Dataset Information

The genetic landscape of high-risk neuroblastoma.

ABSTRACT: Neuroblastoma is a malignancy of the developing sympathetic nervous system that often presents with widespread metastatic disease, resulting in survival rates of less than 50%. To determine the spectrum of somatic mutation in high-risk neuroblastoma, we studied 240 affected individuals (cases) using a combination of whole-exome, genome and transcriptome sequencing as part of the Therapeutically Applicable Research to Generate Effective Treatments (TARGET) initiative. Here we report a low median exonic mutation frequency of 0.60 per Mb (0.48 nonsilent) and notably few recurrently mutated genes in these tumors. Genes with significant somatic mutation frequencies included ALK (9.2% of cases), PTPN11 (2.9%), ATRX (2.5%, and an additional 7.1% had focal deletions), MYCN (1.7%, causing a recurrent p.Pro44Leu alteration) and NRAS (0.83%). Rare, potentially pathogenic germline variants were significantly enriched in ALK, CHEK2, PINK1 and BARD1. The relative paucity of recurrent somatic mutations in neuroblastoma challenges current therapeutic strategies that rely on frequently altered oncogenic drivers.

SUBMITTER: Pugh TJ

PROVIDER: S-EPMC3682833 | biostudies-literature | 2013 Mar

REPOSITORIES: biostudies-literature

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The genetic landscape of high-risk neuroblastoma.

Pugh Trevor J TJ Morozova Olena O Attiyeh Edward F EF Asgharzadeh Shahab S Wei Jun S JS Auclair Daniel D Carter Scott L SL Cibulskis Kristian K Hanna Megan M Kiezun Adam A Kim Jaegil J Lawrence Michael S MS Lichenstein Lee L McKenna Aaron A Pedamallu Chandra Sekhar CS Ramos Alex H AH Shefler Erica E Sivachenko Andrey A Sougnez Carrie C Stewart Chip C Ally Adrian A Birol Inanc I Chiu Readman R Corbett Richard D RD Hirst Martin M Jackman Shaun D SD Kamoh Baljit B Khodabakshi Alireza Hadj AH Krzywinski Martin M Lo Allan A Moore Richard A RA Mungall Karen L KL Qian Jenny J Tam Angela A Thiessen Nina N Zhao Yongjun Y Cole Kristina A KA Diamond Maura M Diskin Sharon J SJ Mosse Yael P YP Wood Andrew C AC Ji Lingyun L Sposto Richard R Badgett Thomas T London Wendy B WB Moyer Yvonne Y Gastier-Foster Julie M JM Smith Malcolm A MA Guidry Auvil Jaime M JM Gerhard Daniela S DS Hogarty Michael D MD Jones Steven J M SJ Lander Eric S ES Gabriel Stacey B SB Getz Gad G Seeger Robert C RC Khan Javed J Marra Marco A MA Meyerson Matthew M Maris John M JM

Nature genetics 20130120 3

Neuroblastoma is a malignancy of the developing sympathetic nervous system that often presents with widespread metastatic disease, resulting in survival rates of less than 50%. To determine the spectrum of somatic mutation in high-risk neuroblastoma, we studied 240 affected individuals (cases) using a combination of whole-exome, genome and transcriptome sequencing as part of the Therapeutically Applicable Research to Generate Effective Treatments (TARGET) initiative. Here we report a low median ...[more]

PMID: 23334666

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Project description:High-risk neuroblastoma (HR-NB) is branded with hematogenous metastasis, relapses, and dismal long-term survival. Intensification of consolidation therapy with tandem/triple autologous stem cell (SC) rescue (with bone marrow [BM]/peripheral blood [PB] CD34+ selection) after myeloablative chemotherapy has improved long-term survival. However, the benefit is limited by the indication of NB cells in CD34+ PBSCs, CD34 expression in NB cells, and the risk of reinfusing NB cancer stem cells (NB CSCs) that could lead to post-transplant relapse. We investigated the association of CD34 surface expression (92 patients) with NB evolution/clinical outcomes. CD34 gene-level status in NB was assessed through RNA-Seq data mining (18 cohorts, n, 3324). Genetic landscape of CD34-expressing NB CSCs (CD133+CD34+) was compared with CD34- CSCs (CD133+CD34-). RNA-seq data revealed equivocal association patterns of CD34 expression with patient survival. Our immunohistochemistry data revealed definite, but rare (mean, 0.73%; range 0.00-7.87%; median, 0.20%) CD34 positivity in NB. CD34+ significantly associated with MYCN amplification (p, 0.003), advanced disease stage (p, 0.016), and progressive disease (PD, p < 0.0009) after clinical therapy. A general high-is-worse tendency was observed in patients with relapsed disease. High CD34+ correlated with poor survival in patients with N-MYC-amplified HR-NB. Gene expression analysis of CD34+-NB CSCs identified significant up (4631) and downmodulation (4678) of genes compared with NB CSCs that lack CD34. IPA recognized the modulation of crucial signaling elements (EMT, stemness maintenance, differentiation, inflammation, clonal expansion, drug resistance, metastasis) that orchestrate NB disease evolution in CD34+ CSCs compared with CD34- CSCs. While the function of CD34 in NB evolution requires further in-depth investigation, careful consideration should be exercised for autologous stem cell rescue with CD34+ selection in NB patients. Graphical abstract.

Dataset Information

The genetic landscape of high-risk neuroblastoma.

Publications

The genetic landscape of high-risk neuroblastoma.

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