Gene Summary

Gene:SRSF2; serine and arginine rich splicing factor 2
Aliases: SC35, PR264, SC-35, SFRS2, SFRS2A, SRp30b
Summary:The protein encoded by this gene is a member of the serine/arginine (SR)-rich family of pre-mRNA splicing factors, which constitute part of the spliceosome. Each of these factors contains an RNA recognition motif (RRM) for binding RNA and an RS domain for binding other proteins. The RS domain is rich in serine and arginine residues and facilitates interaction between different SR splicing factors. In addition to being critical for mRNA splicing, the SR proteins have also been shown to be involved in mRNA export from the nucleus and in translation. Two transcript variants encoding the same protein and one non-coding transcript variant have been found for this gene. In addition, a pseudogene of this gene has been found on chromosome 11. [provided by RefSeq, Sep 2010]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:serine/arginine-rich splicing factor 2
Source:NCBIAccessed: 30 August, 2019


What does this gene/protein do?
Show (18)
Pathways:What pathways are this gene/protein implicaed in?
Show (1)

Cancer Overview

Research Indicators

Publications Per Year (1994-2019)
Graph generated 30 August 2019 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

  • Acute Myeloid Leukaemia
  • Transfection
  • Neoplastic Cell Transformation
  • Chronic Myelomonocytic Leukemia
  • Transcription
  • Proto-Oncogene Proteins
  • Phosphoproteins
  • Serine-Arginine Splicing Factors
  • SRSF2
  • Nuclear Proteins
  • Biomarkers, Tumor
  • Chromosome 17
  • Disease Progression
  • DNA Sequence Analysis
  • Repressor Proteins
  • Homologous Transplantat
  • Ribonucleoproteins
  • DNA-Binding Proteins
  • Alternative Splicing
  • Chronic Myelogenous Leukemia
  • Genetic Predisposition
  • Adolescents
  • Mutation
  • Sequence Deletion
  • Core Binding Factor Alpha 2 Subunit
  • RNA Splicing
  • Haematological Malignancies
  • RNA Splicing Factors
  • Neoplasm Proteins
  • Primary Myelofibrosis
  • Myeloproliferative Disorders
  • Mastocytosis, Systemic
  • DNA Mutational Analysis
  • Epigenetics
  • Proto-Oncogene Proteins c-kit
  • Cancer Gene Expression Regulation
  • Signal Transduction
  • High-Throughput Nucleotide Sequencing
  • Myelodysplastic Syndromes
  • Phenotype
  • Cervical Cancer
  • DNA Methylation
Tag cloud generated 30 August, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (7)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: SRSF2 (cancer-related)

Wang F, Cheng Y, Zhang C, et al.
A novel antisense oligonucleotide anchored on the intronic splicing enhancer of hTERT pre-mRNA inhibits telomerase activity and induces apoptosis in glioma cells.
J Neurooncol. 2019; 143(1):57-68 [PubMed] Related Publications
INTRODUCTION: Alternative splicing of hTERT pre-mRNA is an important step in the regulation of telomerase activity, but the regulation mechanisms and functions remain unclear.
METHODS: RT-PCR analysis was used to detect hTERT splicing in glioma cell lines and brain tissues. TRAP assay was used to detect the telomerase activity. Then, we designed and synthesized 2'-O-methyl-RNA phosphorothioate AONs and transfected them into glioma cells to detect the changes in telomerase activity. MTT assay, plate colony formation assay, western blotting and Annexin V/PI assay were used to detect cell proliferation and apoptosis. At last, bioinformatics analyses were used to predict the expression and function of splicing protein SRSF2 in gliomas.
RESULTS: hTERT splicing occurs both in glioma cell lines and glioma patients' tissues. The telomerase activity was related to the expression level of the full-length hTERT, rather than the total hTERT transcript level. AON-Ex726 was complementary to the sequence of the intronic splicing enhancer (ISE) in intron six, and significantly altered the splicing pattern of hTERT pre-mRNA, reducing the expression level of the full-length hTERT mRNA and increasing the expression level of the -β hTERT mRNA. After transfection with AON-Ex726, the level of apoptosis was increased, while telomerase activity and cell proliferation were significantly decreased. By bioinformatic predictions, we found the AON-Ex726 anchoring sequence in ISE overlaps the binding site of SRSF2 protein, which is up-regulated during the development of gliomas.
CONCLUSIONS: Our findings provided new targets and important clues for the gene therapy of gliomas by regulating the alternative splicing pattern of hTERT pre-mRNA.

