Clonal Heterogeneity and Genetic Instability of Multiple Myeloma and Impact on Treatment

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. SCI-53-SCI-53
Author(s):  
Jonathan J Keats
Keyword(s):  
Multiple Myeloma ◽  
Copy Number ◽  
Somatic Mutations ◽  
Conflicts Of Interest ◽  
Tumor Evolution ◽  
Clonal Heterogeneity ◽  
Genetic Complexity ◽  
Impact On Treatment ◽  
Copy Number Changes ◽  
Individual Disease

Multiple myeloma is a pathological definition for a series of distinct genetic entities with similar phenotypic and clinical characteristics. Multiple studies have now identified distinct subtypes of the disease, which are associated with different clinical outcomes. The genetic complexity underlying these different subtypes is very diverse. Some subtypes like those characterized by immunoglobulin translocations targeting cyclin D1 are associated with very minimal changes or no copy number changes. Conversely, subtypes defined by translocations targeting WHSC1/MMSET or the MAF and MAFB transcription factors often have highly complex and diverse copy number changes. With the substantial advances in DNA sequencing technology we now know there is a diverse array of somatic mutations in multiple myeloma tumors. Through the integration of copy number changes and somatic mutations multiple groups have now shown the existence of multiple co-existing subclones within individual tumors. Additional studies following patients through their individual disease courses have shown these subclones can ebb and flow with time through multiple rounds of therapeutic selection. This session will highlight our current understanding of how the interplay between tumor evolution and clonal heterogeneity should influence our treatment decisions, particularly when applying a personalized medicine approach. Disclosures No relevant conflicts of interest to declare.

HOXA9 Is a Novel Therapeutic Target in Multiple Myeloma.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 832-832 ◽  
Author(s):  
Michael A Chapman ◽  
Jean-Philippe Brunet ◽  
Jonathan J Keats ◽  
Angela Baker ◽  
Mazhar Adli ◽  
...  
Keyword(s):  
Gene Expression ◽  
Multiple Myeloma ◽  
Histone Modification ◽  
Cell Lines ◽  
Therapeutic Target ◽  
Copy Number ◽  
Conflicts Of Interest ◽  
Specific Expression ◽  
Aberrant Expression ◽  
High Level

Abstract Abstract 832 We hypothesized that new therapeutic targets for multiple myeloma (MM) could be discovered through the integrative computational analysis of genomic data. Accordingly, we generated gene expression profiling and copy number data on 250 clinically-annotated MM patient samples. Utilizing an outlier statistical approach, we identified HOXA9 as the top candidate gene for further investigation. HOXA9 expression was particularly high in patients lacking canonical MM chromosomal translocations, and allele-specific expression analysis suggested that this overexpression was mono-allelic. Indeed, focal copy number amplifications at the HOXA locus were observed in some patients. Outlier HOXA9 expression was further validated in both a collection of 52 MM cell lines and 414 primary patient samples previously described. To further verify the aberrant expression of HOXA9 in MM, we performed quantitative RT-PCR, which confirmed expression in all MM patients and cell lines tested, with high-level expression in a subset. To further investigate the mechanism of aberrant HOXA9 expression, we interrogated the pattern of histone modification at the HOXA locus because HOXA gene expression is particularly regulated by such chromatin marks. Accordingly, immunoprecipitation studies showed an aberrantly low level of histone 3 lysine 27 trimethylation marks (H3K27me3) at the HOXA9 locus. H3K27me3 modification is normally associated with silencing of HOXA9 in normal B-cell development. As such, it appears likely that the aberrant expression of HOXA9 in MM is due at least in part to defects in histone modification at this locus. To determine the functional consequences of HOXA9 expression in MM, we performed RNAi-mediated knock-down experiments in MM cell lines. Seven independent HOXA9 shRNAs that diminished HOXA9 expression resulted in growth inhibition of 12/14 MM cell lines tested. Taken together, these experiments indicate that HOXA9 is essential for survival of MM cells, and that the mechanism of HOXA9 expression relates to aberrant histone modification at the HOXA9 locus. The data thus suggest that HOXA9 is an attractive new therapeutic target for MM. Disclosures: No relevant conflicts of interest to declare.

