Whole-genome analysis identifies novel drivers and high-risk double-hit events in relapsed/refractory myeloma
© 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved..
Large-scale analyses of genomic data from patients with newly diagnosed multiple myeloma (ndMM) have been undertaken, however, large-scale analysis of relapsed/refractory MM (rrMM) has not been performed. We hypothesize that somatic variants chronicle the therapeutic exposures and clonal structure of myeloma from ndMM to rrMM stages. We generated whole-genome sequencing (WGS) data from 418 tumors (386 patients) derived from 6 rrMM clinical trials and compared them with WGS from 198 unrelated patients with ndMM in a population-based case-control fashion. We identified significantly enriched events at the rrMM stage, including drivers (DUOX2, EZH2, TP53), biallelic inactivation (TP53), noncoding mutations in bona fide drivers (TP53BP1, BLM), copy number aberrations (CNAs; 1qGain, 17pLOH), and double-hit events (Amp1q-ISS3, 1qGain-17p loss-of-heterozygosity). Mutational signature analysis identified a subclonal defective mismatch repair signature enriched in rrMM and highly active in high mutation burden tumors, a likely feature of therapy-associated expanding subclones. Further analysis focused on the association of genomic aberrations enriched at different stages of resistance to immunomodulatory agent (IMiD)-based therapy. This analysis revealed that TP53, DUOX2, 1qGain, and 17p loss-of-heterozygosity increased in prevalence from ndMM to lenalidomide resistant (LENR) to pomalidomide resistant (POMR) stages, whereas enrichment of MAML3 along with immunoglobulin lambda (IGL) and MYC translocations distinguished POM from the LEN subgroup. Genomic drivers associated with rrMM are those that confer clonal selective advantage under therapeutic pressure. Their role in therapy evasion should be further evaluated in longitudinal patient samples, to confirm these associations with the evolution of clinical resistance and to identify molecular subsets of rrMM for the development of targeted therapies.
Errataetall: |
CommentIn: Blood. 2023 Feb 9;141(6):560-561. - PMID 36757732 |
---|---|
Medienart: |
E-Artikel |
Erscheinungsjahr: |
2023 |
---|---|
Erschienen: |
2023 |
Enthalten in: |
Zur Gesamtaufnahme - volume:141 |
---|---|
Enthalten in: |
Blood - 141(2023), 6 vom: 09. Feb., Seite 620-633 |
Sprache: |
Englisch |
---|
Beteiligte Personen: |
Ansari-Pour, Naser [VerfasserIn] |
---|
Links: |
---|
Themen: |
7S5I7G3JQL |
---|
Anmerkungen: |
Date Completed 13.02.2023 Date Revised 31.08.2023 published: Print CommentIn: Blood. 2023 Feb 9;141(6):560-561. - PMID 36757732 Citation Status MEDLINE |
---|
doi: |
10.1182/blood.2022017010 |
---|
funding: |
|
---|---|
Förderinstitution / Projekttitel: |
|
PPN (Katalog-ID): |
NLM347387322 |
---|
LEADER | 01000naa a22002652 4500 | ||
---|---|---|---|
001 | NLM347387322 | ||
003 | DE-627 | ||
005 | 20231226033710.0 | ||
007 | cr uuu---uuuuu | ||
008 | 231226s2023 xx |||||o 00| ||eng c | ||
024 | 7 | |a 10.1182/blood.2022017010 |2 doi | |
028 | 5 | 2 | |a pubmed24n1157.xml |
035 | |a (DE-627)NLM347387322 | ||
035 | |a (NLM)36223594 | ||
040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
041 | |a eng | ||
100 | 1 | |a Ansari-Pour, Naser |e verfasserin |4 aut | |
245 | 1 | 0 | |a Whole-genome analysis identifies novel drivers and high-risk double-hit events in relapsed/refractory myeloma |
264 | 1 | |c 2023 | |
336 | |a Text |b txt |2 rdacontent | ||
337 | |a ƒaComputermedien |b c |2 rdamedia | ||
338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
500 | |a Date Completed 13.02.2023 | ||
