Multiple Myeloma
Multiple myeloma is the second most common hematological malignancy and the most frequent cancer to involve the skeleton. In multiple myeloma, cancerous plasma cells accumulate in the bone marrow and crowd out healthy blood cells. Rather than produce helpful antibodies, the cancer cells produce abnormal proteins that can cause complications.
Myeloma is the most frequent cancer to involve the skeleton, and over 80 %of myeloma patients have bone disease [1]. Multiple myeloma is clinically and biologically heterogeneous with several genetic alterations proposed as driving events in myelomagenesis. Next-generation sequencing has shown a lack of a universal driver mutation in multiple myeloma [2]. The most common mutations emerging in patients with multiple myeloma are in KRAS (in 23% of patients), NRAS (20%), FAM46C (11%), DIS3 (11%) and TP53 (8%). Other less frequently but recurrently mutated genes include BRAF, TRAF3, PRDM1, CYLD, RB1, IRF4, EGR1, MAX, HIST1H1E and ACTG1 [3] [4] [5] [6].
In this article, we list part of these proteins involved in multiple myeloma based on the information provided by NCG (web resource to analyze duplicability, orthology and network properties of cancer genes).
Here, we display several key targets involved in mechanism of multiple myeloma, including:
- ALOX12 (Arachidonate 12-Lipoxygenase, 12S Type) acts on different polyunsaturated fatty acid substrates to produce biologically active lipid mediators including eicosanes and lipoxins. It plays an important role in inflammation and oxidation [7]. Abnormal DNA methylation and genetic variants of ALOX12 are associated with various human diseases and pathological phenotypes. ALOX12 rs1126667 and rs434473 were significantly associated with early peripheral neuropathy in the treatment of multiple myeloma patients [8].
- CCND1 (Cyclin D1) is involved in normal regulation of the cell cycle and in neoplasia. Fusions, rearrangements, missense mutations, nonsense mutations, silent mutations, and in-frame deletions and insertions are observed in cancers. Eman M. Sewify et al. reported that there is an association between cyclin D1 gene amplification and disease severity, unfavorable prognosis, and increased expression of MDR1 in multiple myeloma patients [9].
- DIS3 (DIS3 Homolog, Exosome Endoribonuclease And 3'-5' Exoribonuclease) is an RNase enzyme homologous to the yeast protein Rrp44, and can be part of the exosome complex in the nucleus of eukaryotic cells. DIS3 has both 3'-5' exonuclease and endonuclease activities. DIS3 is among the most commonly mutated genes in multiple myeloma, with hotspots of mutation consistent with a change in function [10].
- FAM46C (family with sequence similarity 46, member C), a poly (A) polymerase, belongs to the nucleotidyltransferase superfamily, together with 3 other FAM46 proteins (FAM46A, B and D) [11]. It is one of the most frequently mutated genes in multiple myeloma [12]. Loss of function of FAM46C drives multiple myeloma through the destabilisation of endoplasmic reticulum response transcripts. FAM46C mutation as a contributor to myeloma pathogenesis and disease progression via perturbation in plasma cell differentiation and endoplasmic reticulum homeostasis.
- MAGED1 (Melanoma-associated antigen D1) is a member of the MAGE homology domain (MHD)-containing protein superfamily. MAGED1 is expressed ubiquitously in both developing and adult tissues but is particularly abundant in the brain [13]. Venkata D Yellapantula et al. reported that A frequently mutated list of 9 genes including NRAS, KRAS, TP53, PNRC1, MAGED1, FAM46C, DIS3, CCND1 and ALOX12B were identified initially using WGS and WES [14].
References
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[5] Avet-Loiseau, H. et al. 14q32 translocations and monosomy 13 observed in monoclonal gammopathy of undetermined significance delineate a multistep process for the oncogenesis of multiple myeloma [J]. Intergroupe Francophone Myelome. Cancer Res. 1999, 59, 4546–4550.
[6] Shaji K. Kumar, Vincent Rajkumar, Robert A. Kyle et al. Multiple myeloma [J]. NATURE REVIEWS. 2017, 17046.
[7] Zhonghua Zheng, Yin Li, Gehui Jin et al. The biological role of arachidonic acid 12-lipoxygenase (ALOX12) in various human diseases [J]. Biomedicine & Pharmacotherapy. 2020, 129: 110354.
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[10] Brian A. Walker. The Chromosome 13 Conundrum in Multiple Myeloma [J]. Blood Cancer Discov. 2020, 1 (1): 16-17.
[11] Kuchta K, Knizewski L, Wyrwicz LS et al. Comprehensive classification of nucleotidyltransferase fold proteins: identification of novel families and their representatives in human [J]. Nucleic Acids Res. 2009, 37(22):7701-14.
[12] Yuan Xiao Zhu, Chang-Xin Shi, Laura A. Bruins et al. Loss of FAM46C promotes cell survival in myeloma [J]. Cancer Res. 2017, 77(16): 4317–4327.
[13] Salehi AH, Roux PP, Kubu CJ et al. NRAGE, a novel MAGE protein, interacts with the p75 neurotrophin receptor and facilitates nerve growth factor-dependent apoptosis [J]. Neuron. 2000, 27, 279-288.
[14] Venkata D Yellapantula, Christopher Murray, Winnie Liang, et al. Gene Expression Profiling Of Multiple Myeloma Samples Using RNA Sequencing Identifies Frequent Rearrangements Of FCHSD2 [J]. Blood. 2013, 122 (21): 534.