Kong L, Wei Q, Hu X, et al.
miR-193a-3p Promotes Radio-Resistance of Nasopharyngeal Cancer Cells by Targeting SRSF2 Gene and Hypoxia Signaling Pathway.
Med Sci Monit Basic Res. 2019; 25:53-62 [PubMed] Free Access to Full Article Related Publications
BACKGROUND Radio-resistance is an important barrier in nasopharyngeal carcinoma treatment. MicroRNAs are gene expression core regulators in various biological procedures containing cancer radio-resistance. Nevertheless, the clinical association between nasopharyngeal carcinoma and miR-193a-3p/SRSF2 remains unclear. MATERIAL AND METHODS We examined the miR-193a-3p level in radio-sensitive CNE-2 and radio-resistant CNE-1 NPC cell lines, and, based on a literature review, predicted SRSF2 to be the target gene of miR-193a-3p. We explored the expression of SRSF2 at protein and mRNA levels by transfecting either miR-193a-3p-mimic or antagomiR. Finally, we performed signaling pathway analysis to assess the possible role of miR-193a-3p/SRSF2 in signaling pathways. RESULTS miR-193a-3p promotes NPC radio-resistance, and the SRSF2 gene is the direct target for miR-193a-3p in NPC, and thus is negatively correlated with NPC radio-resistance. The hypoxia signaling pathway activity is strongly affected, and it is possible to use the downstream activity of the SRSF2 gene to show the effect of miR-193a-3p on radio-resistance in NPC cells. CONCLUSIONS miR-193a-3p mediates promotion of NPC radio-resistance.

Jawhar M, Döhner K, Kreil S, et al.
KIT D816 mutated/CBF-negative acute myeloid leukemia: a poor-risk subtype associated with systemic mastocytosis.
Leukemia. 2019; 33(5):1124-1134 [PubMed] Related Publications
KIT D816 mutations (KIT D816

Orsini P, Impera L, Parciante E, et al.
Droplet digital PCR for the quantification of Alu methylation status in hematological malignancies.
Diagn Pathol. 2018; 13(1):98 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Alu repeats, belonging to the Short Interspersed Repetitive Elements (SINEs) class, contain about 25% of CpG sites in the human genome. Alu sequences lie in gene-rich regions, so their methylation is an important transcriptional regulation mechanism. Aberrant Alu methylation has been associated with tumor aggressiveness, and also previously discussed in hematological malignancies, by applying different approaches. Moreover, today different techniques designed to measure global DNA methylation are focused on the methylation level of specific repeat elements. In this work we propose a new method of investigating Alu differential methylation, based on droplet digital PCR (ddPCR) technology.
METHODS: Forty-six patients with hematological neoplasms were included in the study: 30 patients affected by chronic lymphocytic leukemia, 7 patients with myelodysplastic syndromes at intermediate/high risk, according with the International Prognostic Scoring System, and 9 patients with myelomonocytic leukemia. Ten healthy donors were included as controls. Acute promyelocytic leukemia-derived NB4 cell line, either untreated or treated with decitabine (DEC) hypomethylating agent, was also analyzed. DNA samples were investigated for Alu methylation level by digestion of genomic DNA with isoschizomers with differential sensitivity to DNA methylation, followed by ddPCR.
RESULTS: Using ddPCR, a significant decrease of the global Alu methylation level in DNA extracted from NB4 cells treated with DEC, as compared to untreated cells, was observed. Moreover, comparing the global Alu methylation levels at diagnosis and after azacytidine (AZA) treatment in MDS patients, a statistically significant decrease of Alu sequences methylation after therapy as compared to diagnosis was evident. We also observed a significant decrease of the Alu methylation level in CLL patients compared to HD, and, finally, for CMML patients, a decrease of Alu sequences methylation was observed in patients harboring the SRSF2 hotspot gene mutation c.284C>D.
CONCLUSIONS: In our work, we propose a method to investigate Alu differential methylation based on ddPCR technology. This assay introduces ddPCR as a more sensitive and immediate technique for Alu methylation analysis. To date, this is the first application of ddPCR to study DNA repetitive elements. This approach may be useful to profile patients affected by hematologic malignancies for diagnostic/prognostic purpose.

