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Genome wide DNA methylation analysis identifies novel molecular subgroups and predicts survival in neuroblastoma

Lookup NU author(s): Wen Hao, Professor Deborah Tweddle, Dr Ed Schwalbe, Dr Gordon Strathdee

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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).

Abstract

© 2022, The Author(s).Background: Neuroblastoma is the most common malignancy in infancy, accounting for 15% of childhood cancer deaths. Outcome for the high-risk disease remains poor. DNA-methylation patterns are significantly altered in all cancer types and can be utilised for disease stratification. Methods: Genome-wide DNA methylation (n = 223), gene expression (n = 130), genetic/clinical data (n = 213), whole-exome sequencing (n = 130) was derived from the TARGET study. Methylation data were derived from HumanMethylation450 BeadChip arrays. t-SNE was used for the segregation of molecular subgroups. A separate validation cohort of 105 cases was studied. Results: Five distinct neuroblastoma molecular subgroups were identified, based on genome-wide DNA-methylation patterns, with unique features in each, including three subgroups associated with known prognostic features and two novel subgroups. As expected, Cluster-4 (infant diagnosis) had significantly better 5-year progression-free survival (PFS) than the four other clusters. However, in addition, the molecular subgrouping identified multiple patient subsets with highly increased risk, most notably infant patients that do not map to Cluster-4 (PFS 50% vs 80% for Cluster-4 infants, P = 0.005), and allowed identification of subgroup-specific methylation differences that may reflect important biological differences within neuroblastoma. Conclusions: Methylation-based clustering of neuroblastoma reveals novel molecular subgroups, with distinct molecular/clinical characteristics and identifies a subgroup of higher-risk infant patients.

Publication metadata

Author(s): Lalchungnunga H, Hao W, Maris JM, Asgharzadeh S, Henrich K-O, Westermann F, Tweddle DA, Schwalbe EC, Strathdee G

Publication type: Article

Publication status: Published

Journal: British Journal of Cancer

Year: 2022

Issue: ePub ahead of Print

Online publication date: 29/09/2022

Acceptance date: 08/09/2022

Date deposited: 31/10/2022

ISSN (print): 0007-0920

ISSN (electronic): 1532-1827

Publisher: Springer Nature

URL: https://doi.org/10.1038/s41416-022-01988-z

DOI: 10.1038/s41416-022-01988-z

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