Transcriptome and methylome analysis of CNS germ cell tumor finds its cell-of-origin in embryogenesis and reveals shared similarities with testicular counterparts.
RNA sequence
embryogenesis
germ cell tumor
methylation
transcriptome
Journal
Neuro-oncology
ISSN: 1523-5866
Titre abrégé: Neuro Oncol
Pays: England
ID NLM: 100887420
Informations de publication
Date de publication:
01 08 2022
01 08 2022
Historique:
pubmed:
10
2
2022
medline:
3
8
2022
entrez:
9
2
2022
Statut:
ppublish
Résumé
CNS germ cell tumors (GCTs) predominantly develop in pediatric and young adult patients with variable responses to surgery, radiation, and chemotherapy. This study aimed to examine the complex and largely unknown pathogenesis of CNS GCTs. We used a combined transcriptomic and methylomic approach in 84 cases and conducted an integrative analysis of the normal cells undergoing embryogenesis and testicular GCTs. Genome-wide transcriptome analysis in CNS GCTs indicated that germinoma had a transcriptomic profile representative of primitive cells during early embryogenesis with high meiosis/mitosis potentials, while nongerminomatous GCTs (NGGCTs) had differentiated phenotypes oriented toward tissue formation and organogenesis. Co-analysis with the transcriptome of human embryonic cells revealed that germinomas had expression profiles similar to those of primordial germ cells, while the expression profiles of NGGCTs were similar to those of embryonic stem cells. Some germinoma cases were characterized by extensive immune-cell infiltration and high expression of cancer-testis antigens. NGGCTs had significantly higher immune-cell infiltration, characterized by immune-suppression phenotype. CNS and testicular GCTs (TGCTs) had similar mutational profiles; TGCTs showed enhanced copy number alterations. Methylation analysis clustered germinoma/seminoma and nongerminoma/nonseminoma separately. Germinoma and seminoma were co-categorized based on the degree of the tumor microenvironment balance. These results suggested that the pathophysiology of GCTs was less dependent on their site of origin and more dependent on the state of differentiation as well as on the tumor microenvironment balance. This study revealed distinct biological properties of GCTs, which will hopefully lead to future treatment development.
Sections du résumé
BACKGROUND
CNS germ cell tumors (GCTs) predominantly develop in pediatric and young adult patients with variable responses to surgery, radiation, and chemotherapy. This study aimed to examine the complex and largely unknown pathogenesis of CNS GCTs.
METHODS
We used a combined transcriptomic and methylomic approach in 84 cases and conducted an integrative analysis of the normal cells undergoing embryogenesis and testicular GCTs.
RESULTS
Genome-wide transcriptome analysis in CNS GCTs indicated that germinoma had a transcriptomic profile representative of primitive cells during early embryogenesis with high meiosis/mitosis potentials, while nongerminomatous GCTs (NGGCTs) had differentiated phenotypes oriented toward tissue formation and organogenesis. Co-analysis with the transcriptome of human embryonic cells revealed that germinomas had expression profiles similar to those of primordial germ cells, while the expression profiles of NGGCTs were similar to those of embryonic stem cells. Some germinoma cases were characterized by extensive immune-cell infiltration and high expression of cancer-testis antigens. NGGCTs had significantly higher immune-cell infiltration, characterized by immune-suppression phenotype. CNS and testicular GCTs (TGCTs) had similar mutational profiles; TGCTs showed enhanced copy number alterations. Methylation analysis clustered germinoma/seminoma and nongerminoma/nonseminoma separately. Germinoma and seminoma were co-categorized based on the degree of the tumor microenvironment balance.
CONCLUSIONS
These results suggested that the pathophysiology of GCTs was less dependent on their site of origin and more dependent on the state of differentiation as well as on the tumor microenvironment balance. This study revealed distinct biological properties of GCTs, which will hopefully lead to future treatment development.
Identifiants
pubmed: 35137206
pii: 6524508
doi: 10.1093/neuonc/noac021
pmc: PMC9340652
doi:
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1246-1258Commentaires et corrections
Type : CommentIn
Informations de copyright
© The Author(s) 2022. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.
Références
Cell. 2015 Jan 15;160(1-2):253-68
pubmed: 25543152
Neurosurgery. 2020 Sep 1;87(3):563-572
pubmed: 32348488
J Neurosurg. 1997 Mar;86(3):446-55
pubmed: 9046301
Proc Natl Acad Sci U S A. 1954 Nov;40(11):1080-7
pubmed: 16578442
Immunity. 2013 Oct 17;39(4):782-95
pubmed: 24138885
BMC Cancer. 2015 Oct 23;15:769
pubmed: 26497383
Cell. 2015 Jun 4;161(6):1425-36
pubmed: 26004067
Nat Struct Mol Biol. 2013 Sep;20(9):1131-9
pubmed: 23934149
Acta Pathol Microbiol Scand. 1965;64(4):407-29
pubmed: 5318716
Cell Rep. 2018 Jun 12;23(11):3392-3406
pubmed: 29898407
Cancer. 2011 Dec 1;117(23):5402-11
pubmed: 21563173
Cell. 2015 Jun 4;161(6):1437-52
pubmed: 26046443
BMC Genomics. 2010 Feb 24;11:132
pubmed: 20178649
Neurooncol Adv. 2021 Aug 10;3(1):vdab110
pubmed: 34549182
Acta Neuropathol. 2017 Mar;133(3):445-462
pubmed: 28078450
Curr Opin Genet Dev. 2003 Oct;13(5):463-71
pubmed: 14550410
Neurol Res. 1989 Jun;11(2):118-26
pubmed: 2569683
Cell. 2015 Jun 4;161(6):1453-67
pubmed: 26046444
Neuro Oncol. 2001 Jul;3(3):174-83
pubmed: 11465398
Int J Androl. 2007 Aug;30(4):256-63; discussion 263-4
pubmed: 17705807
Neuropathol Appl Neurobiol. 2020 Feb;46(2):111-124
pubmed: 31179566
Nature. 2014 Jul 10;511(7508):241-5
pubmed: 24896186
Acta Neuropathol. 2016 Jun;131(6):889-901
pubmed: 26956871
Cell Stem Cell. 2015 Aug 6;17(2):178-94
pubmed: 26189426
Neuro Oncol. 2019 Dec 17;21(12):1565-1577
pubmed: 31420671