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. 2018 Dec 7;362(6419):1165-1170.
doi: 10.1126/science.aat6768.

A mechanistic classification of clinical phenotypes in neuroblastoma

Sandra Ackermann  1   2 , Maria Cartolano  2   3 , Barbara Hero  4 , Anne Welte  1   2 , Yvonne Kahlert  1   2 , Andrea Roderwieser  1   2 , Christoph Bartenhagen  1   2 , Esther Walter  1   2 , Judith Gecht  4 , Laura Kerschke  5 , Ruth Volland  4 , Roopika Menon  6 , Johannes M Heuckmann  6 , Moritz Gartlgruber  7 , Sabine Hartlieb  7 , Kai-Oliver Henrich  7 , Konstantin Okonechnikov  8 , Janine Altmüller  2   9 , Peter Nürnberg  2   9   10 , Steve Lefever  11 , Bram de Wilde  11 , Frederik Sand  1   2 , Fakhera Ikram  1   2   12 , Carolina Rosswog  1   2 , Janina Fischer  1   2 , Jessica Theissen  1   4 , Falk Hertwig  1   2   13   14   15 , Aatur D Singhi  16 , Thorsten Simon  4 , Wenzel Vogel  17   18 , Sven Perner  17   18 , Barbara Krug  19 , Matthias Schmidt  20 , Sven Rahmann  21   22 , Viktor Achter  23 , Ulrich Lang  23   24 , Christian Vokuhl  25 , Monika Ortmann  26 , Reinhard Büttner  26 , Angelika Eggert  13   14   15 , Frank Speleman  11 , Roderick J O'Sullivan  27 , Roman K Thomas  3   14   26   28 , Frank Berthold  4 , Jo Vandesompele  11 , Alexander Schramm  29 , Frank Westermann  7 , Johannes H Schulte  13   14   15   28 , Martin Peifer  2   3 , Matthias Fischer  30   2
Affiliations

A mechanistic classification of clinical phenotypes in neuroblastoma

Sandra Ackermann et al. Science. .

Abstract

Neuroblastoma is a pediatric tumor of the sympathetic nervous system. Its clinical course ranges from spontaneous tumor regression to fatal progression. To investigate the molecular features of the divergent tumor subtypes, we performed genome sequencing on 416 pretreatment neuroblastomas and assessed telomere maintenance mechanisms in 208 of these tumors. We found that patients whose tumors lacked telomere maintenance mechanisms had an excellent prognosis, whereas the prognosis of patients whose tumors harbored telomere maintenance mechanisms was substantially worse. Survival rates were lowest for neuroblastoma patients whose tumors harbored telomere maintenance mechanisms in combination with RAS and/or p53 pathway mutations. Spontaneous tumor regression occurred both in the presence and absence of these mutations in patients with telomere maintenance-negative tumors. On the basis of these data, we propose a mechanistic classification of neuroblastoma that may benefit the clinical management of patients.

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Conflict of interest statement

Competing interests: J.V. is a cofounder of Biogazelle, a company developing RNA-based assays to assess health and treat disease. J.V. is also a cofounder of pxlence, a company providing PCR assays for targeted amplification and sequencing of the human exome. R.K.T. has received consulting fees from NEO New Oncology, a company developing technologies for molecular pathology and clinical research. The other authors declare no competing interests.

