Deconvolution of sarcoma methylomes reveals varying degrees of immune cell infiltrates with association to genomic aberrations.
Deconvolution
Sarcoma
Survival analysis
Tumor-infiltrating leukocytes
Journal
Journal of translational medicine
ISSN: 1479-5876
Titre abrégé: J Transl Med
Pays: England
ID NLM: 101190741
Informations de publication
Date de publication:
12 05 2021
12 05 2021
Historique:
received:
13
03
2021
accepted:
26
04
2021
entrez:
13
5
2021
pubmed:
14
5
2021
medline:
22
5
2021
Statut:
epublish
Résumé
Soft-tissue sarcomas (STS) are a heterogeneous group of mesenchymal tumors for which response to immunotherapies is not well established. Therefore, it is important to risk-stratify and identify STS patients who will most likely benefit from these treatments. To reveal shared and distinct methylation signatures present in STS, we performed unsupervised deconvolution of DNA methylation data from the TCGA sarcoma and an independent validation cohort. We showed that leiomyosarcoma can be subclassified into three distinct methylation groups. More importantly, we identified a component associated with tumor-infiltrating leukocytes, which suggests varying degrees of immune cell infiltration in STS subtypes and an association with prognosis. We further investigated the genomic alterations that may influence tumor infiltration by leukocytes including RB1 loss in undifferentiated pleomorphic sarcomas and ELK3 amplification in dedifferentiated liposarcomas. In summary, we have leveraged unsupervised methylation-based deconvolution to characterize the immune compartment and molecularly stratify subtypes in STS, which may benefit precision medicine in the future.
Sections du résumé
BACKGROUND
Soft-tissue sarcomas (STS) are a heterogeneous group of mesenchymal tumors for which response to immunotherapies is not well established. Therefore, it is important to risk-stratify and identify STS patients who will most likely benefit from these treatments.
RESULTS
To reveal shared and distinct methylation signatures present in STS, we performed unsupervised deconvolution of DNA methylation data from the TCGA sarcoma and an independent validation cohort. We showed that leiomyosarcoma can be subclassified into three distinct methylation groups. More importantly, we identified a component associated with tumor-infiltrating leukocytes, which suggests varying degrees of immune cell infiltration in STS subtypes and an association with prognosis. We further investigated the genomic alterations that may influence tumor infiltration by leukocytes including RB1 loss in undifferentiated pleomorphic sarcomas and ELK3 amplification in dedifferentiated liposarcomas.
CONCLUSIONS
In summary, we have leveraged unsupervised methylation-based deconvolution to characterize the immune compartment and molecularly stratify subtypes in STS, which may benefit precision medicine in the future.
Identifiants
pubmed: 33980253
doi: 10.1186/s12967-021-02858-7
pii: 10.1186/s12967-021-02858-7
pmc: PMC8117561
doi:
Substances chimiques
Elk3 protein, human
0
Proto-Oncogene Proteins c-ets