Lee SD, Yu D, Lee DY, et al.
Upregulated microRNA-193a-3p is responsible for cisplatin resistance in CD44(+) gastric cancer cells.
Cancer Sci. 2019; 110(2):662-673 [PubMed] Free Access to Full Article Related Publications
Cisplatin is a well-known anticancer drug used to treat various cancers. However, development of cisplatin resistance has hindered the efficiency of this drug in cancer treatment. Development of chemoresistance is known to involve many signaling pathways. Recent attention has focused on microRNAs (miRNAs) as potentially important upstream regulators in the development of chemoresistance. CD44 is one of the gastric cancer stem cell markers and plays a role in regulating self-renewal, tumor initiation, metastasis and chemoresistance. The purpose of the present study was to examine the mechanism of miRNA-mediated chemoresistance to cisplatin in CD44-positive gastric cancer stem cells. We sorted gastric cancer cells according to level of CD44 expression by FACS and analyzed their miRNA expression profiles by microarray analysis. We found that miR-193a-3p was significantly upregulated in CD44(+) cells compared with CD44(-) cells. Moreover, SRSF2 of miR-193a-3p target gene was downregulated in CD44(+) cells. We studied the modulation of Bcl-X and caspase 9 mRNA splicing by SRSF2 and found that more pro-apoptotic variants of these genes were generated. We also found that downstream anti-apoptotic genes such as Bcl-2 were upregulated, whereas pro-apoptotic genes such as Bax and cytochrome C were downregulated in CD44(+) cells compared to CD44(-) cells. In addition, we found that an elevated level of miR-193a-3p triggered the development of cisplatin resistance in CD44(+) cells. Inhibition of miR-193a-3p in CD44(+) cells increased SRSF2 expression and also altered the levels of multiple apoptotic genes. Furthermore, inhibition of miR-193a-3p reduced cell viability and increased the number of apoptotic cells. Therefore, miR-193a-3p may be implicated in the development of cisplatin resistance through regulation of the mitochondrial apoptosis pathway. miR-193a-3p could be a promising target for cancer therapy in cisplatin-resistant gastric cancer.

Xu JJ, Smeets MF, Tan SY, et al.
Modeling human RNA spliceosome mutations in the mouse: not all mice were created equal.
Exp Hematol. 2019; 70:10-23 [PubMed] Related Publications
Myelodysplastic syndromes (MDS) and related myelodysplastic/myeloproliferative neoplasms (MDS/MPNs) are clonal stem cell disorders, primarily affecting patients over 65 years of age. Mapping of the MDS and MDS/MPN genome identified recurrent heterozygous mutations in the RNA splicing machinery, with the SF3B1, SRSF2, and U2AF1 genes being frequently mutated. To better understand how spliceosomal mutations contribute to MDS pathogenesis in vivo, numerous groups have sought to establish conditional murine models of SF3B1, SRSF2, and U2AF1 mutations. The high degree of conservation of hematopoiesis between mice and human and the well-established phenotyping and genetic modification approaches make murine models an effective tool with which to study how a gene mutation contributes to disease pathogenesis. The murine models of spliceosomal mutations described to date recapitulate human MDS or MDS/MPN to varying extents. Reasons for the differences in phenotypes reported between alleles of the same mutation are varied, but the nature of the genetic modification itself and subsequent analysis methods are important to consider. In this review, we summarize recently reported murine models of SF3B1, SRSF2, and U2AF1 mutations, with a particular focus on the genetically engineered modifications underlying the models and the experimental approaches applied.

Li B, Mascarenhas JO, Rampal RK
Leukemic Transformation of Myeloproliferative Neoplasms: Therapeutic and Genomic Considerations.
Curr Hematol Malig Rep. 2018; 13(6):588-595 [PubMed] Related Publications
PURPOSE OF REVIEW: Although BCR-ABL1-negative myeloproliferative neoplasms (MPN) are chronic, clonal hematopoietic stem cell (HSC) disorders marked by proliferation of one or more myeloid lineages, a substantial proportion of patients transform to acute myeloid leukemia. Leukemic transformation (LT) from a pre-existing MPN carries a dismal prognosis. Here, we review recent genetic, biological, and clinical data regarding LT.
RECENT FINDINGS: In the last decade, DNA sequencing has revolutionized our understanding of the genomic landscape of LT. Mutations in TP53, ASXL1, EZH2, IDH1/2, and SRSF2 are significantly associated with increased risk of LT of MPNs. Preclinical modeling of these mutations is underway and has yielded important biological insights, some of which have therapeutic implications. Recent progress has led to the identification of recurrent genomic alterations in patients with LT. This has allowed mechanistic and therapeutic insight into the process of LT. In turn, this may lead to more mechanism-based therapeutic strategies that may improve patient outcomes.

