The genetic landscape of high-risk neuroblastoma

By Trevor J Pugh, Olena Morozova, E. Attiyeh, S. Asgharzadeh, Jun S. Wei, D. Auclair, Scott L. Carter, Kristian Cibulskis, M. Hanna, Adam Kiezun and 50 more. Nature Genetics, 2013

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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.

Subfields: Cancer Research, Molecular Biology, Neurology

View Paper: https://www.semanticscholar.org/paper/5e5c940bc871f7a753a41a7ea404e653fd6d27ed

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Michael R. Stratton

Citations in the corpus

THE GENOMIC LANDSCAPE OF PEDIATRIC AND YOUNG ADULT T-LINEAGE ACUTE LYMPHOBLASTIC LEUKEMIA (2017, positive): “This mutation has previously been identified in neuroblastoma and is associated with elevated levels of MYCN expression, suggesting a role in oncogenesis 57 .”
Signatures of mutational processes in human cancer (2013, positive): “The causal relationship between tobacco smoking and signature 4 is supported by a strong positive association between smoking history and the contributions of signature 4 to individual cancers ( P 5 1.1 3 10 2 7 , Supplementary Figs 44–46, 74–76 and 96).”
Neuroblastoma and MYCN (2013, background): “These include gain of function in protein tyrosine phosphatase 11 (PTPN11) and LIN28B, structural mutations in neural growth cone genes (ODZ3, PTPRD, and CSMD1), and heterozygous loss of AT-rich interactive domain 1A and 1B (ARID1A and ARID1B; Molenaar et al. 2012a,b; Pugh et al. 2013; Sausen et al.”
Oncotator: cancer variant annotation tool (2015, neutral): “…2011; Banerji et al., 2012; Barbieri et al., 2012; Barretina et al., 2012; Berger et al., 2012; Hodis et al., 2012; Imielinski et al., 2012; Lee et al., 2012; Lohr et al., 2012; Pugh et al., 2012, 2013, 2014; Ciriello et al., 2013; Francis et al., 2013; Lawrence et al., 2013; Ojesina et al., 2013).”
A Recurrent Mutation in Anaplastic Lymphoma Kinase with Distinct Neoepitope Conformations (2018, background): “This and other sequencing data support ALK as the target with the highest mutation rate among high-risk NBL patients (10, 12, 14).”
ABySS 2.0: resource-efficient assembly of large genomes using a Bloom filter (2016, neutral): “Although this enabling technology found applications in many large cancer cohort studies (Yip et al. 2011; Roberts et al. 2012; Pugh et al. 2013; Ley et al. 2013; Morin et al. 2013), its large memory footprint constituted a substantial bottleneck.”