Identification of novel fusion transcripts in multiple myeloma

Abstract

<jats:sec><jats:title>Aims</jats:title><jats:p>Multiple myeloma (MM) is a heterogeneous disease characterised by genetically complex abnormalities. The classical mutational spectrum includes recurrent chromosomal aberrations and gene-level mutations. Recurrent translocations involving the <jats:italic>IGH</jats:italic> gene such as t(11;14), t(4;14) and t(14;16) are well known. However, the presence of complex genetic abnormalities raises the possibility that fusions other than the recurrent <jats:italic>IGH</jats:italic> translocations exist. We therefore employed a targeted RNA-sequencing panel to identify novel putative fusions in a local cohort of MM.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>Targeted RNA-sequencing was performed on 21 patient samples using the Illumina TruSight RNA Pan-Cancer Panel (comprising 1385 genes). Fusion calls were generated from the Illumina RNA-Sequencing Alignment software (V.1.0.0). These samples had conventional cytogenetic and fluorescence in situ hybridisation data for the common recurrent chromosomal abnormalities (t(11;14), t(4;14), t(14;16) and 17p13 deletion). The MMRF CoMMpass dataset was analysed using the TopHat-fusion pipeline.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>A total of 10 novel fusions were identified by the TruSight RNA Pan-Cancer Panel. Two of these fusions, <jats:italic>HGF</jats:italic>/<jats:italic>CACNA2D1</jats:italic> and <jats:italic>SMC3</jats:italic>/<jats:italic>MXI1</jats:italic>, were validated by reverse transcription PCR and Sanger sequencing as they involve genes that may have biological relevance in MM genesis. Four of these (<jats:italic>MAP2K4</jats:italic>/<jats:italic>MAP2K4P1</jats:italic>) are likely to be spurious secondary to misalignment of reads to a pseudogene. One record of the <jats:italic>HGF/CACNA2D1</jats:italic> fusion was identified from the MMRF CoMMpass dataset.</jats:p></jats:sec><jats:sec><jats:title>Conclusions</jats:title><jats:p>The identification of novel fusions offers insights into the biology of MM and might have clinical relevance. Further functional studies are required to determine the biological and clinical relevance of these novel fusions.</jats:p></jats:sec>

Multi-omics tumor profiling technologies to develop precision medicine in multiple myeloma

“…However, the frequency of less common TCs is poorly studied. Targeted RNA-seq of 21 patients allowed the identification of 2 novel fusions ( HGF / CACNA2D1 and SMC3 / MXI1 ) whose biological and clinical relevance for MM physiopathology has not yet been determined [ 190 ]. Additionally, 94 genes at 8 regions that were not previously associated to MM risk have been identified by integrating genome-wide and transcriptome-wide association studies [ 191 ].…”

Towards Molecular Profiling in Multiple Myeloma: A Literature Review and Early Indications of Its Efficacy for Informing Treatment Strategies

“…Thus, MM cases that are positive for t(4;14) may exhibit increased sensitivity to immunomodulatory drugs, proteasome inhibitors, and several targeted drugs [ 21 ]. Many other chromosomal aberrations have been described in patients with MM [ 22 , 23 ], and have been incorporated into widely used risk prediction models (e.g., mSMART, available at: ). Negative prognostic significance has been attributed especially to t(14;20), t(14;16), and 1q gains.…”

“…On the subchromosomal level, Lin et al (2018) using the Illumina TruSight RNA Pan-Cancer Panel (1385 genes total) recently described 10 novel fusions (e.g., HGF / CACNA2D1 and SMC3 / MXI1 ) in 21 patients with MM [ 22 ].…”

Evolution and structure of clinically relevant gene fusions in multiple myeloma

“…Nasser et al analyzed MMRF CoMMpass RNA-seq data, reconstructed Tophat-Fusion transcripts, and validated fusions with WGS 14 . Lin et al used targeted RNA-seq in 21 MM patients, finding several novel fusions with disease relevance 15 . Morgan et al used targeted sequencing of kinases to understand how translocations dysregulate kinase activity in MM 16 .…”