Comparison of Clinical Characteristics and Genetic Aberrations of Plasma Cell Disorders in Thailand Population

Abstract

Multiple myeloma is an incurable malignancy of plasma cells resulting from impaired terminal B cell development. Almost all patients with multiple myeloma eventually have a relapse. Many studies have demonstrated the importance of the various genomic mutations that characterize multiple myeloma as a complex heterogeneous disease. In recent years, next-generation sequencing has been used to identify the genomic mutation landscape and clonal heterogeneity of multiple myeloma. This is the first study, a prospective observational study, to identify somatic mutations in plasma cell disorders in the Thai population using targeted next-generation sequencing. Twenty-seven patients with plasma cell disorders were enrolled comprising 17 cases of newly diagnosed multiple myeloma, 5 cases of relapsed/refractory multiple myeloma, and 5 cases of other plasma cell disorders. The pathogenic mutations were found in 17 of 27 patients. Seventy percent of those who had a mutation (12/17 patients) habored a single mutation, whereas the others had more than one mutation. Fifteen pathogenic mutation genes were identified: ATM, BRAF, CYLD, DIS3, DNMT3A, FBXW7, FLT3, GNA13, IRF4, KMT2A, NRAS, SAMHD1, TENT5C, TP53, and TRAF3. Most have previously been reported to be involved in the RAS/MAPK pathway, the nuclear factor kappa B pathway, the DNA-repair pathway, the CRBN pathway, tumor suppressor gene mutation, or an epigenetic mutation. However, the current study also identified mutations that had not been reported to be related to myeloma: GNA13 and FBXW7. Therefore, a deep understanding of molecular genomics would inevitably improve the clinical management of plasma cell disorder patients, and the increased knowledge would ultimately result in better outcomes for the patients.

Aberrant DNA methylation in multiple myeloma: A major obstacle or an opportunity?

“…found that DNMT3A is one of the sixty-three identified mutated driver genes in early MM development ( 136 ). In line with this study, a very recent study also reported the presence of a pathogenic DNMT3A mutation in the MGUS stage ( 137 ). Furthermore, the mutation frequency in DNMT3A was shown to increase upon relapse ( 87 ).…”

Gene mutations in newly diagnosed multiple myeloma patients detected by next-generation sequencing technology

“…The recent research on target NGS detection from Thailand reported different ranks to the above-mentioned study. 13 One study conducted in 40 NDMM patients with 30 target gene sequencing reported the common mutations in Chinese were ATM, CUL4B, IRF4, KRAS, and NRAS. 14 The other study from China examined the unpurified BM samples of 28 target genes and reported the most common gene mutations were NRAS, PRDM1, FAM46C, MYC, CCND1, LTB, DIS3, KRAS, CRBN, DNMT3A, IRF4, and BRAF .…”

Dissecting the Puzzling Roles of FAM46C: A Multifaceted Pan-Cancer Tumour Suppressor with Increasing Clinical Relevance

“…The FAM46C gene was originally identified as mutated in 13% of the cases analysed by Chapman and colleagues in their 2011 parallel sequencing of 38 MM patient genomes/exomes [5]. Later, similar mutation frequencies were confirmed by others using techniques ranging from fluorescence in situ hybridization (FISH) approaches to genetargeted next generation sequencing (NGS) [45][46][47][48][49][50][51][52][53]. Mutation mapping revealed alterations throughout the entire ORF of FAM46C, with an exception in a small portion of the Nterminal region, with most mutations being either indels or missense single nucleotide variations predicted to have a deleterious effect on protein structure/functionality [54], suggesting that FAM46C behaves as a tumour suppressor gene.…”