Spectrum and functional validation of PSMB5 mutations in multiple myeloma

Barrio, Santiago; Stühmer, Thorsten; DáVia, Matteo; Barrio-Garcia, C.; Lehners, Nicola; Bešše, Andrej; Cuenca, Isabel; Garitano‐Trojaola, Andoni; Fink, Severin; Leich, Ellen; Chatterjee, Manik; Driessen, Christoph; Martínez‐López, Joaquín; Rosenwald, Andreas; Beckmann, Roland; Bargou, Ralf C.; Braggio, Esteban; Stewart, A. Keith; Raab, Marc S.; Einsele, Hermann; Kortüm, K. Martin

doi:10.1038/s41375-018-0216-8

Cited by 103 publications

(100 citation statements)

References 35 publications

Supporting

Mentioning

100

Contrasting

Order By: Relevance

“…We provide a validated sequencing approach, including the detection of recurrent translocations, that will increase the diagnostic value of such techniques. Moreover as the whole genome and complete RNA expression is covered our approach can rapidly incorporate novel resistance mechanisms such as PSMB5 mutations [49] . And novel clinical master protocols rely on genomic data to decifer actionable genomic alterations and allow the allocation of patients to effective treatment options [50] .…”

Section: Discussionmentioning

confidence: 99%

The combination of WGS and RNA-Seq is superior to conventional diagnostic tests in multiple myeloma: Ready for prime time?

et al. 2020

View full text Add to dashboard Cite

The diagnosis and risk stratification of multiple myeloma (MM) is based on clinical and cytogenetic tests. Magnetic CD138 enrichment followed by interphase FISH (fluorescence in situ hybridisation) is the gold standard to identify prognostic translocations and copy number alterations (CNA). Although clinical implications of gene expression profiling (GEP) or panel based sequencing results are evident, those tests have not yet reached routine clinical application. We set up a single workflow to analyse MM of 211 patients at first diagnosis by whole genome sequencing (WGS) and RNA-Seq and validate the results by FISH analysis. We observed a 96% concordance of FISH and WGS results when assessing translocations involving the IGH locus and an overall concordance of FISH and WGS of 92% when assessing CNA. WGS analysis resulted in the identification of 17 additional MYC-translocations that were missed by FISH analysis. RNA-Seq followed by supervised clustering grouped patients in their expected genetically defined subgroup and prompted the assessment of WGS data in cases that were not congruent with FISH. This allowed the identification of additional IGH-translocations and hyperdiploid cases. We show the reliability of WGS an RNA-Seq in a clinical setting, which is a prerequisite for a novel routine diagnostic test.

show abstract

Section: Discussionmentioning

confidence: 99%

The combination of WGS and RNA-Seq is superior to conventional diagnostic tests in multiple myeloma: Ready for prime time?

et al. 2020

View full text Add to dashboard Cite

show abstract

“…Interestingly, very few nonrecurring mutations or aneuploidies were found in proteasome subunit genes in our cohort, confirming their rarity. 16,55 We assessed high-risk genetic 3 ), double-hit events, 11 apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like (APOBEC) signature contribution, 13 TP53 mutations, 9 and CRBN pathway mutations 15 and found that at least 1 such event was present in 65% of patients ( Figure 2D).…”

Section: Genomic Makeup Of Treatment-resistant Samplesmentioning

confidence: 99%

“…[9][10][11][12][13] In relapsed or refractory MM (RRMM), a small number of mutations implicated in resistance to PIs or IMiDs have been identified through custom targeted gene panels or in occasional patients. [14][15][16] These mutations have been validated in in vitro models, but their clinical relevance needs additional study. Expression levels and splice isoforms of the IMiD target CRBN have been proposed to mediate resistance to those drugs, but results are conflicting and are not ready for the clinic.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2020

View full text Add to dashboard Cite

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.

show abstract

“…Initial studies suggest that cases retain a significant heterogeneity, with subclones showing expansion or reduction based on the type of treatment, increased number of mutations, copy-number abnormalities, complex rearrangements and contribution from novel mutational signatures (17,23,34,35,96). Targeted sequencing studies have highlighted increasing prevalence of mutations conferring resistance to IMiDs (particularly in CRBN, IKZF1, IKZF3) and PIs (PSMB5, PSMB8, PSMB9, PSMD1, and PSMG2) (62,128). However, mutated cases are still a great minority and mutations are often subclonal, suggesting that while functionally relevant, the clinical impact of these mutations and their utility to guide further treatment will need validation.…”

Section: Relapsed and Refractory Myelomamentioning

confidence: 99%

Next-Generation Sequencing for Clinical Management of Multiple Myeloma: Ready for Prime Time?

et al. 2020

View full text Add to dashboard Cite

Personalized treatment is an attractive strategy that promises increased efficacy with reduced side effects in cancer. The feasibility of such an approach has been greatly boosted by next-generation sequencing (NGS) techniques, which can return detailed information on the genome and on the transcriptome of each patient's tumor, thus highlighting biomarkers of response or druggable targets that may differ from case to case. However, while the number of cancers sequenced is growing exponentially, much fewer cases are amenable to a molecularly-guided treatment outside of clinical trials to date. In multiple myeloma, genomic analysis shows a variety of gene mutations, aneuploidies, segmental copy-number changes, translocations that are extremely heterogeneous, and more numerous than other hematological malignancies. Currently, in routine clinical practice we employ reduced FISH panels that only capture three high-risk features as part of the R-ISS. On the contrary, recent advances have suggested that extending genomic analysis to the full spectrum of recurrent mutations and structural abnormalities in multiple myeloma may have biological and clinical implications. Furthermore, increased efficacy of novel treatments can now produce deeper responses, and standard methods do not have enough sensitivity to stratify patients in complete biochemical remission. Consequently, NGS techniques have been developed to monitor the size of the clone to a sensitivity of up to a cell in a million after treatment. However, even these techniques are not within reach of standard laboratories. In this review we will recapitulate recent advances in multiple myeloma genomics, with special focus on the ones that may have immediate translational impact. We will analyze the benefits and pitfalls of NGS-based diagnostics, highlighting crucial aspects that will need to be taken into account before this can be implemented in most laboratories. We will make the point that a new era in myeloma diagnostics and minimal residual disease monitoring is close and conventional genetic testing will not be able to return the required information. This will mandate that even in routine practice NGS should soon be adopted owing to a higher informative potential with increasing clinical benefits.

show abstract

Spectrum and functional validation of PSMB5 mutations in multiple myeloma

Cited by 103 publications

References 35 publications

The combination of WGS and RNA-Seq is superior to conventional diagnostic tests in multiple myeloma: Ready for prime time?

The combination of WGS and RNA-Seq is superior to conventional diagnostic tests in multiple myeloma: Ready for prime time?

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

Next-Generation Sequencing for Clinical Management of Multiple Myeloma: Ready for Prime Time?

Contact Info

Product

Resources

About