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
204Subventions
Organisme : CIHR
ID : 825835
Pays : Canada
Commentaires et corrections
Type : ErratumIn
Références
Nat Commun. 2017 Oct 19;8(1):1050
pubmed: 29051489
Lancet Oncol. 2018 Mar;19(3):416-426
pubmed: 29370992
Cell. 2015 Jan 15;160(1-2):48-61
pubmed: 25594174
Genome Med. 2017 Apr 19;9(1):34
pubmed: 28420421
Cell. 2017 Nov 2;171(4):950-965.e28
pubmed: 29100075
Clin Cancer Res. 2019 May 15;25(10):3074-3083
pubmed: 30635339
Immunity. 2015 May 19;42(5):903-15
pubmed: 25979421
Nat Cancer. 2020 Aug;1(8):800-810
pubmed: 35122049
Genome Biol. 2017 Mar 24;18(1):55
pubmed: 28340624
Nat Commun. 2018 Jan 10;9(1):144
pubmed: 29321523
Oncotarget. 2016 Oct 4;7(40):65137-65146
pubmed: 27556500
Clin Cancer Res. 2015 Aug 1;21(15):3501-11
pubmed: 25896974
Cell Death Dis. 2015 Jun 18;6:e1792
pubmed: 26086965
Nat Rev Rheumatol. 2014 Sep;10(9):543-51
pubmed: 24980140
Proc Natl Acad Sci U S A. 2009 Aug 18;106(33):13974-9
pubmed: 19666526
Lancet Oncol. 2017 Nov;18(11):1493-1501
pubmed: 28988646
Nucleic Acids Res. 2004 Jan 1;32(Database issue):D258-61
pubmed: 14681407
BMC Bioinformatics. 2013 Apr 15;14:128
pubmed: 23586463
Genome Res. 2021 Mar;31(3):448-460
pubmed: 33441414
Nat Commun. 2017 Dec 11;8(1):2032
pubmed: 29230012
Nature. 2020 Jan;577(7791):556-560
pubmed: 31942077
Biochim Biophys Acta. 1981 Apr 27;653(2):204-18
pubmed: 7225396
J Immunother Cancer. 2017 Feb 21;5:18
pubmed: 28239471
Front Bioeng Biotechnol. 2020 Aug 21;8:1003
pubmed: 32974322
PLoS One. 2012;7(7):e41361
pubmed: 22848472
Nat Commun. 2018 Aug 13;9(1):3220
pubmed: 30104673
Eur J Cancer. 2016 Apr;57:104-11
pubmed: 26916546
Gut Liver. 2017 Jan 15;11(1):102-111
pubmed: 27538444
Nat Rev Cancer. 2003 Apr;3(4):253-66
pubmed: 12671664
Cancer Immunol Immunother. 2012 Sep;61(9):1511-20
pubmed: 22527244
Immunity. 2018 Apr 17;48(4):812-830.e14
pubmed: 29628290
Oncogene. 2010 Feb 11;29(6):845-54
pubmed: 19901961
Sarcoma. 2018 Aug 12;2018:9305294
pubmed: 30158830
Cell Cycle. 2015;14(24):3812-9
pubmed: 25714546
Oncol Rep. 2017 Feb;37(2):813-822
pubmed: 27959451
Nature. 2007 Oct 25;449(7165):1003-7
pubmed: 17934449
Methods Mol Biol. 2018;1711:243-259
pubmed: 29344893
Adv Exp Med Biol. 2013;754:31-56
pubmed: 22956495
Clin Cancer Res. 2020 Mar 15;26(6):1258-1266
pubmed: 31900276
Nat Rev Immunol. 2016 Dec;16(12):741-750
pubmed: 27667712
Nat Rev Immunol. 2007 May;7(5):365-78
pubmed: 17438574
Agents Actions Suppl. 1997;48:3-24
pubmed: 9177097
MAbs. 2014 Jan-Feb;6(1):54-72
pubmed: 24423620
Nat Methods. 2014 Nov;11(11):1138-1140
pubmed: 25262207
Nucleic Acids Res. 2000 Jan 1;28(1):27-30
pubmed: 10592173
Stem Cells. 2012 Nov;30(11):2378-86
pubmed: 22969042
Oncoimmunology. 2020 Jul 12;9(1):1792036
pubmed: 32923153
Hepatology. 2014 Oct;60(4):1231-40
pubmed: 24824777
J Clin Oncol. 2018 Jan 10;36(2):180-187
pubmed: 29220290
Int J Cancer. 2017 Sep 1;141(5):877-886
pubmed: 28597939
Nucleic Acids Res. 1983 Oct 11;11(19):6883-94
pubmed: 6314264
Carcinogenesis. 2013 May;34(5):1150-7
pubmed: 23349017
Oncotarget. 2017 Jul 25;8(44):76241-76256
pubmed: 29100308