Markers of survival and metastatic potential in childhood CNS primitive neuro-ectodermal brain tumours

An integrative genomic analysis

Daniel Picard, Suzanne Miller, Cynthia E. Hawkins, Eric Bouffet, Hazel A. Rogers, Tiffany S Y Chan, Seung Ki Kim, Young Shin Ra, Jason Fangusaro, Andrey Korshunov, Helen Toledano, Hideo Nakamura, James T. Hayden, Jennifer Chan, Lucie Lafay-Cousin, Pingzhao Hu, Xing Fan, Karin M. Muraszko, Scott L. Pomeroy, Ching C. Lau & 9 others Ho Keung Ng, Chris Jones, Timothy Van Meter, Steven C. Clifford, Charles G Eberhart, Amar Gajjar, Stefan M. Pfister, Richard G. Grundy, Annie Huang

Research output: Contribution to journalArticle

Abstract

Background: Childhood CNS primitive neuro-ectodermal brain tumours (PNETs) are very aggressive brain tumours for which the molecular features and best treatment approaches are unknown. We assessed a large cohort of these rare tumours to identify molecular markers to enhance clinical management of this disease. Methods: We obtained 142 primary hemispheric CNS PNET samples from 20 institutions in nine countries and examined transcriptional profiles for a subset of 51 samples and copy number profiles for a subset of 77 samples. We used clustering, gene, and pathway enrichment analyses to identify tumour subgroups and group-specific molecular markers, and applied immunohistochemical and gene-expression analyses to validate and assess the clinical significance of the subgroup markers. Findings: We identified three molecular subgroups of CNS PNETs that were distinguished by primitive neural (group 1), oligoneural (group 2), and mesenchymal lineage (group 3) gene-expression signatures with differential expression of cell-lineage markers LIN28 and OLIG2. Patients with group 1 tumours were most often female (male:female ratio 0·61 for group 1 vs 1·25 for group 2 and 1·63 for group 3; p=0·043 [group 1 vs groups 2 and 3]), youngest (median age at diagnosis 2·9 years [95% CI 2·4-5·2] for group 1 vs 7·9 years [6·0-9·7] for group 2 and 5·9 years [4·9-7·8] for group 3; p=0·005), and had poorest survival (median survival 0·8 years [95% CI 0·5-1·2] in group 1, 1·8 years [1·4-2·3] in group 2 and 4·3 years [0·8-7·8] in group 3; p=0·019). Patients with group 3 tumours had the highest incidence of metastases at diagnosis (no distant metastasis:metastasis ratio 0·90 for group 3 vs 2·80 for group 1 and 5·67 for group 2; p=0·037). Interpretation: LIN28 and OLIG2 are promising diagnostic and prognostic molecular markers for CNS PNET that warrant further assessment in prospective clinical trials. Funding: Canadian Institute of Health Research, Brainchild/SickKids Foundation, and the Samantha Dickson Brain Tumour Trust.

Original languageEnglish (US)
Pages (from-to)838-848
Number of pages11
JournalThe Lancet Oncology
Volume13
Issue number8
DOIs
StatePublished - Aug 2012

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Brain Neoplasms
Survival
Neoplasm Metastasis
Neoplasms
Molecular Pathology
Cell Lineage
Disease Management
Transcriptome
Cluster Analysis
Clinical Trials
Gene Expression
Incidence
Health
Genes

ASJC Scopus subject areas

  • Oncology

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Markers of survival and metastatic potential in childhood CNS primitive neuro-ectodermal brain tumours : An integrative genomic analysis. / Picard, Daniel; Miller, Suzanne; Hawkins, Cynthia E.; Bouffet, Eric; Rogers, Hazel A.; Chan, Tiffany S Y; Kim, Seung Ki; Ra, Young Shin; Fangusaro, Jason; Korshunov, Andrey; Toledano, Helen; Nakamura, Hideo; Hayden, James T.; Chan, Jennifer; Lafay-Cousin, Lucie; Hu, Pingzhao; Fan, Xing; Muraszko, Karin M.; Pomeroy, Scott L.; Lau, Ching C.; Ng, Ho Keung; Jones, Chris; Van Meter, Timothy; Clifford, Steven C.; Eberhart, Charles G; Gajjar, Amar; Pfister, Stefan M.; Grundy, Richard G.; Huang, Annie.

In: The Lancet Oncology, Vol. 13, No. 8, 08.2012, p. 838-848.