Tyner JW, Tognon CE, Bottomly D, et al.
Functional genomic landscape of acute myeloid leukaemia.
Nature. 2018; 562(7728):526-531 [PubMed] Free Access to Full Article Related Publications
The implementation of targeted therapies for acute myeloid leukaemia (AML) has been challenging because of the complex mutational patterns within and across patients as well as a dearth of pharmacologic agents for most mutational events. Here we report initial findings from the Beat AML programme on a cohort of 672 tumour specimens collected from 562 patients. We assessed these specimens using whole-exome sequencing, RNA sequencing and analyses of ex vivo drug sensitivity. Our data reveal mutational events that have not previously been detected in AML. We show that the response to drugs is associated with mutational status, including instances of drug sensitivity that are specific to combinatorial mutational events. Integration with RNA sequencing also revealed gene expression signatures, which predict a role for specific gene networks in the drug response. Collectively, we have generated a dataset-accessible through the Beat AML data viewer (Vizome)-that can be leveraged to address clinical, genomic, transcriptomic and functional analyses of the biology of AML.

Lee SC, North K, Kim E, et al.
Synthetic Lethal and Convergent Biological Effects of Cancer-Associated Spliceosomal Gene Mutations.
Cancer Cell. 2018; 34(2):225-241.e8 [PubMed] Free Access to Full Article Related Publications
Mutations affecting RNA splicing factors are the most common genetic alterations in myelodysplastic syndrome (MDS) patients and occur in a mutually exclusive manner. The basis for the mutual exclusivity of these mutations and how they contribute to MDS is not well understood. Here we report that although different spliceosome gene mutations impart distinct effects on splicing, they are negatively selected for when co-expressed due to aberrant splicing and downregulation of regulators of hematopoietic stem cell survival and quiescence. In addition to this synthetic lethal interaction, mutations in the splicing factors SF3B1 and SRSF2 share convergent effects on aberrant splicing of mRNAs that promote nuclear factor κB signaling. These data identify shared consequences of splicing-factor mutations and the basis for their mutual exclusivity.

Patnaik MM, Tefferi A
Chronic myelomonocytic leukemia: 2018 update on diagnosis, risk stratification and management.
Am J Hematol. 2018; 93(6):824-840 [PubMed] Free Access to Full Article Related Publications
DISEASE OVERVIEW: Chronic myelomonocytic leukemia (CMML) is a clonal hematopoietic stem cell disorder with overlapping features of myelodysplastic syndromes and myeloproliferative neoplasms, with an inherent risk for leukemic transformation (∼15%-20% over 3-5 years).
DIAGNOSIS: Diagnosis is based on the presence of sustained (>3 months) peripheral blood monocytosis (≥1 × 10
RISK STRATIFICATION: Molecularly integrated prognostic models include; the Groupe Français des Myélodysplasies (GFM), Mayo Molecular Model (MMM), and the CMML specific prognostic model (CPSS-Mol). Risk factors incorporated into the MMM include presence of nonsense or frameshift ASXL1 mutations, absolute monocyte count > 10 × 10
RISK-ADAPTED THERAPY: Hypomethylating agents such as 5-azacitidine and decitabine are commonly used, with overall response rates of ∼30%-40% and complete remission rates of ∼7%-17%; with no impact on mutational allele burdens. Allogeneic stem cell transplant is the only potentially curative option, but is associated with significant morbidity and mortality.

Liang Y, Tebaldi T, Rejeski K, et al.
SRSF2 mutations drive oncogenesis by activating a global program of aberrant alternative splicing in hematopoietic cells.
Leukemia. 2018; 32(12):2659-2671 [PubMed] Free Access to Full Article Related Publications
Recurrent mutations in the splicing factor SRSF2 are associated with poor clinical outcomes in myelodysplastic syndromes (MDS). Their high frequency suggests these mutations drive oncogenesis, yet the molecular explanation for this process is unclear. SRSF2 mutations could directly affect pre-mRNA splicing of a vital gene product; alternatively, a whole network of gene products could be affected. Here we determine how SRSF2 mutations globally affect RNA binding and splicing in vivo using HITS-CLIP. Remarkably, the majority of differential binding events do not translate into alternative splicing of exons with SRSF2

Bartels S, Schipper E, Hasemeier B, et al.
Hotspot mutations in cancer genes may be missed in routine diagnostics due to neighbouring sequence variants.
Exp Mol Pathol. 2018; 105(1):37-40 [PubMed] Related Publications
The detection of hotspot mutations in key cancer genes is now an essential part of the diagnostic work-up in molecular pathology. Nearly all assays for mutation detection involve an amplification step. A second single nucleotide variant (SNV) on the same allele adjacent to a mutational hotspot can interfere with primer binding, leading to unnoticed allele-specific amplification of the wild type allele and thereby false-negative mutation testing. We present two diagnostic cases with false negative sequence results for JAK2 and SRSF2. In both cases mutations would have escaped detection if only one strand of DNA had been analysed. Because many commercially available diagnostic kits rely on the analysis of only one DNA strand they are prone to fail in cases like these. Detailed protocols and quality control measures to prevent corresponding pitfalls are presented.