500 | |a Date Revised 31.08.2023 | ||
500 | |a published: Print | ||
500 | |a CommentIn: Blood. 2023 Feb 9;141(6):560-561. - PMID 36757732 | ||
500 | |a Citation Status MEDLINE | ||
520 | |a © 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved. | ||
520 | |a Large-scale analyses of genomic data from patients with newly diagnosed multiple myeloma (ndMM) have been undertaken, however, large-scale analysis of relapsed/refractory MM (rrMM) has not been performed. We hypothesize that somatic variants chronicle the therapeutic exposures and clonal structure of myeloma from ndMM to rrMM stages. We generated whole-genome sequencing (WGS) data from 418 tumors (386 patients) derived from 6 rrMM clinical trials and compared them with WGS from 198 unrelated patients with ndMM in a population-based case-control fashion. We identified significantly enriched events at the rrMM stage, including drivers (DUOX2, EZH2, TP53), biallelic inactivation (TP53), noncoding mutations in bona fide drivers (TP53BP1, BLM), copy number aberrations (CNAs; 1qGain, 17pLOH), and double-hit events (Amp1q-ISS3, 1qGain-17p loss-of-heterozygosity). Mutational signature analysis identified a subclonal defective mismatch repair signature enriched in rrMM and highly active in high mutation burden tumors, a likely feature of therapy-associated expanding subclones. Further analysis focused on the association of genomic aberrations enriched at different stages of resistance to immunomodulatory agent (IMiD)-based therapy. This analysis revealed that TP53, DUOX2, 1qGain, and 17p loss-of-heterozygosity increased in prevalence from ndMM to lenalidomide resistant (LENR) to pomalidomide resistant (POMR) stages, whereas enrichment of MAML3 along with immunoglobulin lambda (IGL) and MYC translocations distinguished POM from the LEN subgroup. Genomic drivers associated with rrMM are those that confer clonal selective advantage under therapeutic pressure. Their role in therapy evasion should be further evaluated in longitudinal patient samples, to confirm these associations with the evolution of clinical resistance and to identify molecular subsets of rrMM for the development of targeted therapies | ||
650 | 4 | |a Journal Article | |
650 | 4 | |a Research Support, Non-U.S. Gov't | |
650 | 7 | |a Dual Oxidases |2 NLM | |
650 | 7 | |a EC 1.11.1.- |2 NLM | |
650 | 7 | |a Lenalidomide |2 NLM | |
650 | 7 | |a F0P408N6V4 |2 NLM | |
650 | 7 | |a Immunologic Factors |2 NLM | |
650 | 7 | |a Dexamethasone |2 NLM | |
650 | 7 | |a 7S5I7G3JQL |2 NLM | |
700 | 1 | |a Samur, Mehmet |e verfasserin |4 aut | |
700 | 1 | |a Flynt, Erin |e verfasserin |4 aut | |
700 | 1 | |a Gooding, Sarah |e verfasserin |4 aut | |
700 | 1 | |a Towfic, Fadi |e verfasserin |4 aut | |
700 | 1 | |a Stong, Nicholas |e verfasserin |4 aut | |
700 | 1 | |a Estevez, Maria Ortiz |e verfasserin |4 aut | |
700 | 1 | |a Mavrommatis, Konstantinos |e verfasserin |4 aut | |
700 | 1 | |a Walker, Brian |e verfasserin |4 aut | |
700 | 1 | |a Morgan, Gareth |e verfasserin |4 aut | |
700 | 1 | |a Munshi, Nikhil |e verfasserin |4 aut | |
700 | 1 | |a Avet-Loiseau, Herve |e verfasserin |4 aut | |
700 | 1 | |a Thakurta, Anjan |e verfasserin |4 aut | |
773 | 0 | 8 | |i Enthalten in |t Blood |d 1946 |g 141(2023), 6 vom: 09. Feb., Seite 620-633 |w (DE-627)NLM000014761 |x 1528-0020 |7 nnns |
773 | 1 | 8 | |g volume:141 |g year:2023 |g number:6 |g day:09 |g month:02 |g pages:620-633 |
856 | 4 | 0 | |u http://dx.doi.org/10.1182/blood.2022017010 |3 Volltext |
912 | |a GBV_USEFLAG_A | ||
912 | |a GBV_NLM | ||
951 | |a AR | ||
952 | |d 141 |j 2023 |e 6 |b 09 |c 02 |h 620-633 |