Research output: Contribution to journalArticle

Picard, D, Miller, S, Hawkins, CE, Bouffet, E, Rogers, HA, Chan, TSY, Kim, SK, Ra, YS, Fangusaro, J, Korshunov, A, Toledano, H, Nakamura, H, Hayden, JT, Chan, J, Lafay-Cousin, L, Hu, P, Fan, X, Muraszko, KM, Pomeroy, SL, Lau, CC, Ng, HK, Jones, C, Van Meter, T, Clifford, SC, Eberhart, CG, Gajjar, A, Pfister, SM, Grundy, RG & Huang, A 2012, 'Markers of survival and metastatic potential in childhood CNS primitive neuro-ectodermal brain tumours: An integrative genomic analysis', The Lancet Oncology, vol. 13, no. 8, pp. 838-848. https://doi.org/10.1016/S1470-2045(12)70257-7
Picard, Daniel ; Miller, Suzanne ; Hawkins, Cynthia E. ; Bouffet, Eric ; Rogers, Hazel A. ; Chan, Tiffany S Y ; Kim, Seung Ki ; Ra, Young Shin ; Fangusaro, Jason ; Korshunov, Andrey ; Toledano, Helen ; Nakamura, Hideo ; Hayden, James T. ; Chan, Jennifer ; Lafay-Cousin, Lucie ; Hu, Pingzhao ; Fan, Xing ; Muraszko, Karin M. ; Pomeroy, Scott L. ; Lau, Ching C. ; Ng, Ho Keung ; Jones, Chris ; Van Meter, Timothy ; Clifford, Steven C. ; Eberhart, Charles G ; Gajjar, Amar ; Pfister, Stefan M. ; Grundy, Richard G. ; Huang, Annie. / Markers of survival and metastatic potential in childhood CNS primitive neuro-ectodermal brain tumours : An integrative genomic analysis. In: The Lancet Oncology. 2012 ; Vol. 13, No. 8. pp. 838-848.
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abstract = "Background: Childhood CNS primitive neuro-ectodermal brain tumours (PNETs) are very aggressive brain tumours for which the molecular features and best treatment approaches are unknown. We assessed a large cohort of these rare tumours to identify molecular markers to enhance clinical management of this disease. Methods: We obtained 142 primary hemispheric CNS PNET samples from 20 institutions in nine countries and examined transcriptional profiles for a subset of 51 samples and copy number profiles for a subset of 77 samples. We used clustering, gene, and pathway enrichment analyses to identify tumour subgroups and group-specific molecular markers, and applied immunohistochemical and gene-expression analyses to validate and assess the clinical significance of the subgroup markers. Findings: We identified three molecular subgroups of CNS PNETs that were distinguished by primitive neural (group 1), oligoneural (group 2), and mesenchymal lineage (group 3) gene-expression signatures with differential expression of cell-lineage markers LIN28 and OLIG2. Patients with group 1 tumours were most often female (male:female ratio 0·61 for group 1 vs 1·25 for group 2 and 1·63 for group 3; p=0·043 [group 1 vs groups 2 and 3]), youngest (median age at diagnosis 2·9 years [95{\%} CI 2·4-5·2] for group 1 vs 7·9 years [6·0-9·7] for group 2 and 5·9 years [4·9-7·8] for group 3; p=0·005), and had poorest survival (median survival 0·8 years [95{\%} CI 0·5-1·2] in group 1, 1·8 years [1·4-2·3] in group 2 and 4·3 years [0·8-7·8] in group 3; p=0·019). Patients with group 3 tumours had the highest incidence of metastases at diagnosis (no distant metastasis:metastasis ratio 0·90 for group 3 vs 2·80 for group 1 and 5·67 for group 2; p=0·037). Interpretation: LIN28 and OLIG2 are promising diagnostic and prognostic molecular markers for CNS PNET that warrant further assessment in prospective clinical trials. Funding: Canadian Institute of Health Research, Brainchild/SickKids Foundation, and the Samantha Dickson Brain Tumour Trust.",
author = "Daniel Picard and Suzanne Miller and Hawkins, {Cynthia E.} and Eric Bouffet and Rogers, {Hazel A.} and Chan, {Tiffany S Y} and Kim, {Seung Ki} and Ra, {Young Shin} and Jason Fangusaro and Andrey Korshunov and Helen Toledano and Hideo Nakamura and Hayden, {James T.} and Jennifer Chan and Lucie Lafay-Cousin and Pingzhao Hu and Xing Fan and Muraszko, {Karin M.} and Pomeroy, {Scott L.} and Lau, {Ching C.} and Ng, {Ho Keung} and Chris Jones and {Van Meter}, Timothy and Clifford, {Steven C.} and Eberhart, {Charles G} and Amar Gajjar and Pfister, {Stefan M.} and Grundy, {Richard G.} and Annie Huang",
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TY - JOUR

T1 - Markers of survival and metastatic potential in childhood CNS primitive neuro-ectodermal brain tumours

T2 - An integrative genomic analysis

AU - Picard, Daniel

AU - Miller, Suzanne

AU - Hawkins, Cynthia E.

AU - Bouffet, Eric

AU - Rogers, Hazel A.

