Identification of MYCN Non-amplified Neuroblastoma Subgroups Points Towards Molecular Signatures for Precision Prognosis and Therapy Stratification

Overview

Journal Br J Cancer

Specialty Oncology

Date 2024 Mar 30

PMID 38553589

Authors

Xiaoxiao Hu

Yilu Zhou

Charlotte Hill

Kai Chen

Cheng Cheng

Xiaowei Liu

Peiwen Duan

Yaoyao Gu

Yeming Wu

Rob M Ewing

Zhongrong Li

Zhixiang Wu

Yihua Wang

Affiliations

Soon will be listed here.

Abstract

Background: Despite the extensive study of MYCN-amplified neuroblastomas, there is a significant unmet clinical need in MYCN non-amplified cases. In particular, the extent of heterogeneity within the MYCN non-amplified population is unknown.

Methods: A total of 1566 samples from 16 datasets were identified in Gene Expression Omnibus (GEO) and ArrayExpress. Characterisation of the subtypes was analysed by ConsensusClusterPlus. Independent predictors for subgrouping were constructed from the single sample predictor based on the multiclassPairs package. Findings were verified using immunohistochemistry and CIBERSORTx analysis.

Results: We demonstrate that MYCN non-amplified neuroblastomas are heterogeneous and can be classified into 3 subgroups based on their transcriptional signatures. Within these groups, subgroup_2 has the worst prognosis and this group shows a 'MYCN' signature that is potentially induced by the overexpression of Aurora Kinase A (AURKA); whilst subgroup_3 is characterised by an 'inflamed' gene signature. The clinical implications of this subtype classification are significant, as each subtype demonstrates a unique prognosis and vulnerability to investigational therapies. A total of 420 genes were identified as independent subgroup predictors with average balanced accuracy of 0.93 and 0.84 for train and test datasets, respectively.

Conclusion: We propose that transcriptional subtyping may enhance precision prognosis and therapy stratification for patients with MYCN non-amplified neuroblastomas.

Citing Articles

Targeting the ubiquitin-proteasome system: a novel therapeutic strategy for neuroblastoma.

He Y, Wang J, Xiao T Front Oncol. 2024; 14:1443256.

PMID: 39391247 PMC: 11464458. DOI: 10.3389/fonc.2024.1443256.

References

Otto T, Horn S, Brockmann M, Eilers U, Schuttrumpf L, Popov N . Stabilization of N-Myc is a critical function of Aurora A in human neuroblastoma. Cancer Cell. 2008; 15(1):67-78. DOI: 10.1016/j.ccr.2008.12.005. View

Oberthuer A, Juraeva D, Hero B, Volland R, Sterz C, Schmidt R . Revised risk estimation and treatment stratification of low- and intermediate-risk neuroblastoma patients by integrating clinical and molecular prognostic markers. Clin Cancer Res. 2014; 21(8):1904-15. DOI: 10.1158/1078-0432.CCR-14-0817. View

van Groningen T, Koster J, Valentijn L, Zwijnenburg D, Akogul N, Hasselt N . Neuroblastoma is composed of two super-enhancer-associated differentiation states. Nat Genet. 2017; 49(8):1261-1266. DOI: 10.1038/ng.3899. View

Colon N, Chung D . Neuroblastoma. Adv Pediatr. 2011; 58(1):297-311. PMC: 3668791. DOI: 10.1016/j.yapd.2011.03.011. View

Yang Y, Ding L, Zhou Q, Fen L, Cao Y, Sun J . Silencing of AURKA augments the antitumor efficacy of the AURKA inhibitor MLN8237 on neuroblastoma cells. Cancer Cell Int. 2020; 20:9. PMC: 6947931. DOI: 10.1186/s12935-019-1072-y. View

Newman A, Liu C, Green M, Gentles A, Feng W, Xu Y . Robust enumeration of cell subsets from tissue expression profiles. Nat Methods. 2015; 12(5):453-7. PMC: 4739640. DOI: 10.1038/nmeth.3337. View

Seeger R, Brodeur G, Sather H, Dalton A, Siegel S, Wong K . Association of multiple copies of the N-myc oncogene with rapid progression of neuroblastomas. N Engl J Med. 1985; 313(18):1111-6. DOI: 10.1056/NEJM198510313131802. View