Hurtado AM, Luengo-Gil G, Chen-Liang TH, et al.
Transcriptomic rationale for synthetic lethality-targeting ERCC1 and CDKN1A in chronic myelomonocytic leukaemia.
Br J Haematol. 2018; 182(3):373-383 [PubMed] Related Publications
Despite the absence of mutations in the DNA repair machinery in myeloid malignancies, the advent of high-throughput sequencing and discovery of splicing and epigenetics defects in chronic myelomonocytic leukaemia (CMML) prompted us to revisit a pathogenic role for genes involved in DNA damage response. We screened for misregulated DNA repair genes by enhanced RNA-sequencing on bone marrow from a discovery cohort of 27 CMML patients and 9 controls. We validated 4 differentially expressed candidates in CMML CD34

Park JJ, Diefenbach RJ, Joshua AM, et al.
Oncogenic signaling in uveal melanoma.
Pigment Cell Melanoma Res. 2018; 31(6):661-672 [PubMed] Related Publications
Uveal melanoma is the most common primary cancer of the eye, and despite rapidly emerging insights into the molecular profile of this disease, prognosis of patients with metastatic uveal melanoma remains poor with mortality rates unchanged in over 35 years. Early genetic events activate G protein-coupled receptor signaling in nearly all uveal tumors via mutually exclusive mutations in the GNAQ, GNA11, CYSLTR2, or PLCB4 genes. A multitude of signaling cascades downstream of G protein activation, including protein kinase C and mitogen-activated protein kinase activity, are actionable, and many ongoing clinical trials are targeting these pathways. Additional cytogenetic and genetic changes, however, including chromosome 3 monosomy, mutations in the BAP1 tumor suppressor gene, alterations in the splicing factors SRSF2/SF3B1, and mutations in the translation initiation factor EIF1AX, modulate signaling output in uveal tumors and modify the risk of metastases. Here, we review the complex interactions between genetic, molecular signaling, and prognostic profiles in uveal melanoma; the clinical implications of these interactions; and the latest potential targets for rational therapy.

Suma S, Sakata-Yanagimoto M, Nguyen TB, et al.
Blastic plasmacytoid dendritic cell neoplasm arising from clonal hematopoiesis.
Int J Hematol. 2018; 108(4):447-451 [PubMed] Related Publications
Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare subtype of myeloid neoplasm. Clonal evolution in the development of BPDCN remains to be elucidated. In the present study, we examined clonal evolution in a case of BPDCN by analyzing the distribution of gene mutations in tumor cells and non-tumor blood cells. The p.D1129fs and p.K1005fs TET2 mutations, p.P95H SRSF2 mutation, and p.L287fs NPM1 mutation were identified in a skin tumor at diagnosis and peripheral blood mononuclear cells at relapse. Notably, the p.D1129fs TET2 and p.L287fs NPM1 mutations were observed only in tumor cells, while the p.K1005fs TET2 and p.P95H SRSF2 mutations were found in both tumor cells and non-tumor blood cells. Recent genetic studies have suggested that some blood cancers may originate from clonal hematopoiesis, harboring somatic mutations. In the present case, the data suggest that BPDCN originated from clonal hematopoiesis with the p.K1005fs TET2 and p.P95H SRSF2 mutations via acquisition of the additional p.D1129fs TET2 and p.L287fs NPM1 mutations.