AU - Chan, Tiffany S Y

AU - Kim, Seung Ki

AU - Ra, Young Shin

AU - Fangusaro, Jason

AU - Korshunov, Andrey

AU - Toledano, Helen

AU - Nakamura, Hideo

AU - Hayden, James T.

AU - Chan, Jennifer

AU - Lafay-Cousin, Lucie

AU - Hu, Pingzhao

AU - Fan, Xing

AU - Muraszko, Karin M.

AU - Pomeroy, Scott L.

AU - Lau, Ching C.

AU - Ng, Ho Keung

AU - Jones, Chris

AU - Van Meter, Timothy

AU - Clifford, Steven C.

AU - Eberhart, Charles G

AU - Gajjar, Amar

AU - Pfister, Stefan M.

AU - Grundy, Richard G.

AU - Huang, Annie

PY - 2012/8

Y1 - 2012/8

N2 - Background: Childhood CNS primitive neuro-ectodermal brain tumours (PNETs) are very aggressive brain tumours for which the molecular features and best treatment approaches are unknown. We assessed a large cohort of these rare tumours to identify molecular markers to enhance clinical management of this disease. Methods: We obtained 142 primary hemispheric CNS PNET samples from 20 institutions in nine countries and examined transcriptional profiles for a subset of 51 samples and copy number profiles for a subset of 77 samples. We used clustering, gene, and pathway enrichment analyses to identify tumour subgroups and group-specific molecular markers, and applied immunohistochemical and gene-expression analyses to validate and assess the clinical significance of the subgroup markers. Findings: We identified three molecular subgroups of CNS PNETs that were distinguished by primitive neural (group 1), oligoneural (group 2), and mesenchymal lineage (group 3) gene-expression signatures with differential expression of cell-lineage markers LIN28 and OLIG2. Patients with group 1 tumours were most often female (male:female ratio 0·61 for group 1 vs 1·25 for group 2 and 1·63 for group 3; p=0·043 [group 1 vs groups 2 and 3]), youngest (median age at diagnosis 2·9 years [95% CI 2·4-5·2] for group 1 vs 7·9 years [6·0-9·7] for group 2 and 5·9 years [4·9-7·8] for group 3; p=0·005), and had poorest survival (median survival 0·8 years [95% CI 0·5-1·2] in group 1, 1·8 years [1·4-2·3] in group 2 and 4·3 years [0·8-7·8] in group 3; p=0·019). Patients with group 3 tumours had the highest incidence of metastases at diagnosis (no distant metastasis:metastasis ratio 0·90 for group 3 vs 2·80 for group 1 and 5·67 for group 2; p=0·037). Interpretation: LIN28 and OLIG2 are promising diagnostic and prognostic molecular markers for CNS PNET that warrant further assessment in prospective clinical trials. Funding: Canadian Institute of Health Research, Brainchild/SickKids Foundation, and the Samantha Dickson Brain Tumour Trust.

AB - Background: Childhood CNS primitive neuro-ectodermal brain tumours (PNETs) are very aggressive brain tumours for which the molecular features and best treatment approaches are unknown. We assessed a large cohort of these rare tumours to identify molecular markers to enhance clinical management of this disease. Methods: We obtained 142 primary hemispheric CNS PNET samples from 20 institutions in nine countries and examined transcriptional profiles for a subset of 51 samples and copy number profiles for a subset of 77 samples. We used clustering, gene, and pathway enrichment analyses to identify tumour subgroups and group-specific molecular markers, and applied immunohistochemical and gene-expression analyses to validate and assess the clinical significance of the subgroup markers. Findings: We identified three molecular subgroups of CNS PNETs that were distinguished by primitive neural (group 1), oligoneural (group 2), and mesenchymal lineage (group 3) gene-expression signatures with differential expression of cell-lineage markers LIN28 and OLIG2. Patients with group 1 tumours were most often female (male:female ratio 0·61 for group 1 vs 1·25 for group 2 and 1·63 for group 3; p=0·043 [group 1 vs groups 2 and 3]), youngest (median age at diagnosis 2·9 years [95% CI 2·4-5·2] for group 1 vs 7·9 years [6·0-9·7] for group 2 and 5·9 years [4·9-7·8] for group 3; p=0·005), and had poorest survival (median survival 0·8 years [95% CI 0·5-1·2] in group 1, 1·8 years [1·4-2·3] in group 2 and 4·3 years [0·8-7·8] in group 3; p=0·019). Patients with group 3 tumours had the highest incidence of metastases at diagnosis (no distant metastasis:metastasis ratio 0·90 for group 3 vs 2·80 for group 1 and 5·67 for group 2; p=0·037). Interpretation: LIN28 and OLIG2 are promising diagnostic and prognostic molecular markers for CNS PNET that warrant further assessment in prospective clinical trials. Funding: Canadian Institute of Health Research, Brainchild/SickKids Foundation, and the Samantha Dickson Brain Tumour Trust.

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