Study of chromatin remodeling genes implicates SMARCA4 as a putative player in oncogenesis in neuroblastoma

Bellini, Angela; Bessoltane‐Bentahar, Nadia; Bhalshankar, Jaydutt; Clément, Nathalie; Raynal, Virginie; Baulande, Sylvain; Bernard, Virginie; Danzon, Adrien; Chicard, Mathieu; Colmet‐Daage, Léo; Pierron, Gaëlle; Roux, Laura Le; Planchon, Julien Masliah; Combaret, Valérie; Lapouble, Eve; Corradini, Nadège; Thébaud, Estelle; Gambart, Marion; Valteau‐Couanet, Dominique; Michon, Jean; Louis‐Brennetot, Caroline; Janoueix‐Lerosey, Isabelle; Defachelles, Anne‐Sophie; Bourdeaut, Franck; Delattre, Olivier; Schleiermacher, Gudrun

doi:10.1002/ijc.32361

Cited by 19 publications

(18 citation statements)

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“…20% mutated allele fraction [MAF]) or subclonal levels (, 20% MAF). [19][20][21][22][23] ALK can also be activated by genomic focal amplification, described in 1%-2% of NBs, almost exclusively with MNA, 17,24 or, more rarely, following structural rearrangements. 25 Genetic alterations of ALK are associated with poorer survival in the overall NB population.…”

Section: Introductionmentioning

confidence: 99%

Frequency and Prognostic Impact of ALK Amplifications and Mutations in the European Neuroblastoma Study Group (SIOPEN) High-Risk Neuroblastoma Trial (HR-NBL1)

Bellini

Pötschger

Bernard

et al. 2021

JCO

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PURPOSE In neuroblastoma (NB), the ALK receptor tyrosine kinase can be constitutively activated through activating point mutations or genomic amplification. We studied ALK genetic alterations in high-risk (HR) patients on the HR-NBL1/SIOPEN trial to determine their frequency, correlation with clinical parameters, and prognostic impact. MATERIALS AND METHODS Diagnostic tumor samples were available from 1,092 HR-NBL1/SIOPEN patients to determine ALK amplification status (n = 330), ALK mutational profile (n = 191), or both (n = 571). RESULTS Genomic ALK amplification ( ALKa) was detected in 4.5% of cases (41 out of 901), all except one with MYCN amplification (MNA). ALKa was associated with a significantly poorer overall survival (OS) (5-year OS: ALKa [n = 41] 28% [95% CI, 15 to 42]; no- ALKa [n = 860] 51% [95% CI, 47 to 54], [ P < .001]), particularly in cases with metastatic disease. ALK mutations ( ALKm) were detected at a clonal level (> 20% mutated allele fraction) in 10% of cases (76 out of 762) and at a subclonal level (mutated allele fraction 0.1%-20%) in 3.9% of patients (30 out of 762), with a strong correlation between the presence of ALKm and MNA ( P < .001). Among 571 cases with known ALKa and ALKm status, a statistically significant difference in OS was observed between cases with ALKa or clonal ALKm versus subclonal ALKm or no ALK alterations (5-year OS: ALKa [n = 19], 26% [95% CI, 10 to 47], clonal ALKm [n = 65] 33% [95% CI, 21 to 44], subclonal ALKm (n = 22) 48% [95% CI, 26 to 67], and no alteration [n = 465], 51% [95% CI, 46 to 55], respectively, P = .001). Importantly, in a multivariate model, involvement of more than one metastatic compartment (hazard ratio [HR], 2.87; P < .001), ALKa (HR, 2.38; P = .004), and clonal ALKm (HR, 1.77; P = .001) were independent predictors of poor outcome. CONCLUSION Genetic alterations of ALK (clonal mutations and amplifications) in HR-NB are independent predictors of poorer survival. These data provide a rationale for integration of ALK inhibitors in upfront treatment of HR-NB with ALK alterations.

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Section: Introductionmentioning

confidence: 99%

Frequency and Prognostic Impact of ALK Amplifications and Mutations in the European Neuroblastoma Study Group (SIOPEN) High-Risk Neuroblastoma Trial (HR-NBL1)

Bellini

Pötschger

Bernard

et al. 2021

JCO

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“…Additionally, inactivating somatic mutations in SMARCA4 have been reported in many cancer cell lines, including non-small cell lung cancer and small cell carcinoma of the ovary 21,22 . Recently, we and others have found SMARCA4 somatic point mutations in NB, highlighting its role in the oncogenesis of this neuroblastic tumor 7,23 .…”

