Expressed fusion gene landscape and its impact in multiple myeloma

Cleynen, Alice; Szalat, Raphaël; Samur, Mehmet K.; Pont, Sébastien Robiou du; Buisson, Laure; Boyle, E.; Chrétien, Marie‐Lorraine; Anderson, Kenneth C.; Minvielle, Stéphane; Moreau, Philippe; Attal, Michel; Parmigiani, Giovanni; Corre, Jill; Munshi, Nikhil C.; Avet-Loiseau, Hervé

doi:10.1038/s41467-017-00638-w

Cited by 33 publications

(35 citation statements)

References 43 publications

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“…Only 14 fusions involving TPT1 have been reported in the Mitelman Database of Chromosome Aberrations and Gene Fusions in Cancer . They have been found in multiple myeloma, breast, lung, kidney, stomach, thyroid, uterus and prostate cancer . However, the presence of SNORA31 and SNORA31B inside these fusions was never highlighted.…”

Section: Resultsmentioning

confidence: 99%

Analysis of fusion transcripts indicates widespread deregulation of snoRNAs and their host genes in breast cancer

Persson

Søkilde

Häkkinen

et al. 2020

Intl Journal of Cancer

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Genomic rearrangements in cancer can join the sequences of two separate genes. Studies of such gene fusion events have mainly focused on identification of fusion proteins from the chimeric transcripts. We have previously investigated how fusions instead can affect the expression of intronic microRNA (miRNA) genes that are encoded within fusion gene partners. Here, we extend our analysis to small nucleolar RNAs (snoRNAs) that also are embedded within protein-coding or noncoding host genes. We found that snoRNA hosts are selectively enriched in fusion transcripts, like miRNA host genes, and that this enrichment is associated with all snoRNA classes. These structural changes may have functional consequences for the cell; proteins involved in the protein translation machinery are overrepresented among snoRNA host genes, a gene architecture assumed to be needed for closely coordinated expression of snoRNAs and host proteins. Our data indicate that this structure is frequently disrupted in cancer. We furthermore observed that snoRNA genes involved in fusions tend to associate with stronger promoters than the natural host, suggesting a mechanism that selects for snoRNA overexpression. In summary, we highlight a previously unexplored frequent structural change in cancer that affects important components of cellular physiology.Additional Supporting Information may be found in the online version of this article.

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Section: Resultsmentioning

confidence: 99%

Analysis of fusion transcripts indicates widespread deregulation of snoRNAs and their host genes in breast cancer

Persson

Søkilde

Häkkinen

et al. 2020

Intl Journal of Cancer

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“…Novel fusion genes have also been identified in myeloma using RNA sequencing data, and some have been associated with adverse outcome, such as CSNK1G2 and CCND1 (with shortened progression-free survival [PFS]) and MMSET and BCL2L11 (with shortened overall survival [OS]). 50…”

Section: Rna Alterationsmentioning

confidence: 99%

“…Ongoing analysis is identifying further targets that can be incorporated into such studies. For example, fusion genes have been identified in myeloma, and although rare (1%), 50,82 the majority contain a kinase domain, suggesting kinase inhibitors may have a potential role.…”

Section: Advances In Predictive Biomarkersmentioning

confidence: 99%

Toward personalized treatment in multiple myeloma based on molecular characteristics

Pawlyn

Davies

2019

Blood

157

119

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To date, the choice of therapy for an individual multiple myeloma patient has been based on clinical factors such as age and comorbidities. The widespread evolution, validation, and clinical utilization of molecular technologies, such as fluorescence in situ hybridization and next-generation sequencing has enabled the identification of a number of prognostic and predictive biomarkers for progression-free survival, overall survival, and treatment response. In this review, we argue that in order to continue to improve myeloma patient outcomes incorporating such biomarkers into the routine diagnostic workup of patients will allow for the use of personalized, biologically based treatments.

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“…These structural rearrangements place the Ig super-enhancer next to an oncogene, resulting in its overexpression [ 10 ]. The common gene fusions seen in MM involve the Ig loci, including cases with a t(4;14) where the breakpoint within MMSET results in an Ig-MMSET transcript, but an alteration in functionality as a consequence is not seen [ 11 , 12 ]. A key signaling abnormality in MM is increased MEK/ERK pathway activation due to activating point mutations in KRAS , NRAS , and BRAF seen in up to 50% of patients [ 13 ].…”

Section: Introductionmentioning

confidence: 99%

Kinase domain activation through gene rearrangement in multiple myeloma

Morgan

He²,

Tytarenko

et al. 2018

Leukemia

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Chromosomal rearrangements that result in oncogenic kinase activation are present in many solid and hematological malignancies, but none have been reported in multiple myeloma (MM). Here we analyzed 1421 samples from 958 myeloma patients using a targeted assay and detected fusion genes in 1.5% of patients. These fusion genes were in-frame and the majority of them contained kinase domains from either receptor tyrosine kinases (ALK, ROS1, NTRK3, and FGFR1) or cytoplasmic kinases (BRAF, MAP3K14, and MAPK14), which would result in the activation of MEK/ERK, NF-κB, or inflammatory signaling pathways. Fusion genes were present in smoldering MM, newly diagnosed MM, and relapse patient samples indicating they are not solely late events. Most fusion genes were subclonal in nature, but one EML4-ALK fusion was clonal indicating it is a driver of disease pathogenesis. Samples with fusions of receptor tyrosine kinases were not found in conjunction with clonal Ras/Raf mutations indicating a parallel mechanism of MEK/ERK pathway activation. Fusion genes involving MAP3K14 (NIK), which regulates the NF-κB pathway, were detected as were t(14;17) rearrangements involving NIK in 2% of MM samples. Activation of kinases in myeloma through rearrangements presents an opportunity to use treatments existing in other cancers.

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Expressed fusion gene landscape and its impact in multiple myeloma

Cited by 33 publications

References 43 publications

Analysis of fusion transcripts indicates widespread deregulation of snoRNAs and their host genes in breast cancer

Analysis of fusion transcripts indicates widespread deregulation of snoRNAs and their host genes in breast cancer

Toward personalized treatment in multiple myeloma based on molecular characteristics

Kinase domain activation through gene rearrangement in multiple myeloma

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