Chang CJ, Kotini AG, Olszewska M, et al.
Dissecting the Contributions of Cooperating Gene Mutations to Cancer Phenotypes and Drug Responses with Patient-Derived iPSCs.
Stem Cell Reports. 2018; 10(5):1610-1624 [PubMed] Free Access to Full Article Related Publications
Connecting specific cancer genotypes with phenotypes and drug responses constitutes the central premise of precision oncology but is hindered by the genetic complexity and heterogeneity of primary cancer cells. Here, we use patient-derived induced pluripotent stem cells (iPSCs) and CRISPR/Cas9 genome editing to dissect the individual contributions of two recurrent genetic lesions, the splicing factor SRSF2 P95L mutation and the chromosome 7q deletion, to the development of myeloid malignancy. Using a comprehensive panel of isogenic iPSCs-with none, one, or both genetic lesions-we characterize their relative phenotypic contributions and identify drug sensitivities specific to each one through a candidate drug approach and an unbiased large-scale small-molecule screen. To facilitate drug testing and discovery, we also derive SRSF2-mutant and isogenic normal expandable hematopoietic progenitor cells. We thus describe here an approach to dissect the individual effects of two cooperating mutations to clinically relevant features of malignant diseases.

Pritchard AL, Johansson PA, Nathan V, et al.
Germline mutations in candidate predisposition genes in individuals with cutaneous melanoma and at least two independent additional primary cancers.
PLoS One. 2018; 13(4):e0194098 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: While a number of autosomal dominant and autosomal recessive cancer syndromes have an associated spectrum of cancers, the prevalence and variety of cancer predisposition mutations in patients with multiple primary cancers have not been extensively investigated. An understanding of the variants predisposing to more than one cancer type could improve patient care, including screening and genetic counselling, as well as advancing the understanding of tumour development.
METHODS: A cohort of 57 patients ascertained due to their cutaneous melanoma (CM) diagnosis and with a history of two or more additional non-cutaneous independent primary cancer types were recruited for this study. Patient blood samples were assessed by whole exome or whole genome sequencing. We focussed on variants in 525 pre-selected genes, including 65 autosomal dominant and 31 autosomal recessive cancer predisposition genes, 116 genes involved in the DNA repair pathway, and 313 commonly somatically mutated in cancer. The same genes were analysed in exome sequence data from 1358 control individuals collected as part of non-cancer studies (UK10K). The identified variants were classified for pathogenicity using online databases, literature and in silico prediction tools.
RESULTS: No known pathogenic autosomal dominant or previously described compound heterozygous mutations in autosomal recessive genes were observed in the multiple cancer cohort. Variants typically found somatically in haematological malignancies (in JAK1, JAK2, SF3B1, SRSF2, TET2 and TYK2) were present in lymphocyte DNA of patients with multiple primary cancers, all of whom had a history of haematological malignancy and cutaneous melanoma, as well as colorectal cancer and/or prostate cancer. Other potentially pathogenic variants were discovered in BUB1B, POLE2, ROS1 and DNMT3A. Compared to controls, multiple cancer cases had significantly more likely damaging mutations (nonsense, frameshift ins/del) in tumour suppressor and tyrosine kinase genes and higher overall burden of mutations in all cancer genes.
CONCLUSIONS: We identified several pathogenic variants that likely predispose to at least one of the tumours in patients with multiple cancers. We additionally present evidence that there may be a higher burden of variants of unknown significance in 'cancer genes' in patients with multiple cancer types. Further screens of this nature need to be carried out to build evidence to show if the cancers observed in these patients form part of a cancer spectrum associated with single germline variants in these genes, whether multiple layers of susceptibility exist (oligogenic or polygenic), or if the occurrence of multiple different cancers is due to random chance.

Bowler E, Porazinski S, Uzor S, et al.
Hypoxia leads to significant changes in alternative splicing and elevated expression of CLK splice factor kinases in PC3 prostate cancer cells.
BMC Cancer. 2018; 18(1):355 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Mounting evidence suggests that one of the ways that cells adapt to hypoxia is through alternative splicing. The aim of this study was firstly to examine the effect of hypoxia on the alternative splicing of cancer associated genes using the prostate cancer cell line PC3 as a model. Secondly, the effect of hypoxia on the expression of several regulators of splicing was examined.
METHODS: PC3 cells were grown in 1% oxygen in a hypoxic chamber for 48 h, RNA extracted and sent for high throughput PCR analysis at the RNomics platform at the University of Sherbrooke, Canada. Genes whose exon inclusion rate PSI (ψ) changed significantly were identified, and their altered exon inclusion rates verified by RT-PCR in three cell lines. The expression of splice factors and splice factor kinases in response to hypoxia was examined by qPCR and western blotting. The splice factor kinase CLK1 was inhibited with the benzothiazole TG003.
RESULTS: In PC3 cells the exon inclusion rate PSI (ψ) was seen to change by > 25% in 12 cancer-associated genes; MBP, APAF1, PUF60, SYNE2, CDC42BPA, FGFR10P, BTN2A2, UTRN, RAP1GDS1, PTPN13, TTC23 and CASP9 (caspase 9). The expression of the splice factors SRSF1, SRSF2, SRSF3, SAM68, HuR, hnRNPA1, and of the splice factor kinases SRPK1 and CLK1 increased significantly in hypoxia. We also observed that the splice factor kinase CLK3, but not CLK2 and CLK4, was also induced in hypoxic DU145 prostate, HT29 colon and MCF7 breast cancer cell lines. Lastly, we show that the inhibition of CLK1 in PC3 cells with the benzothiazole TG003 increased expression of the anti-apoptotic isoform caspase 9b.
CONCLUSIONS: Significant changes in alternative splicing of cancer associated genes occur in prostate cancer cells in hypoxic conditions. The expression of several splice factors and splice factor kinases increases during hypoxia, in particular the Cdc-like splice factor kinases CLK1 and CLK3. We suggest that in hypoxia the elevated expression of these regulators of splicing helps cells adapt through alternative splicing of key cancer-associated genes. We suggest that the CLK splice factor kinases could be targeted in cancers in which hypoxia contributes to resistance to therapy.