Section: Discussionmentioning

confidence: 79%

19p loss is significantly enriched in older age neuroblastoma patients and correlates with poor prognosis

et al. 2020

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Genomic aberrations of neuroblastoma occurring in late childhood and adolescence are still understudied. Publicly available DNA copy number profiles of 556 tumors (discovery set) and of 208 tumors obtained by array-CGH assay (validation set) were used to test if 19p loss is significantly over-represented in children and adolescents with neuroblastoma. The 19p loss occurrence was separately tested within different age groups in the discovery and validation set and the resulting P values were combined by metaanalysis and corrected by Bonferroni's method. In both sets, 19p loss was associated with older age at diagnosis. Particularly, the lowest age group significantly associated with 19p loss (discovery set: 20%; validation set: 35%) was 6 years. The 19p loss correlated with inferior overall survival in patients over 6 years of age. Relevant tumor suppressor genes (KEAP1, DNM2, SMARCA4, SLC44A2 and CDKN2D) and microRNAs (miR-181c, miR-27a, and mirR-199a-1) are located in the genomic region involved in 19p loss. Downregulation of DNM2, SLC44A2 and CDKN2D was associated with poor patient outcome and older age. Among the recurrent NB chromosomal aberrations, only 1q gain was enriched in patients older than 6, and its presence was mutually exclusive with respect to 19p loss. Our data demonstrate that 19p loss is a genomic biomarker of NB diagnosed in older children that can predict clinical outcome.npj Genomic Medicine (2020) 5:18 ; https://doi.

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“…the ERG/DUX4 and ZNF384 [100,101] rearranged subgroups but is overall, not taken these subgroups into account, low [18,[100][101][102][103]. Moreover, in the typical pediatric cancers including Wilms tumor [104][105][106], neuroblastoma [104,107,108] and pediatric hepatoblastoma [104,[109][110][111] somatic KMT2D variants only (very) infrequently occur. In contrast, in other cancers including, amongst others, pediatric-and adult diffuse large B-cell lymphoma (DLBCL) (20-35%) [11,15,112,113], adult follicular lymphoma (70-90%) [14,15], nodal marginal zone lymphoma (≈20-30%) [114][115][116], (non)small cell lung cancer/lung squamous cell carcinoma (≈20-30%) [11,65,117], upper tract urothelial carcinoma/bladder cancer (≈25-45%) [11,[118][119][120], esophageal (squamous cell) carcinoma (≈10-25%) [11,121,122] and pediatric-and adult medulloblastoma (overall ≈5-30%, large differences between individual molecular subgroups) [123][124][125] somatic KMT2D variants are (highly) recurrent but these cancers have not been reported in patients with KS (yet).…”

Section: Somatic Kmt2d Variants In Malignancies In Patients With Kabu...mentioning

confidence: 99%

Molecular characterization of an embryonal rhabdomyosarcoma occurring in a patient with Kabuki syndrome: report and literature review in the light of tumor predisposition syndromes

et al. 2022

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Kabuki syndrome is a well-recognized syndrome characterized by facial dysmorphism and developmental delay/intellectual disability and in the majority of patients a germline variant in KMT2D is found. As somatic KMT2D variants can be found in 5–10% of tumors a tumor predisposition in Kabuki syndrome is discussed. So far less than 20 patients with Kabuki syndrome and a concomitant malignancy have been published. Here we report on a female patient with Kabuki syndrome and a c.2558_2559delCT germline variant in KMT2D who developed an embryonal rhabdomyosarcoma (ERMS) at 10 years. On tumor tissue we performed DNA-methylation profiling and exome sequencing (ES). Copy number analyses revealed aneuploidies typical for ERMS including (partial) gains of chromosomes 2, 3, 7, 8, 12, 15, and 20 and 3 focal deletions of chromosome 11p. DNA methylation profiling mapped the case to ERMS by a DNA methylation-based sarcoma classifier. Sequencing suggested gain of the wild-type KMT2D allele in the trisomy 12. Including our patient literature review identified 18 patients with Kabuki syndrome and a malignancy. Overall, the landscape of malignancies in patients with Kabuki syndrome was reminiscent of that of the pediatric population in general. Histopathological and molecular data were only infrequently reported and no report included next generation sequencing and/or DNA-methylation profiling. Although we found no strong arguments pointing towards KS as a tumor predisposition syndrome, based on the small numbers any relation cannot be fully excluded. Further planned studies including profiling of additional tumors and long term follow-up of KS-patients into adulthood could provide further insights.

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Study of chromatin remodeling genes implicates SMARCA4 as a putative player in oncogenesis in neuroblastoma

Cited by 19 publications

References 51 publications

Frequency and Prognostic Impact of ALK Amplifications and Mutations in the European Neuroblastoma Study Group (SIOPEN) High-Risk Neuroblastoma Trial (HR-NBL1)

Frequency and Prognostic Impact of ALK Amplifications and Mutations in the European Neuroblastoma Study Group (SIOPEN) High-Risk Neuroblastoma Trial (HR-NBL1)

19p loss is significantly enriched in older age neuroblastoma patients and correlates with poor prognosis

Molecular characterization of an embryonal rhabdomyosarcoma occurring in a patient with Kabuki syndrome: report and literature review in the light of tumor predisposition syndromes

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