Novel Germline Genetic Variants Associated with Familial Chronic Lymphocytic Leukemia (CLL)

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 465-465
Author(s):  
Jennifer R Brown ◽  
Michael S Lawrence ◽  
Megan Hanna ◽  
Bethany Tesar ◽  
Petar Stojanov ◽  
...  
Keyword(s):  
Tumor Suppressor ◽  
Somatic Mutation ◽  
Cell Biology ◽  
Copy Number ◽  
Somatic Mutations ◽  
Risk Allele ◽  
Conflicts Of Interest ◽  
Similar Distribution ◽  
Mirna Cluster ◽  
Depth Analysis

Abstract Abstract 465 CLL is among the most heritable of all cancers. To understand the genetic basis of this heritability, we have undertaken a comprehensive genomic analysis of familial CLLs including copy number analysis, gene expression profiling (GEP) and whole exome sequencing (WES). First, we examined whether familial and sporadic cases differ in the spectrum of acquired somatic mutations by WES of tumor and germline DNA of 36 familial CLLs (from 31 affected families). Compared to 55 sporadic CLLs, we observed that the somatic mutation rate in the familial CLLs was similar (mean 0.89 mutations/Mb (range 0.29–3.06) for the sporadics vs mean 0.97/Mb (range 0.11–3.78) for the familials, p=0.40). We also examined the spectrum of somatic mutations by testing for enrichment of 9 recently identified putative tumor drivers in our large CLL sequencing study (reported elsewhere in this meeting). We observed a similar distribution of these recurrent CLL mutations among the 36 familial CLLs as the 55 sporadic CLLs. These results were further confirmed by genotyping of the CLL driver mutations in an additional 32 familial and 67 sporadic CLLs. Collectively, these studies suggest that while the predisposing germline events may differ between familial and sporadic CLL, the spectrum of mutations and pattern of mutagenesis appear similar in the established CLL tumors. We therefore proceeded to examine the genetic characterization of germline DNA to identify predisposing loci, which we hypothesized might be enriched in a familial disease context. We first examined germline copy number variations (CNVs), which have not been previously characterized in this disease. We used high resolution Affymetrix 6.0 SNP arrays to study both tumor and germline DNA of 58 individuals representing 44 different families with CLL and lymphoproliferative disorders (LPDs). We identified two families (A and B) with autosomal dominant inheritance of CLL who carried distinct germline CNVs that affect genes previously implicated in CLL. Members of Family A carried a 525 kb germline deletion targeting DLEU7 at 13q14, but not affecting DLEU2, miR-15a, or miR-16–1. Importantly, by examining the tumor genome from these family members, we observed a uniform loss of the second allele of DLEU7 in 2/2 available CLLs from this family, suggesting an acquired “second hit” of a tumor suppressor gene. These findings underline the complexity of the most common somatically acquired copy number aberration (CNA) in CLL, 13q14 deletion, by demonstrating the role of additional regions other than the heavily investigated miRNA cluster. Members of Family B carried a 720 kb germline gain of 6p25 affecting the IRF4 gene, previously implicated in CLL through the identification of a GWAS risk allele located in the 3' UTR of IRF4, as well as the recent description of a recurrent somatic mutation affecting 1.5% of CLL cases. In Family B, the coding regions of the four genes located in this 6p gain, namely IRF4, DUSP22, EXOC2 and HUS1B, were sequenced, and no somatic mutations or novel SNPs were identified. However, the 6p gain in Family B represents an allele-specific enrichment of the haplotype carrying the GWAS risk SNP and, as previously described for that allele, results in lower expression of IRF4 in the two CLLs tested in this family. GEP further identified a signature associated with 6p gain that preserved low expression of IRF4 and showed high expression of KLF6. These results demonstrate that germline CNVs may facilitate the “path to cancer” by providing either an allelic deletion of a tumor suppressor or an amplification of a risk allele. As most familial CLL cases have not been accounted for by known SNPs or germline CNVs, we have initiated an in depth analysis of the WES germline results from familial cases compared to both sporadic CLL patients and normal individuals. Candidate variants have been filtered to exclude all SNPs described in the 1000 Genomes project and to focus on highly conserved sites. Thus far we have found that rare germline variants in patients with familial CLL contain a rich source of loci with relevance to B cell biology. Studies in progress are focused on further analysis of informative families and functional analyses of candidate variants. These comprehensive genomic analyses are expected to identify multiple cooperating genetic mechanisms that contribute to CLL pathogenesis, including CNVs and somatic and germline mutations. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Genetic Profile of Adenoid Cystic Carcinomas (ACC) with High-Grade Transformation versus Solid Type