Yao XY, Zhou JD, Yang J, et al.
SETBP1 mutations in Chinese patients with acute myeloid leukemia and myelodysplastic syndrome.
Pathol Res Pract. 2018; 214(5):706-712 [PubMed] Related Publications
BACKGROUND: Somatic mutations in SETBP1 gene have recently been detected in hematologic malignancies. The present study aimed to explore the frequency and clinical correlations of SETBP1 mutations in patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS).
METHODS: In this study, we used high-resolution melting analysis (HRMA) to detect the SETBP1 mutations in a cohort of 363 patients with AML or MDS.
RESULTS: A total of 1.2% (3/249) of AML and 1.8% (2/114) of MDS patients were found with heterozygous SETBP1 mutations. In AML, patients with SETBP1 mutations showed higher hemoglobin (P = 0.004) and were more frequently recurrent in AML-M4 subtype (P = 0.034). All five SETBP1 mutated patients had normal karyotypes. The patients with SETBP1 mutations had significantly higher incidences of concurrent SRSF2 mutations (P = 0.002). HRMA could detect SETBP1 mutations with 5% sensitivity, obviously higher than 25% of Sanger sequencing.
CONCLUSIONS: We established a rapid, inexpensive, high-throughput and sensitive method to screen SETBP1 mutations. SETBP1 mutations were a rare molecular event in AML and MDS patients.

Rothenberg-Thurley M, Amler S, Goerlich D, et al.
Persistence of pre-leukemic clones during first remission and risk of relapse in acute myeloid leukemia.
Leukemia. 2018; 32(7):1598-1608 [PubMed] Free Access to Full Article Related Publications
Some patients with acute myeloid leukemia (AML) who are in complete remission after induction chemotherapy harbor persisting pre-leukemic clones, carrying a subset of leukemia-associated somatic mutations. There is conflicting evidence on the prognostic relevance of these clones for AML relapse. Here, we characterized paired pre-treatment and remission samples from 126 AML patients for mutations in 68 leukemia-associated genes. Fifty patients (40%) retained ≥1 mutation during remission at a VAF of ≥2%. Mutation persistence was most frequent in DNMT3A (65% of patients with mutations at diagnosis), SRSF2 (64%), TET2 (55%), and ASXL1 (46%), and significantly associated with older age (p < 0.0001) and, in multivariate analyses adjusting for age, genetic risk, and allogeneic transplantation, with inferior relapse-free survival (hazard ratio (HR), 2.34; p = 0.0039) and overall survival (HR, 2.14; p = 0.036). Patients with persisting mutations had a higher cumulative incidence of relapse before, but not after allogeneic stem cell transplantation. Our work underlines the relevance of mutation persistence during first remission as a novel risk factor in AML. Persistence of pre-leukemic clones may contribute to the inferior outcome of elderly AML patients. Allogeneic transplantation abrogated the increased relapse risk associated with persisting pre-leukemic clones, suggesting that mutation persistence may guide post-remission treatment.

