Analysis of the genomic landscape of multiple myeloma highlights novel prognostic markers and disease subgroups

Bolli, Niccolò; Biancon, Giulia; Moarii, Matahi; Gimondi, Silvia; Li, Y; Philippis, Chiara De; Maura, Francesco; Sathiaseelan, Vijitha; Tai, Yu‐Tzu; Mudie, Laura; O¿Meara, Sarah; Teague, Jon W.; Butler, Adam; Carniti, Cristiana; Gerstung, Moritz; Bagratuni, Tina; Kastritis, Eftathios; Dimopoulos, M. A.; Corradini, Paolo; Anderson, Kenneth C.; Moreau, P; Minvielle, Stéphane; Campbell, Purdey J; Papaemmanuil, Elli; Avet-Loiseau, Hervé; Munshi, Nikhil C.

doi:10.1038/leu.2017.344

Cited by 47 publications

(65 citation statements)

References 34 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…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%

“…PRDM1 is a crucial transcription factor in plasma cells and its mutations-deletions have been observed as late events in MM development, 64 with a possible prognostic role, even at diagnosis. 9 We had data on pomalidomide-based salvage treatment of 14 patients. Of these, 4 showed primary refractoriness, including 3 with loss of chr13 and del(17p).…”

Section: Survival Analysismentioning

confidence: 99%

“…8 More recently, NGS-based studies have suggested that extended genotyping is feasible and can offer improved prognostication at diagnosis. [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.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

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

Section: Genomic Makeup Of Treatment-resistant Samplesmentioning

confidence: 99%

Section: Survival Analysismentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

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

et al. 2020

View full text Add to dashboard Cite

show abstract

“…These subtypes vary in chemosensitivity and survival, suggesting that although patients share a common histological and clinical phenotype, the underlying biology is distinctly heterogeneous. Preliminary studies have suggested that these patterns exist in MM as well 5,7,9–12 , but have not yet been systematically defined in large cohorts with broad sequencing coverage.…”

mentioning

confidence: 99%

Genomic landscape and chronological reconstruction of driver events in multiple myeloma

Maura

Bolli

Angelopoulos

et al. 2018

Preprint

115

View full text Add to dashboard Cite

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).

show abstract

“…More than 40 genetic lesions were druggable but only 3 of them are already targeted in the clinical practice [159]. Although there are new therapeutic approaches for patients with high-risk MM [23,24] and the introduction of active treatments with different mechanisms of action compared to chemotherapy, therapy-sensitive patients have a very variable duration of response [93]. The MM natural history is characterized by further recurrences of diseases whose response to treatments is not durable.…”

Section: Future Perspectivesmentioning

confidence: 99%

High-Risk Multiple Myeloma: Integrated Clinical and Omics Approach Dissects the Neoplastic Clone and the Tumor Microenvironment

Solimando¹,

Viá²,

Cicco³

et al. 2019

Preprint

View full text Add to dashboard Cite

Multiple myeloma (MM) is a genetically heterogenous disease that includes a subgroup of 10-15% of patients facing dismal survival despite most intensive treatment. The aim of this review article is to provide an integrated clinical and biological overview on the high-risk MM discussing the novel therapeutic perspectives aimed to target the neoplastic clone and its microenvironment. The dissection of the molecular determinants of the aggressive phenotypes and drug resistance can foster a better tailored clinical management of high-risk profile and refractoriness to therapy. Among the current clinical difficulties in MM, patient’s management manipulating the tumor niche represents a major challenge given the limited knowledge about the MM-milieu interaction. The angiogenesis and bystander infiltrate constitute pivotal mechanisms of mutual collaboration between MM and the non-tumoral counterpart. Immuno-modulatory and anti-angiogenic therapy hold great efficacy but variable and unpredictable responses in high-risk MM. Therefore, it would be worth to better select the population and the MM stage that could profit to a dual immune/vasculogenesis targeting. The comprehensive knowledge of the genetic heterogeneity and MM high-risk ecosystem enforce a systematic bench-to-bedside approach. Despite significant improvements in the biology knowledge, MM is still a chronic and incurable neoplasia and therapeutic options able to overcome the relapsing/refractory behavior represent an unmet clinical need. Here, we corroborate previous biological findings providing a synthetic outlook of novel druggable targets. We also summarize the existing multi-omics-based risk profiling tools, in order to better personalize the patient-oriented clinical management.

show abstract

Analysis of the genomic landscape of multiple myeloma highlights novel prognostic markers and disease subgroups

Cited by 47 publications

References 34 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-Risk Multiple Myeloma: Integrated Clinical and Omics Approach Dissects the Neoplastic Clone and the Tumor Microenvironment

Contact Info

Product

Resources

About