Spatial and temporal intratumour heterogeneity has potential consequences for single biopsy-based neuroblastoma treatment decisions

Schmelz, Karin; Toedling, Joern; Huska, Matt; Cwikla, Maja C.; Kruetzfeldt, Louisa-Marie; Proba, Jutta; Ambros, Peter F.; Ambros, Inge M.; Boral, Şengül; Lodrini, Marco; Chen, Celine; Burkert, Martin; Guergen, Dennis; Szymansky, Annabell; Astrahantseff, Kathy; Kuenkele, Annette; Haase, Kerstin; Fischer, Matthias; Deubzer, Hedwig E.; Hertwig, Falk; Hundsdoerfer, Patrick; Henssen, Anton; Schwarz, Roland F.; Schulte, Johannes H.; Eggert, Angelika

doi:10.1038/s41467-021-26870-z

Cited by 60 publications

(35 citation statements)

References 66 publications

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“…25 A recent study reported temporal heterogeneity of an ALK mutation with loss of an ALK R1275Q mutation in the postchemotherapy sample, but in this case the patient did not go on to relapse. 26 Our study is consistent with ALK mutations in neuroblastoma being branch-type rather than truncal and may not confer a survival advantage.…”

Section: Discussionsupporting

confidence: 87%

Loss of ALK hotspot mutations in relapsed neuroblastoma

Allinson

Potts

Goodman

et al. 2022

Genes Chromosomes & Cancer

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ALK is the most commonly mutated oncogene in neuroblastoma with increased mutation frequency reported at relapse. Here we report the loss of an ALK mutation in two patients at relapse and a paired neuroblastoma cell line at relapse. ALK detection methods including Sanger sequencing, targeted next-generation sequencing and a new ALK Agena MassARRAY technique were used to detect common hotspot ALK variants in tumors at diagnosis and relapse from two high-risk neuroblastoma patients. Copy number analysis including single nucleotide polymorphism array and array comparative genomic hybridization confirmed adequate tumor cell content in DNA used for mutation testing. Case 1 presented with an ALK F1174L mutation at diagnosis with a variant allele frequency (VAF) ranging between 23.5% and 28.5%, but the mutation was undetectable at relapse. Case 2 presented with an ALK R1257Q mutation at diagnosis (VAF = 39%-47.4%) which decreased to <0.01% at relapse. Segmental chromosomal aberrations were maintained between diagnosis and relapse confirming sufficient tumor cell content for mutation detection. The diagnostic SKNBE1n cell line harbors an ALK F1174S mutation, which was lost in the relapsed SKNBE2c cell line. To our knowledge, these are the first reported cases of loss of ALK mutations at relapse in neuroblastoma in the absence of ALK inhibitor therapy, reflecting intra-tumoral spatial and temporal heterogeneity. As ALK inhibitors are increasingly used in the treatment of refractory/relapsed neuroblastoma, our

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Section: Discussionsupporting

confidence: 87%

Loss of ALK hotspot mutations in relapsed neuroblastoma

Allinson

Potts

Goodman

et al. 2022

Genes Chromosomes & Cancer

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“…Notwithstanding the metastatic nature of HR-NB, most genomic studies of disease progression focused on small cohorts of paired diagnostic-relapse tumors [3][4][5][6][7][8][9] . Recently, broad copy number aberrations (CNA) and whole-exome sequencing (WES) from multi-region biopsies suggested elevated genetic heterogeneity in high-risk disease [10][11][12] . However, the majority of disease-defining alterations in HR-NB 13,14 result from structural variants (SVs) that cannot be captured by lowresolution WES/CNA analysis.…”

Section: Introductionmentioning

confidence: 99%

Clonal evolution during metastatic spread in high-risk neuroblastoma

Gundem

Levine

Roberts

et al. 2022

Preprint

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High-risk neuroblastoma is generally metastatic and often lethal. Using genomic profiling of 470 sequential and spatially separated samples from 283 patients, we characterize subtype-specific genetic evolutionary trajectories from diagnosis, through progression and end-stage metastatic disease. Clonal tracing timed disease initiation to embryogenesis. Continuous acquisition of structural variants at disease defining loci (MYCN, TERT, MDM2-CDK4) followed by convergent evolution of mutations targeting shared pathways emerged as the predominant feature of progression. At diagnosis metastatic clones were already established at distant sites where they could stay dormant, only to cause relapses years later and spread via metastasis-to-metastasis and polyclonal seeding after therapy.

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“…However, the remarkable heterogeneity of the disease makes it difficult to discover novel candidate genes, relevant for biological behaviour or targeted treatment. Moreover, this heterogeneity may increase under the treatment, and influence clinical interpretation of genetic findings and treatment strategy as pointed out recently [ 44 ]. In our study, we identified novel coding variants of genes possibly contributing to the understanding of these processes.…”

Section: Discussionmentioning

confidence: 99%

Whole exome sequencing of high-risk neuroblastoma identifies novel non-synonymous variants

et al. 2022

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Neuroblastoma (NBL), one of the main death-causing cancers in children, is known for its remarkable genetic heterogeneity and varied patient outcome spanning from spontaneous regression to widespread disease. Specific copy number variations and single gene rearrangements have been proven to be associated with biological behavior and prognosis; however, there is still an unmet need to enlarge the existing armamentarium of prognostic and therapeutic targets. We performed whole exome sequencing (WES) of samples from 18 primary tumors and six relapse samples originating from 18 NBL patients. Our cohort consists of 16 high-risk, one intermediate, and one very low risk patient. The obtained results confirmed known mutational hotspots in ALK and revealed other non-synonymous variants of NBL-related genes (TP53, DMD, ROS, LMO3, PRUNE2, ERBB3, and PHOX2B) and of genes cardinal for other cancers (KRAS, PIK3CA, and FLT3). Beyond, GOSeq analysis determined genes involved in biological adhesion, neurological cell-cell adhesion, JNK cascade, and immune response of cell surface signaling pathways. We were able to identify novel coding variants present in more than one patient in nine biologically relevant genes for NBL, including TMEM14B, TTN, FLG, RHBG, SHROOM3, UTRN, HLA-DRB1, OR6C68, and XIRP2. Our results may provide novel information about genes and signaling pathways relevant for the pathogenesis and clinical course in high-risk NBL.

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Spatial and temporal intratumour heterogeneity has potential consequences for single biopsy-based neuroblastoma treatment decisions

Cited by 60 publications

References 66 publications

Loss of ALK hotspot mutations in relapsed neuroblastoma

Loss of ALK hotspot mutations in relapsed neuroblastoma

Clonal evolution during metastatic spread in high-risk neuroblastoma

Whole exome sequencing of high-risk neuroblastoma identifies novel non-synonymous variants

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