دورية أكاديمية
أعرض في EDS

Integrative multi-omics identifies high risk multiple myeloma subgroup associated with significant DNA loss and dysregulated DNA repair and cell cycle pathways.

التفاصيل البيبلوغرافية
العنوان: Integrative multi-omics identifies high risk multiple myeloma subgroup associated with significant DNA loss and dysregulated DNA repair and cell cycle pathways.
المؤلفون: Ortiz-Estévez M; BMS Center for Innovation and Translational Research Europe (CITRE), A Bristol Myers Squibb Company, Sevilla, Spain., Towfic F; Bristol Myers Squibb, San Diego, CA, USA., Flynt E; Bristol Myers Squibb, 181 Passaic Ave, Summit, NJ, 07901, USA., Stong N; Bristol Myers Squibb, 181 Passaic Ave, Summit, NJ, 07901, USA., Jang IS; Bristol Myers Squibb, San Diego, CA, USA., Wang K; Bristol Myers Squibb, San Diego, CA, USA., Trotter MWB; BMS Center for Innovation and Translational Research Europe (CITRE), A Bristol Myers Squibb Company, Sevilla, Spain., Thakurta A; Bristol Myers Squibb, 181 Passaic Ave, Summit, NJ, 07901, USA. anjan.thakurta@bms.com.
المصدر: BMC medical genomics [BMC Med Genomics] 2021 Dec 18; Vol. 14 (1), pp. 295. Date of Electronic Publication: 2021 Dec 18.
نوع المنشور: Journal Article
اللغة: English
بيانات الدورية: Publisher: BioMed Central Country of Publication: England NLM ID: 101319628 Publication Model: Electronic Cited Medium: Internet ISSN: 1755-8794 (Electronic) Linking ISSN: 17558794 NLM ISO Abbreviation: BMC Med Genomics Subsets: MEDLINE
أسماء مطبوعة: Original Publication: London : BioMed Central
مواضيع طبية MeSH: Multiple Myeloma*/epidemiology , Multiple Myeloma*/genetics, Cell Cycle/genetics ; DNA Damage/genetics ; DNA Repair/genetics ; Genomics/methods ; Humans ; Risk
مستخلص: 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 -6 )], which uniquely presents a broad genomic loss (> 9% of entire genome, t-test p value < 1e-5) driving dysregulation of various transcriptional programs affecting DNA repair and cell cycle/mitotic processes. This subgroup was validated on multiple independent datasets, and a master regulator analyses identified transcription factors controlling MDMS8 transcriptomic profile, including CKS1B and PRKDC among others, which are regulators of the DNA repair and cell cycle pathways.
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.
(© 2021. The Author(s).)
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تواريخ الأحداث: Date Created: 20211219 Date Completed: 20220407 Latest Revision: 20220531
رمز التحديث: 20231215
مُعرف محوري في PubMed: PMC8684160
DOI: 10.1186/s12920-021-01140-5
PMID: 34922559
قاعدة البيانات: MEDLINE
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