Integrative multi-omics identifies high risk multiple myeloma subgroup associated with significant DNA loss and dysregulated DNA repair and cell cycle pathways.
Journal
BMC medical genomics
ISSN: 1755-8794
Titre abrégé: BMC Med Genomics
Pays: England
ID NLM: 101319628
Informations de publication
Date de publication:
18 12 2021
18 12 2021
Historique:
received:
21
09
2021
accepted:
30
11
2021
entrez:
19
12
2021
pubmed:
20
12
2021
medline:
8
4
2022
Statut:
epublish
Résumé
Despite significant therapeutic advances in improving lives of multiple myeloma (MM) patients, it remains mostly incurable, with patients ultimately becoming refractory to therapies. MM is a genetically heterogeneous disease and therapeutic resistance is driven by a complex interplay of disease pathobiology and mechanisms of drug resistance. We applied a multi-omics strategy using tumor-derived gene expression, single nucleotide variant, copy number variant, and structural variant profiles to investigate molecular subgroups in 514 newly diagnosed MM (NDMM) samples and identified 12 molecularly defined MM subgroups (MDMS1-12) with distinct genomic and transcriptomic features. Our integrative approach let us identify NDMM subgroups with transversal profiles to previously described ones, based on single data types, which shows the impact of this approach for disease stratification. One key novel subgroup is our MDMS8, associated with poor clinical outcome [median overall survival, 38 months (global log-rank p-value < 1 × 10 Using multi-omics unsupervised clustering we were able to discover a new high-risk multiple myeloma patient segment. This high-risk group presents diverse previously known genetic markers, but also a new characteristic defined by accumulation of genomic loss which seems to drive transcriptional dysregulation of cell cycle, DNA repair and DNA damage. Finally, our work identified various master regulators, including E2F2 and CKS1B as the genes controlling these key biological pathways.
Sections du résumé
BACKGROUND
Despite significant therapeutic advances in improving lives of multiple myeloma (MM) patients, it remains mostly incurable, with patients ultimately becoming refractory to therapies. MM is a genetically heterogeneous disease and therapeutic resistance is driven by a complex interplay of disease pathobiology and mechanisms of drug resistance. We applied a multi-omics strategy using tumor-derived gene expression, single nucleotide variant, copy number variant, and structural variant profiles to investigate molecular subgroups in 514 newly diagnosed MM (NDMM) samples and identified 12 molecularly defined MM subgroups (MDMS1-12) with distinct genomic and transcriptomic features.
RESULTS
Our integrative approach let us identify NDMM subgroups with transversal profiles to previously described ones, based on single data types, which shows the impact of this approach for disease stratification. One key novel subgroup is our MDMS8, associated with poor clinical outcome [median overall survival, 38 months (global log-rank p-value < 1 × 10
CONCLUSION
Using multi-omics unsupervised clustering we were able to discover a new high-risk multiple myeloma patient segment. This high-risk group presents diverse previously known genetic markers, but also a new characteristic defined by accumulation of genomic loss which seems to drive transcriptional dysregulation of cell cycle, DNA repair and DNA damage. Finally, our work identified various master regulators, including E2F2 and CKS1B as the genes controlling these key biological pathways.
Identifiants
pubmed: 34922559
doi: 10.1186/s12920-021-01140-5
pii: 10.1186/s12920-021-01140-5
pmc: PMC8684160
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
295Informations de copyright
© 2021. The Author(s).