2010 ◽  
Vol 33 (5-6) ◽  
pp. 217-228 ◽  
Author(s):  
Ana Flávia Costa ◽  
Albina Altemani ◽  
Hedy Vékony ◽  
Elisabeth Bloemena ◽  
Florentino Fresno ◽  
...  
Keyword(s):  
Copy Number ◽  
Genetic Profile ◽  
High Grade ◽  
Ki 67 ◽  
Genetic Changes ◽  
Genome Wide ◽  
Genetic Complexity ◽  
Poorly Differentiated ◽  
High Grade Transformation ◽  
Copy Number Changes

Background: ACC can occasionally undergo dedifferentiation also referred to as high-grade transformation (ACC-HGT). However, ACC-HGT can also undergo transformation to adenocarcinomas which are not poorly differentiated. ACC-HGT is generally considered to be an aggressive variant of ACC, even more than solid ACC. This study was aimed to describe the genetic changes of ACC-HGT in relation to clinico-pathological features and to compare results to solid ACC.Methods: Genome-wide DNA copy number changes were analyzed by microarray CGH in ACC-HGT, 4 with transformation into moderately differentiated adenocarcinoma (MDA) and two into poorly differentiated carcinoma (PDC), 5 solid ACC. In addition, Ki-67 index and p53 immunopositivity was assessed.Results: ACC-HGT carried fewer copy number changes compared to solid ACC. Two ACC-HGT cases harboured a breakpoint at 6q23, near the cMYB oncogene. The complexity of the genomic profile concurred with the clinical course of the patient. Among the ACC-HGT, p53 positivity significantly increased from the conventional to the transformed (both MDA and PDC) component.Conclusion: ACC-HGT may not necessarily reflect a more advanced stage of tumor progression, but rather a transformation to another histological form in which the poorly differentiated forms (PDC) presents a genetic complexity similar to the solid ACC.

scholarly journals Reconstructing mutational lineages in breast cancer by multi-patient-targeted single cell DNA sequencing

2021 ◽  
Author(s):  
Nicholas Navin ◽  
Jake Leighton ◽  
Min Hu ◽  
Emi Sei ◽  
Funda Meric-Bernstam
Keyword(s):  
Breast Cancer ◽  
Dna Sequencing ◽  
Single Cell ◽  
Copy Number ◽  
Somatic Mutations ◽  
Single Cells ◽  
Tumor Evolution ◽  
Sequencing Method ◽  
Genomic Regions ◽  
Microfluidics Platform

Single cell DNA sequencing (scDNA-seq) methods are powerful tools for profiling mutations in cancer cells, however most genomic regions characterized in single cells are non-informative. To overcome this issue, we developed a Multi-Patient-Targeted (MPT) scDNA-seq sequencing method. MPT involves first performing bulk exome sequencing across a cohort of cancer patients to identify somatic mutations, which are then pooled together to develop a single custom targeted panel for high-throughput scDNA-seq using a microfluidics platform. We applied MPT to profile 330 mutations across 23,500 cells from 5 TNBC patients, which showed that 3 tumors were monoclonal and 2 tumors were polyclonal. From this data, we reconstructed mutational lineages and identified early mutational and copy number events, including early TP53 mutations that occurred in all five patients. Collectively, our data suggests that MPT can overcome technical obstacles for studying tumor evolution using scDNA-seq by profiling information-rich mutation sites.

scholarly journals Simultaneous FLT3, NPM1 and DNMT3A mutations in adult patients with acute myeloid leukemia – case study

2019 ◽  
Vol 27 (3) ◽  
pp. 245-254 ◽  
Author(s):  
Florin Tripon ◽  
George Andrei Crauciuc ◽  
Valeriu George Moldovan ◽  
Alina Bogliș ◽  
István Benedek ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Cytogenetic Analysis ◽  
Copy Number ◽  
Myeloid Leukemia ◽  
Somatic Mutations ◽  
Molecular Technique ◽  
Chromosomal Anomalies ◽  
Copy Number Changes ◽  
Next Generation Sequencing Ngs ◽  
Acute Myeloid

