Dataset Information

DNA repair pathways in human multiple myeloma: role in oncogenesis and potential targets for treatment.

ABSTRACT: Every day, cells are faced with thousands of DNA lesions, which have to be repaired to preserve cell survival and function. DNA repair is more or less accurate and could result in genomic instability and cancer. We review here the current knowledge of the links between molecular features, treatment, and DNA repair in multiple myeloma (MM), a disease characterized by the accumulation of malignant plasma cells producing a monoclonal immunoglobulin. Genetic instability and abnormalities are two hallmarks of MM cells and aberrant DNA repair pathways are involved in disease onset, primary translocations in MM cells, and MM progression. Two major drugs currently used to treat MM, the alkylating agent Melphalan and the proteasome inhibitor Bortezomib act directly on DNA repair pathways, which are involved in response to treatment and resistance. A better knowledge of DNA repair pathways in MM could help to target them, thus improving disease treatment.

SUBMITTER: Gourzones-Dmitriev C

PROVIDER: S-EPMC3899190 | biostudies-literature | 2013 Sep

REPOSITORIES: biostudies-literature

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DNA repair pathways in human multiple myeloma: role in oncogenesis and potential targets for treatment.

Gourzones-Dmitriev Claire C Kassambara Alboukadel A Sahota Surinder S Rème Thierry T Moreaux Jérôme J Bourquard Pascal P Hose Dirk D Pasero Philippe P Constantinou Angelos A Klein Bernard B

Cell cycle (Georgetown, Tex.) 20130809 17

Every day, cells are faced with thousands of DNA lesions, which have to be repaired to preserve cell survival and function. DNA repair is more or less accurate and could result in genomic instability and cancer. We review here the current knowledge of the links between molecular features, treatment, and DNA repair in multiple myeloma (MM), a disease characterized by the accumulation of malignant plasma cells producing a monoclonal immunoglobulin. Genetic instability and abnormalities are two hal ...[more]

PMID: 23966156

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Project description:BackgroundDespite 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.ResultsOur 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.ConclusionUsing 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.

Dataset Information

DNA repair pathways in human multiple myeloma: role in oncogenesis and potential targets for treatment.

Publications

DNA repair pathways in human multiple myeloma: role in oncogenesis and potential targets for treatment.

Similar Datasets

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