Valentijn L, Koster J, Haneveld F, Aissa R, van Sluis P, Broekmans M . Functional MYCN signature predicts outcome of neuroblastoma irrespective of MYCN amplification. Proc Natl Acad Sci U S A. 2012; 109(47):19190-5. PMC: 3511149. DOI: 10.1073/pnas.1208215109. View

Rajbhandari P, Lopez G, Capdevila C, Salvatori B, Yu J, Rodriguez-Barrueco R . Cross-Cohort Analysis Identifies a TEAD4-MYCN Positive Feedback Loop as the Core Regulatory Element of High-Risk Neuroblastoma. Cancer Discov. 2018; 8(5):582-599. PMC: 5967627. DOI: 10.1158/2159-8290.CD-16-0861. View

10.

Wakamatsu Y, Watanabe Y, Nakamura H, Kondoh H . Regulation of the neural crest cell fate by N-myc: promotion of ventral migration and neuronal differentiation. Development. 1997; 124(10):1953-62. DOI: 10.1242/dev.124.10.1953. View

11.

Song X, Huang C, Wang S, Yan L, Wang J, Li Y . Neck management in patients with olfactory neuroblastoma. Oral Oncol. 2019; 101:104505. DOI: 10.1016/j.oraloncology.2019.104505. View

12.

Boeva V, Louis-Brennetot C, Peltier A, Durand S, Pierre-Eugene C, Raynal V . Heterogeneity of neuroblastoma cell identity defined by transcriptional circuitries. Nat Genet. 2017; 49(9):1408-1413. DOI: 10.1038/ng.3921. View

13.

Rosswog C, Schmidt R, Oberthuer A, Juraeva D, Brors B, Engesser A . Molecular Classification Substitutes for the Prognostic Variables Stage, Age, and MYCN Status in Neuroblastoma Risk Assessment. Neoplasia. 2017; 19(12):982-990. PMC: 5678736. DOI: 10.1016/j.neo.2017.09.006. View

14.

Oberthuer A, Hero B, Berthold F, Juraeva D, Faldum A, Kahlert Y . Prognostic impact of gene expression-based classification for neuroblastoma. J Clin Oncol. 2010; 28(21):3506-15. DOI: 10.1200/JCO.2009.27.3367. View

15.

Wang Y, Chen K, Cai Y, Cai Y, Yuan X, Wang L . Annexin A2 could enhance multidrug resistance by regulating NF-κB signaling pathway in pediatric neuroblastoma. J Exp Clin Cancer Res. 2017; 36(1):111. PMC: 5559827. DOI: 10.1186/s13046-017-0581-6. View

16.

Brockmann M, Poon E, Berry T, Carstensen A, Deubzer H, Rycak L . Small molecule inhibitors of aurora-a induce proteasomal degradation of N-myc in childhood neuroblastoma. Cancer Cell. 2013; 24(1):75-89. PMC: 4298657. DOI: 10.1016/j.ccr.2013.05.005. View

17.

Cohn S, Pearson A, London W, Monclair T, Ambros P, Brodeur G . The International Neuroblastoma Risk Group (INRG) classification system: an INRG Task Force report. J Clin Oncol. 2008; 27(2):289-97. PMC: 2650388. DOI: 10.1200/JCO.2008.16.6785. View

18.

Brodeur G, Seeger R, Schwab M, Varmus H, Bishop J . Amplification of N-myc in untreated human neuroblastomas correlates with advanced disease stage. Science. 1984; 224(4653):1121-4. DOI: 10.1126/science.6719137. View

19.

Haynes W, Vallania F, Liu C, Bongen E, Tomczak A, Andres-Terre M . EMPOWERING MULTI-COHORT GENE EXPRESSION ANALYSIS TO INCREASE REPRODUCIBILITY. Pac Symp Biocomput. 2016; 22:144-153. PMC: 5167529. DOI: 10.1142/9789813207813_0015. View

20.

Su Y, Luo B, Lu Y, Wang D, Yan J, Zheng J . Anlotinib Induces a T Cell-Inflamed Tumor Microenvironment by Facilitating Vessel Normalization and Enhances the Efficacy of PD-1 Checkpoint Blockade in Neuroblastoma. Clin Cancer Res. 2021; 28(4):793-809. PMC: 9377760. DOI: 10.1158/1078-0432.CCR-21-2241. View