Abstract Background: Nowadays, cytogenetics and molecular genetics, but not only, are mandatory in acute myeloid leukemia (AML) management, as a consequence of their impact on AML pathogenesis, classification, risk-stratification, prognosis and treatment. Objective: The aim of our study was to present our algorithm for the analysis of copy number changes, aneuploidies and somatic mutations focusing on a rare AML case positive for four somatic mutations. Methods: Cytogenetic analysis, Multiplex Ligationdependent Probe Amplification (MLPA) analysis, somatic mutation analysis (for FLT3 ITD, FLT3 D835, DNMT3A R882 and NPM1 c.863_864ins) by using several PCR techniques and also next-generation sequencing (NGS) analysis were performed. Results: Cytogenetic analysis did not reveal structural or numerical chromosomal anomalies. The patient’s DNA showed no copy number changes or aberrations (CNAs) following the MLPA analysis. By using several molecular technologies we found four mutations: FLT3-ITD, FLT3 D835 (c.2504A>T, D835V), DNMT3A R882C, and NPM1 c.863_864insTCTG. Challenges, benefits, applications and the limitations of each molecular technique used for the investigation of the mentioned mutation, and not only, are also described. Conclusion: All these techniques can be useful in the diagnosis of AML patients, each of them covering the limits of the other technique. New strategies for a positive, fast, accurate and reliable diagnosis are mandatory in cases with AML.

Multiple Myeloma Sequencing Reveals Subclonality and Timing of Genetic Alterations

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2897-2897
Author(s):  
Jens Lohr ◽  
Petar Stojanov ◽  
Michael S Lawrence ◽  
Daniel Auclair ◽  
Scott Carter ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Time Course ◽  
Somatic Mutations ◽  
Plasma Cells ◽  
Conflicts Of Interest ◽  
Genetic Alterations ◽  
Copy Number Variations ◽  
Classification Systems ◽  
Driver Mutations ◽  
Kras Mutations

Abstract Abstract 2897 Multiple myeloma is considered to be a homogenous disease within a given patient, and current classification systems and treatment algorithms are based on this assumption. We have asked if there is genetic heterogeneity of multiple myeloma within a patient and if this heterogeneity can be quantified. To address this question, we have used massively parallel whole exome and whole genome sequencing of tumors and matched normal controls of 64 patients with multiple myeloma. We present an analytic strategy to distinguish potential driver mutations based on their clonality. We demonstrate that in some patients there are many somatic mutations that are only present in a subclonal fraction of the malignant plasma cells, and the subclonal fraction comprises up to 50%. These mutations are therefore less likely to confer a selective clonal advantage and are less attractive therapeutic targets because they only affect a small fraction of the myeloma cells. As an example, we found KRAS to be one of the most prevalent mutated genes in multiple myeloma, and KRAS mutations are significantly more likely clonal than subclonal, while other mutations in other genes are predominantly subclonal. We also used this approach to investigate how copy number variations are related to somatic mutations, i.e. to define the temporal sequence of these events. This question is particularly relevant for hyperdiploidy in multiple myeloma, since this is associated with trisomies of odd numbered chromosomes. However, these trisomies do not occur with the same frequency in all odd numbered chromosomes and some hyperdiploid samples are also associated with trisomies of various even numbered chromosomes. It is unclear if these trisomies occur as a single catastrophic event, or rather in a sequential fashion. By assuming a constant rate of somatic mutations and utilizing this rate as a “timer” for chromosomal duplications we demonstrate that trisomies of odd-numbered chromosomes appear to occur early in a distinct order, whereas trisomies of even-numbered chromosomes and chromosome 1q occur late. Our analyses allow us to determine which somatic mutations occurred before chromosomal duplication and may therefore give insight in the time course of pathogenic genetic alterations in multiple myeloma. Our work may also play an important role in prioritizing somatic mutations for therapeutic targeting in multiple myeloma. Disclosures: No relevant conflicts of interest to declare.

