Emergence of New <i>ALK</i> Mutations at Relapse of Neuroblastoma

Schleiermacher, Gudrun; Javanmardi, Niloufar; Bernard, Virginie; Leroy, Quentin; Cappo, Julie; Frio, Thomas Rio; Pierron, Gaëlle; Lapouble, Eve; Combaret, Valérie; Speleman, Franki; Wilde, Bram De; Djos, Anna; Øra, Ingrid; Hedborg, Fredrik; Träger, Catarina; Holmqvist, Britt-Marie; Abrahamsson, Jonas; Peuchmaur, Michel; Michon, Jean; Janoueix‐Lerosey, Isabelle; Kogner, Per; Delattre, Olivier; Martinsson, Tommy

doi:10.1200/jco.2013.54.0674

Cited by 179 publications

(110 citation statements)

References 26 publications

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“…Temporal heterogeneity concerning copy-number changes and gene mutations was reported in neuroblastoma (37)(38)(39). In line with the studies performed on matched primary and relapse neuroblastomas, despite a decrease in subclonal copynumber changes in the relapse samples compared with the primary tumors (39), a number of de novo aberrations were found in the relapse samples (37,39).…”

Section: Discussionsupporting

confidence: 58%

Impact of Disseminated Neuroblastoma Cells on the Identification of the Relapse-Seeding Clone

Abbasi

Rifatbegovic

Brunner

et al. 2017

Clinical Cancer Research

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Purpose: Tumor relapse is the most frequent cause of death in stage 4 neuroblastomas. Since genomic information on the relapse precursor cells could guide targeted therapy, our aim was to find the most appropriate tissue for identifying relapse-seeding clones.Experimental design: We analyzed 10 geographically and temporally separated samples of a single patient by SNP array and validated the data in 154 stage 4 patients.Results: In the case study, aberrations unique to certain tissues and time points were evident besides concordant aberrations shared by all samples. Diagnostic bone marrowderived disseminated tumor cells (DTCs) as well as the metastatic tumor and DTCs at relapse displayed a 1q deletion, not detected in any of the seven primary tumor samples. In the validation cohort, the frequency of 1q deletion was 17.8%, 10%, and 27.5% in the diagnostic DTCs, diagnostic tumors, and DTCs at relapse, respectively. This aberration was significantly associated with 19q and ATRX deletions. We observed a significant increased likelihood of an adverse event in the presence of 19q deletion in the diagnostic DTCs.Conclusions: Different frequencies of 1q and 19q deletions in the primary tumors as compared with DTCs, their relatively high frequency at relapse, and their effect on event-free survival (19q deletion) indicate the relevance of analyzing diagnostic DTCs. Our data support the hypothesis of a branched clonal evolution and a parallel progression of primary and metastatic tumor cells. Therefore, searching for biomarkers to identify the relapse-seeding clone should involve diagnostic DTCs alongside the tumor tissue. Clin Cancer Res; 23(15); 4224-32.Ó2017 AACR.

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Section: Discussionsupporting

confidence: 58%

Impact of Disseminated Neuroblastoma Cells on the Identification of the Relapse-Seeding Clone

Abbasi

Rifatbegovic

Brunner

et al. 2017

Clinical Cancer Research

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“…The majority of patients with familial neuroblastoma have germline mutations in ALK [19], and sporadic neuroblastoma tumors also occasionally harbor ALK abnormalities, including 2-3% of tumors with genomic amplification and approximately 10% with missense mutations [19,[21][22][23][24][25].…”

Section: Epidemiology and Geneticsmentioning

confidence: 99%

Overview and recent advances in the treatment of neuroblastoma

Whittle

Smith

Doherty

et al. 2017

Expert Review of Anticancer Therapy

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Introduction: Children with neuroblastoma have widely divergent outcomes, ranging from cure in >90% of patients with low risk disease to <50% for those with high risk disease. Recent research has shed light on the biology of neuroblastoma, allowing for more accurate risk stratification and treatment reduction in many cases, although newer treatment strategies for children with high-risk and relapsed neuroblastoma are needed to improve outcomes. Areas covered: Neuroblastoma epidemiology, diagnosis, risk stratification, and recent advances in treatment of both newly diagnosed and relapsed neuroblastoma. Expert commentary: The identification of newer tumor targets and of novel cell-mediated immunotherapy agents may lead to novel therapeutic approaches, and clinical trials for regimens designed to target individual genetic aberrations in tumors are underway. A combination of therapeutic modalities will likely be required to improve survival and cure rates for patients with high-risk neuroblastoma.ARTICLE HISTORY

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“…Once paired-end reads merged and adaptors trimmed by SeqPrep with default parameters, merged reads were aligned via BWA allowing up to one difference in the 22-base-long seeds and reporting only unique alignments (26).…”

Section: Bioinformatics Detection Of Variationsmentioning

confidence: 99%

“…Thus, ALK might represent a bone fide target in neuroblastoma therapy. We have recently used deep sequencing to search for ALK mutations in neuroblastoma relapse samples (26). Furthermore, in a recent study, the feasibility of a new method of ALK mutations detection in circulating tumor DNA (ctDNA) using droplet digital PCR (ddPCR) has been described.…”

Section: Introductionmentioning

confidence: 99%

Deep Sequencing Reveals Occurrence of Subclonal ALK Mutations in Neuroblastoma at Diagnosis

Bellini

Bernard

Leroy

et al. 2015

Clinical Cancer Research

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Purpose: In neuroblastoma, activating ALK receptor tyrosine kinase point mutations play a major role in oncogenesis. We explored the potential occurrence of ALK mutations at a subclonal level using targeted deep sequencing.Experimental Design: In a clinically representative series of 276 diagnostic neuroblastoma samples, exons 23 and 25 of the ALK gene, containing the F1174 and R1275 mutation hotspots, respectively, were resequenced with an extremely high depth of coverage.Results: At the F1174 hotspot (exon 23), mutations were observed in 15 of 277 samples (range of fraction of mutated allele per sample: 0.562%-40.409%). At the R1275 hotspot (exon 25), ALK mutations were detected in 12 of 276 samples (range of fraction of mutated allele: 0.811%-73.001%). Altogether, subclonal events with a mutated allele fraction below 20% were observed in 15/27 ALK-mutated samples. The presence of an ALK mutation was associated with poorer 5-year overall survival (OS: 75% vs. 57%, P ¼ 0.0212 log-rank test), with a strong correlation between F1174 ALK mutations and MYCN amplification being observed.Conclusions: In this series, deep sequencing allows the detection of F1174 and R1275 ALK mutational events at diagnosis in 10% of cases, with subclonal events in more than half of these, which would have gone undetected by Sanger sequencing. These findings are of clinical importance given the potential role of ALK mutations in clonal evolution and relapse. These findings also demonstrate the importance of deep sequencing techniques for the identification of patients especially when considering targeted therapy.

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Emergence of New ALK Mutations at Relapse of Neuroblastoma

Cited by 179 publications

References 26 publications

Impact of Disseminated Neuroblastoma Cells on the Identification of the Relapse-Seeding Clone

Impact of Disseminated Neuroblastoma Cells on the Identification of the Relapse-Seeding Clone

Overview and recent advances in the treatment of neuroblastoma

Deep Sequencing Reveals Occurrence of Subclonal ALK Mutations in Neuroblastoma at Diagnosis

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