TY - JOUR
T1 - Clinical and molecular heterogeneity of pineal parenchymal tumors
T2 - a consensus study
AU - Liu, Anthony P.Y.
AU - Li, Bryan K.
AU - Pfaff, Elke
AU - Gudenas, Brian
AU - Vasiljevic, Alexandre
AU - Orr, Brent A.
AU - Dufour, Christelle
AU - Snuderl, Matija
AU - Karajannis, Matthias A.
AU - Rosenblum, Marc K.
AU - Hwang, Eugene I.
AU - Ng, Ho Keung
AU - Hansford, Jordan R.
AU - Szathmari, Alexandru
AU - Faure-Conter, Cécile
AU - Merchant, Thomas E.
AU - Levine, Max
AU - Bouvier, Nancy
AU - von Hoff, Katja
AU - Mynarek, Martin
AU - Rutkowski, Stefan
AU - Sahm, Felix
AU - Kool, Marcel
AU - Hawkins, Cynthia
AU - Onar-Thomas, Arzu
AU - Robinson, Giles W.
AU - Gajjar, Amar
AU - Pfister, Stefan M.
AU - Bouffet, Eric
AU - Northcott, Paul A.
AU - Jones, David T.W.
AU - Huang, Annie
N1 - Publisher Copyright:
© 2021, The Author(s), under exclusive licence to Springer-Verlag GmbH, DE part of Springer Nature.
PY - 2021/5
Y1 - 2021/5
N2 - Recent genomic studies have shed light on the biology and inter-tumoral heterogeneity underlying pineal parenchymal tumors, in particular pineoblastomas (PBs) and pineal parenchymal tumors of intermediate differentiation (PPTIDs). Previous reports, however, had modest sample sizes and lacked the power to integrate molecular and clinical findings. The different proposed molecular group structures also highlighted a need to reach consensus on a robust and relevant classification system. We performed a meta-analysis on 221 patients with molecularly characterized PBs and PPTIDs. DNA methylation profiles were analyzed through complementary bioinformatic approaches and molecular subgrouping was harmonized. Demographic, clinical, and genomic features of patients and samples from these pineal tumor groups were annotated. Four clinically and biologically relevant consensus PB groups were defined: PB-miRNA1 (n = 96), PB-miRNA2 (n = 23), PB-MYC/FOXR2 (n = 34), and PB-RB1 (n = 25). A final molecularly distinct group, designated PPTID (n = 43), comprised histological PPTID and PBs. Genomic and transcriptomic profiling allowed the characterization of oncogenic drivers for individual tumor groups, specifically, alterations in the microRNA processing pathway in PB-miRNA1/2, MYC amplification and FOXR2 overexpression in PB-MYC/FOXR2, RB1 alteration in PB-RB1, and KBTBD4 insertion in PPTID. Age at diagnosis, sex predilection, and metastatic status varied significantly among tumor groups. While patients with PB-miRNA2 and PPTID had superior outcome, survival was intermediate for patients with PB-miRNA1, and dismal for those with PB-MYC/FOXR2 or PB-RB1. Reduced-dose CSI was adequate for patients with average-risk, PB-miRNA1/2 disease. We systematically interrogated the clinical and molecular heterogeneity within pineal parenchymal tumors and proposed a consensus nomenclature for disease groups, laying the groundwork for future studies as well as routine use in tumor diagnostic classification and clinical trial stratification.
AB - Recent genomic studies have shed light on the biology and inter-tumoral heterogeneity underlying pineal parenchymal tumors, in particular pineoblastomas (PBs) and pineal parenchymal tumors of intermediate differentiation (PPTIDs). Previous reports, however, had modest sample sizes and lacked the power to integrate molecular and clinical findings. The different proposed molecular group structures also highlighted a need to reach consensus on a robust and relevant classification system. We performed a meta-analysis on 221 patients with molecularly characterized PBs and PPTIDs. DNA methylation profiles were analyzed through complementary bioinformatic approaches and molecular subgrouping was harmonized. Demographic, clinical, and genomic features of patients and samples from these pineal tumor groups were annotated. Four clinically and biologically relevant consensus PB groups were defined: PB-miRNA1 (n = 96), PB-miRNA2 (n = 23), PB-MYC/FOXR2 (n = 34), and PB-RB1 (n = 25). A final molecularly distinct group, designated PPTID (n = 43), comprised histological PPTID and PBs. Genomic and transcriptomic profiling allowed the characterization of oncogenic drivers for individual tumor groups, specifically, alterations in the microRNA processing pathway in PB-miRNA1/2, MYC amplification and FOXR2 overexpression in PB-MYC/FOXR2, RB1 alteration in PB-RB1, and KBTBD4 insertion in PPTID. Age at diagnosis, sex predilection, and metastatic status varied significantly among tumor groups. While patients with PB-miRNA2 and PPTID had superior outcome, survival was intermediate for patients with PB-miRNA1, and dismal for those with PB-MYC/FOXR2 or PB-RB1. Reduced-dose CSI was adequate for patients with average-risk, PB-miRNA1/2 disease. We systematically interrogated the clinical and molecular heterogeneity within pineal parenchymal tumors and proposed a consensus nomenclature for disease groups, laying the groundwork for future studies as well as routine use in tumor diagnostic classification and clinical trial stratification.
KW - Consensus
KW - DNA methylation profiling
KW - Molecular groups
KW - Pineal parenchymal tumors of intermediate differentiation
KW - Pineoblastoma
KW - Risk-stratification
UR - http://www.scopus.com/inward/record.url?scp=85101224550&partnerID=8YFLogxK
U2 - 10.1007/s00401-021-02284-5
DO - 10.1007/s00401-021-02284-5
M3 - Article
C2 - 33619588
AN - SCOPUS:85101224550
SN - 0001-6322
VL - 141
SP - 771
EP - 785
JO - Acta Neuropathologica
JF - Acta Neuropathologica
IS - 5
ER -