Shifts in Intra-Clonal Dynamics Rather Than Novel Mutations Are the Main Engine Driving Tumor Evolution in Relapsed CLL

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 284-284
Author(s):  
Dan-Avi Landau ◽  
Petar Stojanov ◽  
Michael S Lawrence ◽  
Carrie Sougnez ◽  
Aaron McKeena ◽  
...  
Keyword(s):  
Copy Number ◽  
Somatic Mutations ◽  
Selective Pressure ◽  
Allelic Frequency ◽  
Tumor Evolution ◽  
Novel Mutations ◽  
Number Variation ◽  
Cancer Drivers ◽  
Relapsed Disease ◽  
Allelic Fraction

Abstract Abstract 284 Tumor evolution is a complex process, and is the biologic underpinning of disease progression, resistance to therapy and relapse. Using whole-exome sequencing (WES) of sequential samples from patients with relapsed chronic lymphocytic leukemia (CLL) treated with conventional chemotherapy, we studied genetic tumor evolution of cancer relapse. We performed WES using paired-end reads on DNA from two peripheral blood-derived CLL tumor samples at least one year apart and on germline DNA for 20 patients. Here we report the analysis of tumor exomes from the first seven patients, of whom 6 had relapsed disease after chemotherapy and one untreated patient without intervening therapy between samples. All samples had a tumor purity that exceeded 90%. Sequencing coverage was >86% of target territory, with 132x depth obtained for all samples. In total, 187 coding region mutations (124 nonsynonymous, 63 synonymous) were identified (median: 21 somatic mutations/patient; range: 10–64), not including Ig gene mutations which were >80% clonal and remained clonally stable in our cohort. We measured the abundance of specific mutations in each patient tumor to assess clonality. An allelic frequency of 0.3–0.6 likely represents heterozygous mutations in most or all tumor cells (‘clonal') while a frequency of <0.3 represents mutations in a subset of tumor cells (‘subclonal'). Overall, 118 (63%) somatic mutations were clonal, and their allelic frequency remained unchanged in the relapse samples. 65 (35%) mutations were subclonal (average allelic frequency 0.13±0.075). Ten subclonal mutations, found in 3 of 7 initial samples, evolved into clonal mutations in the relapse samples, compared with only a single opposite occurrence where a clonal mutation became subclonal (p< 0.005, FDR q<0.01). The remaining 4 of 7 tumors showed only minor shifts in allelic frequencies over time, and included the individual who did not receive chemotherapy between samples. In Patient A, a subclone with three mutations appeared to expand to become the dominant clone, with a change in allelic fraction from an average of 0.17 (0.14–0.23) to an average of 0.43 (0.41–0.46) (p<0.000001). Two of three mutations were non-silent and are likely cancer drivers: NRAS (Q61R, found in 38/38 samples in COSMIC- Catalogue of Somatic Mutations in Cancer, Sanger Institute), and a cancer related gene PLK1. The third mutation is likely a passenger mutation as it was a synonymous mutation in ADAM18. In Patient B, a subclone containing a novel, recently identified driver in CLL, SF3B1, became the dominant clone that included additional mutations in cancer-related genes, CSMD1 and KIAA1199 (change in allelic fraction from an average of 0.16 (0.12–0.18) to an average of 0.37 (0.35–0.38) (p<0.001)). In another example, Patient C, a TP53 mutation increased in allelic frequency from 0.18 in the initial sample to 0.69 in the relapse sample (p<0.005). Analysis of copy number variation (CNV) by CapSeg (a novel algorithm that examines CNV from WES) revealed this change in allelic frequency to be coupled with a ploidy change in del(17p) from 0.8 to 0.5, consistent with a loss of both alleles. Only one sample demonstrated the appearance of novel mutations with relapse (Patient C), with 19 new mutations (13 non-silent, 3 Silent) of a total of 46 appearing at relapse. All however were subclonal, and thus less likely to have driven tumor relapse. A comparison of the 10 mutations that were selected by chemotherapy to all other mutations demonstrated an enrichment in mutations seen in the COSMIC database (p<0.05), which hints at a higher proportion of cancer drivers in this set. Our ongoing analyses are focused on the association of clinical features with copy number variation and changes in gene expression. In summary, our analysis of serial exomes from seven patients provided important insights into the genetic evolution of CLL under the selective pressure of chemotherapy. We demonstrate a significant change in clonal dynamics in one half of treated patients, which suggests that relapsed disease following treatment is driven by expansion of subclones under the selective pressure of chemotherapy rather than by novel mutagenesis. This observation may have clinical implications, as it suggests that pre-treatment WES may allow not only for the delineation of current genetic abnormalities, but through investigation of subclonal mutations, may also predict genetic evolution in future relapse. Disclosures: No relevant conflicts of interest to declare.

