicates previously reported susceptibility loci at 1p36.22, 10q21.3 and 15q15.1, and identifies new loci at 6p25.1, 20p11.22 and 20p11.23. Effect estimates exhibit odds ratios in excess of 1.7, which is high for cancer GWAS, and striking in light of the rarity of EWS cases in familial cancer syndromes. Expression quantitative trait locus (eQTL) analyses identify candidate genes at 6p25.1 (RREB1) and 20p11.23 (KIZ). The 20p11.22 locus is near NKX2-2, a highly overexpressed gene in EWS. Interestingly, most loci reside near GGAA repeat sequences and may disrupt binding of the EWSR1-FLI1 fusion protein. The high locus to case discovery ratio from 733 EWS cases suggests a genetic architecture in which moderate risk SNPs constitute a significant fraction of risk.

Kathleen I Pishas, Christina D Drenberg, Cenny Taslim, Emily R Theisen, Kirsten M Johnson, Ranajeet S Saund, Ioana L Pop, Brian D Crompton, Elizabeth R Lawlor, Franck Tirode, Jaume Mora, Olivier Delattre, Mary C Beckerle, David F Callen, Sunil Sharma, Stephen L Lessnick (2018 Jul 13)

Therapeutic Targeting of KDM1A/LSD1 in Ewing Sarcoma with SP-2509 Engages the Endoplasmic Reticulum Stress Response.

Molecular cancer therapeutics : 1902-1916 : DOI : 10.1158/1535-7163.MCT-18-0373 En savoir plus

Multi-agent chemotherapeutic regimes remain the cornerstone treatment for Ewing sarcoma, the second most common bone malignancy diagnosed in pediatric and young adolescent populations. We have reached a therapeutic ceiling with conventional cytotoxic agents, highlighting the need to adopt novel approaches that specifically target the drivers of Ewing sarcoma oncogenesis. As KDM1A/ysine-pecific emethylase 1 (LSD1) is highly expressed in Ewing sarcoma cell lines and tumors, with elevated expression levels associated with worse overall survival ( = 0.033), this study has examined biomarkers of sensitivity and mechanisms of cytotoxicity to targeted inhibition using SP-2509 (reversible inhibitor). We report, that innate resistance to SP-2509 was not observed in our Ewing sarcoma cell line cohort ( = 17; IC range, 81 -1,593 nmol/L), in contrast resistance to the next-generation irreversible inhibitor GSK-LSD1 was observed across multiple cell lines (IC > 300 μmol/L). Although status and basal KDM1A mRNA and protein levels did not correlate with SP-2509 response, induction of KDM1B following SP-2509 treatment was strongly associated with SP-2509 hypersensitivity. We show that the transcriptional profile driven by SP-2509 strongly mirrors genetic depletion. Mechanistically, RNA-seq analysis revealed that SP-2509 imparts robust apoptosis through engagement of the endoplasmic reticulum stress pathway. In addition, were specifically induced/repressed, respectively following SP-2509 treatment only in our hypersensitive cell lines. Together, our findings provide key insights into the mechanisms of SP-2509 cytotoxicity as well as biomarkers that can be used to predict inhibitor sensitivity in Ewing sarcoma. .

Thomas G P Grünewald, Florencia Cidre-Aranaz, Didier Surdez, Eleni M Tomazou, Enrique de Álava, Heinrich Kovar, Poul H Sorensen, Olivier Delattre, Uta Dirksen (2018 Jul 7)

Ewing sarcoma.

Nature reviews. Disease primers : 5 : DOI : 10.1038/s41572-018-0003-x En savoir plus

Ewing sarcoma is the second most frequent bone tumour of childhood and adolescence that can also arise in soft tissue. Ewing sarcoma is a highly aggressive cancer, with a survival of 70-80% for patients with standard-risk and localized disease and ~30% for those with metastatic disease. Treatment comprises local surgery, radiotherapy and polychemotherapy, which are associated with acute and chronic adverse effects that may compromise quality of life in survivors. Histologically, Ewing sarcomas are composed of small round cells expressing high levels of CD99. Genetically, they are characterized by balanced chromosomal translocations in which a member of the FET gene family is fused with an ETS transcription factor, with the most common fusion being EWSR1-FLI1 (85% of cases). Ewing sarcoma breakpoint region 1 protein (EWSR1)-Friend leukaemia integration 1 transcription factor (FLI1) is a tumour-specific chimeric transcription factor (EWSR1-FLI1) with neomorphic effects that massively rewires the transcriptome. Additionally, EWSR1-FLI1 reprogrammes the epigenome by inducing de novo enhancers at GGAA microsatellites and by altering the state of gene regulatory elements, creating a unique epigenetic signature. Additional mutations at diagnosis are rare and mainly involve STAG2, TP53 and CDKN2A deletions. Emerging studies on the molecular mechanisms of Ewing sarcoma hold promise for improvements in early detection, disease monitoring, lower treatment-related toxicity, overall survival and quality of life.

Irene Jiménez, Mathieu Chicard, Léo Colmet-Daage, Nathalie Clément, Adrien Danzon, Eve Lapouble, Gaelle Pierron, Mylène Bohec, Sylvain Baulande, Dominique Berrebi, Paul Fréneaux, Aurore Coulomb, Louise Galmiche-Rolland, Sabine Sarnacki, Georges Audry, Pascale Philippe-Chomette, Hervé J Brisse, François Doz, Jean Michon, Olivier Delattre, Gudrun Schleiermacher (2018 Jun 21)

Circulating tumor DNA analysis enables molecular characterization of pediatric renal tumors at diagnosis.

International journal of cancer : DOI : 10.1002/ijc.31620 En savoir plus

Circulating tumor DNA (ctDNA) is a powerful tool for the molecular characterization of cancer. The most frequent pediatric kidney tumors (KT) are Wilms’ tumors (WT), but other diagnoses may occur. According to the SIOP strategy, in most countries pediatric KT have a presumptive diagnosis of WT if they are clinically and radiologically compatible. The histologic confirmation is established after post-chemotherapy nephrectomy. Thus, there is a risk for a small fraction of patients to receive neoadjuvant chemotherapy that is not adapted to the disease. The aim of this work is to perform molecular diagnosis of pediatric KT by tumor genetic characterization based on the analysis of ctDNA. We analyzed ctDNA extracted from plasma samples of 18 pediatric patients with KT by whole-exome sequencing and compared the results to their matched tumor and germline DNA. Copy number alterations (CNAs) and single nucleotide variations (SNVs) were analyzed. We were able to detect tumor cell specific genetic alterations-CNAs, SNVs or both-in ctDNA in all patients except in one (for whom the plasma sample was obtained long after nephrectomy). These results open the door to new applications for the study of ctDNA with regards to the molecular diagnosis of KT, with a possibility of its usefulness for adapting the treatment early after diagnosis, but also for disease monitoring and follow up.