Références
Leukemia. 2019 Jan;33(1):159-170
pubmed: 29967379
N Engl J Med. 2005 Jun 16;352(24):2487-98
pubmed: 15958804
Oncotarget. 2016 May 24;7(21):31014-28
pubmed: 27105536
Life Sci Alliance. 2020 Jan 20;3(1):
pubmed: 31959624
PLoS One. 2015 Mar 30;10(3):e0120833
pubmed: 25822495
Acta Biochim Biophys Sin (Shanghai). 2019 Dec 13;51(12):1276-1285
pubmed: 31774908
Cell. 2017 Oct 19;171(3):540-556.e25
pubmed: 28988769
Proc Natl Acad Sci U S A. 2013 Mar 12;110(11):4245-50
pubmed: 23431203
Nat Rev Cancer. 2012 Apr 12;12(5):335-48
pubmed: 22495321
Blood. 2015 Mar 19;125(12):1870-6
pubmed: 25628468
Science. 1998 Sep 11;281(5383):1680-3
pubmed: 9733516
J Clin Oncol. 2015 Sep 10;33(26):2863-9
pubmed: 26240224
Haematologica. 2011 Jan;96(1):87-95
pubmed: 20884712
Bioinformatics. 2012 Mar 15;28(6):882-3
pubmed: 22257669
Genes Chromosomes Cancer. 2002 Oct;35(2):176-81
pubmed: 12203782
Blood. 2008 Feb 1;111(3):1603-9
pubmed: 18006703
BMC Cancer. 2018 Jan 8;18(1):53
pubmed: 29310601
J Clin Oncol. 2005 May 20;23(15):3412-20
pubmed: 15809451
Blood. 2018 Aug 9;132(6):587-597
pubmed: 29884741
N Engl J Med. 2016 Jan 14;374(2):135-45
pubmed: 26536169
Oncol Lett. 2019 Feb;17(2):1921-1933
pubmed: 30675256
Leukemia. 2012 Nov;26(11):2406-13
pubmed: 22722715
Nat Genet. 2016 Aug;48(8):838-47
pubmed: 27322546
Nature. 2002 Dec 12;420(6916):629-35
pubmed: 12478284
Pac Symp Biocomput. 2009;:504-15
pubmed: 19209726
Blood. 2010 Oct 7;116(14):2543-53
pubmed: 20574050
Leukemia. 2018 Jan;32(1):120-130
pubmed: 28642592
Bioinformatics. 2011 Jun 15;27(12):1739-40
pubmed: 21546393
Nature. 2012 Oct 4;490(7418):61-70
pubmed: 23000897
Br J Haematol. 2019 Apr;185(2):254-260
pubmed: 30768679
Leukemia. 2018 Dec;32(12):2626-2635
pubmed: 29749396
Anticancer Res. 2018 Jun;38(6):3267-3272
pubmed: 29848673
Leukemia. 2016 May;30(5):1071-8
pubmed: 26669975
Nat Rev Cancer. 2017 Feb;17(2):116-130
pubmed: 27977008
Blood. 2006 Sep 15;108(6):2020-8
pubmed: 16728703
N Engl J Med. 2016 Jun 9;374(23):2209-2221
pubmed: 27276561
Cell Rep. 2018 Apr 03;23(1):239-254.e6
pubmed: 29617664
Proc Natl Acad Sci U S A. 2005 Oct 25;102(43):15545-50
pubmed: 16199517
Blood. 2007 Mar 15;109(6):2276-84
pubmed: 17105813
Genome Biol. 2014 Feb 03;15(2):R29
pubmed: 24485249
Blood. 2019 Mar 14;133(11):1217-1221
pubmed: 30692124
J Cell Mol Med. 2020 Feb;24(3):2157-2168
pubmed: 31943751
Cancer Cell. 2018 Apr 9;33(4):690-705.e9
pubmed: 29622464
PLoS One. 2013 Jun 20;8(6):e66361
pubmed: 23840451
Int J Cardiol. 2014 Feb 1;171(2):161-8
pubmed: 24380498
Blood. 2003 Jun 15;101(12):4998-5006
pubmed: 12623842
Leukemia. 2018 Nov;32(11):2435-2444
pubmed: 29654269
Blood Cancer J. 2019 Aug 6;9(8):60
pubmed: 31387987
Nat Genet. 2018 Jul;50(7):979-989
pubmed: 29915428