No Recurrent Mutation of SF3B1, U2AF1 and SRSF2 Spliceosomal Gene in Multiple Myeloma but Polymorphisms of These Genes Are Associated with the Prediction of Worse Prognosis

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3958-3958
Author(s):  
Trang Nguyen Thi Dai ◽  
Hye-Ran Kim ◽  
Min-Gu Kang ◽  
Stephanie J. Won ◽  
Hwan-Young Kim ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Light Chain ◽  
Somatic Mutations ◽  
Conflicts Of Interest ◽  
Bone Lesion ◽  
Disease Free Survival ◽  
Free Light Chain ◽  
Immunoglobulin Level ◽  
Exon 2 ◽  
Number Of Patients

Abstract Abstract 3958 Background: Recently, a striking example of the effects on acquired somatic mutations in splicing factors such as SF3B1, U2AF1, and SRSF2 has been described. The sequencing of the DNA from abnormal blood cells from patients with several types of leukemia such as AML, CLL, CMML, pre-leukemic syndromes, and MDS, has shown that a high proportion of these cases are associated with somatic mutations in spliceosomal proteins. Also, evidence of cancer-specific alternative splicing and oncogenic somatic mutations in spliceosome subunits has been steadily growing. However, there is not much research regarding aberrant splicing pathways in Multiple myeloma (MM) patients. Therefore, we tried to investigate the presence and prognostic implication of mutation of the SF3B1 and U2AF1 protein in these patients in South Korea. Materials and Methods: We examined a cohort of 87 MM patients and 100 healthy controls for somatic mutations in SF3B1, U2AF1 and SRSF2 by using direct sequencing method. The medical records were reviewed for age, sex, plasma cell percentage, serum M protein, immunoglobulin level, free light chain ratio, calcium, creatinine, hemoglobin, bone lesion, albumin, beta 2 microglobulin, lactate dehydrogenase, treatment outcome, and so on. The collected data was analyzed by SPSS for Windows version 18.0. We performed Pearson's chi-square tests, one way ANOVA analysis, and Student t-test. Survival rates of myeloma patients according to the result of SF3B1, U2AF1 and SRSF2 sequencing were analyzed using Kaplan-Meier log-rank test. Results: Our 87 MM patients showed no mutation including known recurrent ones in SF3B1, U2AF1 and SRSF2 genes. However, the patients displayed 39198T>T/C polymorphism (70.1%) in exon 18 of SF3B1, 8345T>T/G polymorphism (13.8%) in exon 2 of U2AF1 and 5399C/T polymorphism (100%) in exon 1 of SRSF2. In the entire cohort, the number of patients with no polymorphism, one polymorphism, two polymorphisms and three polymorphisms was counted up to 0%, 24.1%, 67.8% and 8.0%, respectively. The T/C polymorphism at position 39198 of SF3B1 exon 18 and the T/G polymorphism at position 8345 of U2AF1 exon 2 were analyzed by allele-specific PCR using normal control. Results in 100 normal controls, polymorphism of SF3B1 exon 18 was taken into account of 82.0%, the remaining is non polymorphism while U2AF1 exon 2 showed 10.0% polymorphism and 90.0% non polymorphism. Sex (p=0.048) and free light chain ratio (p=0.002) showed significant results according to polymorphism status while other clinical characteristics were not associated. The patient with polymorphisms in both SF3B1 and U2AF1 had worse overall survival (P=0.042) and disease-free survival (P<0.01), compared to patients without polymorphism. Conclusion: Our results show no recurrent SF3B1, U2AF1 and SRSF2 mutations in MM patients rather polymorphisms in SF3B1 and U2AF1 gene were significantly implicated in the prediction of poor prognosis. Disclosures: No relevant conflicts of interest to declare.

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