Figures

Fig. 1.
Fig. 1.. Mutations of RAS and p53 pathway genes in pretreatment neuroblastomas are associated with poor survival of patients.
(A) Schematic representation of the RAS and p53 pathways highlighting genes mutated in pretreatment neuroblastoma of the combined WES and WGS and targeted sequencing cohort (n = 416). The fraction of tumors affected by SNVs or by somatic copy number alterations (SCNAs) is indicated in the gene boxes as percentages and by color code. RAS represents the genes NRAS, HRAS, and KRAS. (B to D) Diseasespecific survival of all patients (B), high-risk patients (C), and non–high-risk patients (D) of the same cohort (n = 416) according to the absence (blue) or presence (red) of RAS or p53 pathway gene mutations (5-year disease-specific survival ± SE: 0.807 ± 0.023 versus 0.498 ± 0.061, 0.657 ± 0.037 versus 0.341 ± 0.071, and 0.993 ± 0.007 versus 0.822 ± 0.081, respectively).
Fig. 2.
Fig. 2.. Telomere maintenance mechanisms in pretreatment neuroblastomas.
(A) Distribution of telomere maintenance mechanisms, RAS and p53 pathway gene mutations, and clinical covariates in 208 pretreatment neuroblastomas (ordered from left to right). The red line in the top panel indicates the TERT expression threshold as described in fig. S15. CT, chemotherapy; MNA, MYCN amplification. (B) TERT mRNA expression (left) and corresponding enzymatic telomerase activity (right) in 52 neuroblastoma samples. Boxes represent the first and third quartiles; whiskers represent minimum and maximum values; TERT high represents tumors lacking genomic MYCN or TERT alterations with TERT expression above threshold.
Fig. 3.
Fig. 3.. Telomere maintenance mechanisms discriminate favorable and adverse clinical course in non–high-risk neuroblastoma bearing RAS or p53 pathway mutations.
(A) Telomere maintenance status and clinical covariates in the combined discovery and validation cohort of non-high-risk patients whose tumors harbored RAS or p53 pathway mutations (n = 43). Patients are ordered from left to the right. The red line in the top panel indicates the TERT expression threshold. NBL, neuroblastoma ID; w/o, without. (B) Event-free (top) and disease-specific (bottom) survival of the same patients according to the absence (blue) or presence (red) of telomere maintenance mechanisms (n = 41; 5-year event-free survival ± SE, 0.847 ± 0.071 versus 0.071 ± 0.069; 5-year disease-specific survival ± SE, 1.0 versus 0.556 ± 0.136). (C) Magnetic resonance imaging (MRI) scans of a patient whose tumor harbored an ALKR1275Q mutation in the absence of telomere maintenance activity at diagnosis and upon partial tumor regression. (D) Iodine-123 metaiodobenzylguanidine scintigraphy scans of a stage 4 patient with an ALKF1174L mutated, telomere maintenance–negative neuroblastoma at diagnosis and upon complete regression of osteomedullary metastases. LDR, posterior projection (left–dorsal–right); RVL, anterior projection (right–ventral–left). (E) MRI scans of a patient with ALKF1245Y (F1245Y, Phe1245→Tyr) mutated, telomere maintenance–negative thoracic neuroblastoma at diagnosis and after partial regression. Tumor lesions are highlighted by arrows or arrowheads.
Fig. 4.
Fig. 4.. Clinical neuroblastoma subgroups are defined by telomere maintenance and RAS and p53 pathways alterations.
(A) Event-free (left) and disease-specific (right) survival of patients according to the absence or presence of RAS or p53 pathway gene mutations and telomere maintenance activity (n = 208; 5-year event-free survival ± SE, 0.867 ± 0.038 versus 0.833 ± 0.108 versus 0.440 ± 0.061 versus 0.245 ± 0.075; 5-year disease-specific survival ± SE, 1.0 versus 1.0 versus 0.742 ± 0.055 versus 0.414 ± 0.088). Statistical results of pairwise group comparisons are indicated. (B) Multivariable Cox regression analysis for event-free survival (n = 201), considering the prognostic variables age at diagnosis, stage, chromosome 1p status, RAS or p53 pathway mutation, and telomere maintenance activation. MYCN status was not considered separately, as telomere maintenance–positive cases comprised all MYCN-amplified cases by definition. Multivariable analysis for disease-specific survival could not be calculated, because no deadly event occurred in patients whose tumors lacked telomere maintenance, and thus, no hazard ratio can be calculated for this variable. (C) Schematic representation of the proposed mechanistic definition of clinical neuroblastoma subgroups. The classification is built on the presence or absence of telomere maintenance mechanisms and RAS or p53 pathway mutations. In addition, associations with other genetic features [MYCN, TERT, and ATRX alterations; segmental copy number alterations (35); tumor cell ploidy (1, 2); gene expression–based classification (36)] and clinical characteristics (age at diagnosis, stage of disease) are indicated.
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