Bi-allelic inactivation is more prevalent at relapse in multiple myeloma, identifying RB1 as an independent prognostic marker

Chavan, Shweta S.; He, Jie; Tytarenko, Ruslana G.; Deshpande, Shayu; Patel, Purvi; Bailey, Mark; Stein, Caleb K.; Stephens, Owen; Weinhold, Niels; Petty, Nathan; Steward, Douglas; Rasche, Leo; Bauer, Michael; Ashby, Cody; Peterson, Erich A.; Ali, Siraj M.; Ross, Jeffrey S.; Miller, Vincent A.; Stephens, P. J.; Thanendrarajan, Sharmilan; Schinke, Carolina; Zangari, Maurizio; Rhee, Frits van; Barlogie, Bart; Mughal, Tariq I.; Davies, Faith E.; Morgan, Gareth J.; Walker, Brian A.

doi:10.1038/bcj.2017.12

Cited by 55 publications

(54 citation statements)

References 32 publications

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“…For tumor suppressors, we found frequent instances of biallelic inactivation through mutations and deletions that were particularly notable for TP53 in which 6 of 7 patients showed both a mutated and a deleted allele (Figure 2A-B). 23,54 Combining CNAs and mutations, our selected cohort of double-resistant patients showed inactivation of the TP53 pathway through mutations and/or deletions in 45% of the patients ( Figure 2C), more than what was previously reported in NDMM. In paired samples from the CoMMpass cohort, we also observed the same phenomenon (supplemental Figure 4A).…”

Section: Genomic Makeup Of Treatment-resistant Samplessupporting

confidence: 46%

Integrative analysis of the genomic and transcriptomic landscape of double-refractory multiple myeloma

et al. 2020

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In multiple myeloma, novel treatments with proteasome inhibitors (PIs) and immunomodulatory agents (IMiDs) have prolonged survival but the disease remains incurable. At relapse, next-generation sequencing has shown occasional mutations of drug targets but has failed to identify unifying features that underlie chemotherapy resistance. We studied 42 patients refractory to both PIs and IMiDs. Whole-exome sequencing was performed in 40 patients, and RNA sequencing (RNA-seq) was performed in 27. We found more mutations than were reported at diagnosis and more subclonal mutations, which implies ongoing evolution of the genome of myeloma cells during treatment. The mutational landscape was different from that described in published studies on samples taken at diagnosis. The TP53 pathway was the most frequently inactivated (in 45% of patients). Conversely, point mutations of genes associated with resistance to IMiDs were rare and were always subclonal. Refractory patients were uniquely characterized by having a mutational signature linked to exposure to alkylating agents, whose role in chemotherapy resistance and disease progression remains to be elucidated. RNA-seq analysis showed that treatment or mutations had no influence on clustering, which was instead influenced by karyotypic events. We describe a cluster with both amp(1q) and del(13) characterized by CCND2 upregulation and also overexpression of MCL1, which represents a novel target for experimental treatments. Overall, high-risk features were found in 65% of patients. However, only amp(1q) predicted survival. Gene mutations of IMiD and PI targets are not a preferred mode of drug resistance in myeloma. Chemotherapy resistance of the bulk tumor population is likely attained through differential, yet converging evolution of subclones that are overall variable from patient to patient and within the same patient.

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Section: Genomic Makeup Of Treatment-resistant Samplessupporting

confidence: 46%

Integrative analysis of the genomic and transcriptomic landscape of double-refractory multiple myeloma

et al. 2020

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“…8 ). SVs also led to loss of tumor suppressor genes such as BIRC2/3 , CDKN2A/B, CDKN2C , TRAF3 30 and FAM46C , either within focal deletions or more complex events. These data confirm that SVs, accessing both simple and complex mechanisms of genome rearrangement, is a major force shaping the myeloma genome.…”

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confidence: 99%

Genomic landscape and chronological reconstruction of driver events in multiple myeloma

Maura

Bolli

Angelopoulos

et al. 2018

Preprint

115

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Multiple myeloma (MM) has a heterogeneous genome, evolving through both pre-clinical and post-diagnosis phases. Here, using sequences from 67 MM genomes serially collected from 30 patients together with public datasets, we establish a hierarchy of driver lesions. Point mutations, structural variants and copy number aberrations define at least 7 genomic subgroups of MM, each with distinct sets of co-operating driver mutations. Complex structural events are major drivers of MM, including chromothripsis, chromoplexy and a replication-based mechanism of templated insertions: these typically occur early. Hyperdiploidy also occurs early, with individual chromosomes often gained in more than one chronological epoch of MM evolution, showing a preferred order of acquisition. Positively selected point mutations frequently occur in later phases of disease development, as do structural variants involving MYC. Thus, initiating driver events of MM, drawn from a limited repertoire of structural and numerical chromosomal changes, shape preferred trajectories of subsequent evolution. MFAG (n.17658).

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“…37 Biallelic inactivation of recurrently altered tumor suppressor genes has recently been suggested as a key driver mechanism of disease progression in MM. 38,39 With the D006 digitalMLPA probemix, homozygous losses of CDKN2C/FAF1, BIRC3, TRAF3, and TP53 were detected, which were reported to be affected by biallelic deletions in MM and being enriched at the time of relapse. Notably, homozygous deletions in CYLD, which was found in a patient in a previous study 40 but was not analyzable by the targeted FoundationOne Heme panel in a recent study, 38 could also be identified.…”

Section: Discussionmentioning

confidence: 99%

High-Throughput Copy Number Profiling by Digital Multiplex Ligation-Dependent Probe Amplification in Multiple Myeloma

Kosztolányi

Kiss

Atanesyan

et al. 2018

The Journal of Molecular Diagnostics

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Multiple myeloma (MM) is a genetically heterogeneous disease with a diverse clinical outcome. Copy number alterations (CNAs), including whole chromosome and subchromosomal gains and losses, are common contributors of the pathogenesis and have demonstrated prognostic impact in MM. We tested the performance of digital multiplex ligation-dependent probe amplification (digitalMLPA), a novel technique combining MLPA and next-generation sequencing, to detect disease-related CNAs. Copy number status at 371 genomic loci was simultaneously analyzed in 56 diagnostic bone marrow samples, which were also examined by conventional MLPA and interphase fluorescence in situ hybridization (iFISH). On average, digitalMLPA identified 4.4 subchromosomal CNAs per patient. The increased number of probes compared with conventional MLPA allowed a detailed mapping of CNAs, especially on chromosome 1, where 24 different patterns were observed in 38 patients harboring loss(1p) and/or gain(1q). iFISH, MLPA, and digitalMLPA results at loci investigated by multiple methods showed a congruency of 95%. Besides precise characterization of hyperdiploid karyotypes not efficiently achievable by iFISH or MLPA, digitalMLPA unraveled 156 CNAs not detected by the other two methods in 45 patients (80%). In addition, we provide proof of principle that digitalMLPA can detect known point mutations, in this case the BRAF. Our study demonstrates the robustness of digitalMLPA to profile CNAs and to screen point mutations in MM, which could efficiently be used in myeloma diagnostics.

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Bi-allelic inactivation is more prevalent at relapse in multiple myeloma, identifying RB1 as an independent prognostic marker

Cited by 55 publications

References 32 publications

Integrative analysis of the genomic and transcriptomic landscape of double-refractory multiple myeloma

Integrative analysis of the genomic and transcriptomic landscape of double-refractory multiple myeloma

Genomic landscape and chronological reconstruction of driver events in multiple myeloma

High-Throughput Copy Number Profiling by Digital Multiplex Ligation-Dependent Probe Amplification in Multiple Myeloma

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