Lasho TL, Mudireddy M, Finke CM, et al.
Targeted next-generation sequencing in blast phase myeloproliferative neoplasms.
Blood Adv. 2018; 2(4):370-380 [PubMed] Free Access to Full Article Related Publications
Among 248 consecutive patients with blast phase myeloproliferative neoplasm (MPN-BP), DNA collected at the time of blast transformation was available in 75 patients (median age, 66 years; 64% men). MPN-BP followed primary myelofibrosis in 39 patients, essential thrombocythemia in 20 patients, and polycythemia vera in 16 patients. A myeloid neoplasm-relevant 33-gene panel was used for next-generation sequencing. Driver mutation distribution was

Seiler M, Yoshimi A, Darman R, et al.
H3B-8800, an orally available small-molecule splicing modulator, induces lethality in spliceosome-mutant cancers.
Nat Med. 2018; 24(4):497-504 [PubMed] Related Publications
Genomic analyses of cancer have identified recurrent point mutations in the RNA splicing factor-encoding genes SF3B1, U2AF1, and SRSF2 that confer an alteration of function. Cancer cells bearing these mutations are preferentially dependent on wild-type (WT) spliceosome function, but clinically relevant means to therapeutically target the spliceosome do not currently exist. Here we describe an orally available modulator of the SF3b complex, H3B-8800, which potently and preferentially kills spliceosome-mutant epithelial and hematologic tumor cells. These killing effects of H3B-8800 are due to its direct interaction with the SF3b complex, as evidenced by loss of H3B-8800 activity in drug-resistant cells bearing mutations in genes encoding SF3b components. Although H3B-8800 modulates WT and mutant spliceosome activity, the preferential killing of spliceosome-mutant cells is due to retention of short, GC-rich introns, which are enriched for genes encoding spliceosome components. These data demonstrate the therapeutic potential of splicing modulation in spliceosome-mutant cancers.

Naumann N, Jawhar M, Schwaab J, et al.
Incidence and prognostic impact of cytogenetic aberrations in patients with systemic mastocytosis.
Genes Chromosomes Cancer. 2018; 57(5):252-259 [PubMed] Related Publications
The clinical behavior of systemic mastocytosis (SM) is strongly associated with activating mutations in KIT (D816V in >80% of cases), with the severity of the phenotype influenced by additional somatic mutations, for example, in SRSF2, ASXL1, or RUNX1. Complex molecular profiles are frequently associated with the presence of an associated hematologic neoplasm (AHN) and an unfavorable clinical outcome. However, little is known about the incidence and prognostic impact of cytogenetic aberrations. We analyzed cytogenetic and molecular characteristics of 109 patients (KIT D816V+, n = 102, 94%) with indolent (ISM, n = 26) and advanced SM (n = 83) with (n = 73, 88%) or without AHN. An aberrant karyotype was identified in SM-AHN (16/73, 22%) patients only. In patients with an aberrant karyotype, additional somatic mutations were identified in 12/16 (75%) patients. Seven of 10 (70%) patients with a poor-risk karyotype, for example, monosomy 7 or complex karyotype, and 1/6 (17%) patients with a good-risk karyotype progressed to secondary acute myeloid leukemia (n = 7) or mast cell leukemia (n = 1) within a median of 40 months (range 2-190, P = .04). In advanced SM, the median overall survival (OS) of poor-risk karyotype patients was significantly shorter than in good-risk/normal karyotype patients (4 vs 39 months; hazard ratio 11.7, 95% CI 5.0-27.3; P < .0001). Additionally, the shortened OS in patients with poor-risk karyotype was independent from the mutation status. In summary, a poor-risk karyotype is an independent prognostic variable in advanced SM. Cytogenetic and molecular analyses should be routinely performed in all patients with advanced SM ± AHN because these investigations greatly support prognostication and treatment decisions.

Han X, Li W, He N, et al.
Gene mutation patterns of Chinese acute myeloid leukemia patients by targeted next-generation sequencing and bioinformatic analysis.
Clin Chim Acta. 2018; 479:25-37 [PubMed] Related Publications
PURPOSES: The conventional risk stratification of acute myeloid leukemia (AML), based on cytogenetics, cannot meet the demand for accurate prognostic evaluations. In recent years, gene mutations are found to be potential markers for more accurate risk stratification, but reports on mutation screening of Chinese AML are limited. We aim to display the mutation patterns of Chinese AML patients, reveal the genotype-phenotype correlations and make a comparison with Caucasians patients.
METHODS: Genome DNA from 78 patients' bone marrow were extracted for targeted gene mutation panel by next-generation sequencing (NGS) technology. Statistics and bioinformatics were used to analyze the correlations between gene mutations and clinical features, as well as the comparison of our results with the Cancer Genome Atlas Research Network (TCGA) public AML dataset.
RESULTS: We found patients with mutations of FLT3 and TET2 had higher bone marrow blasts, peripheral blasts and white blood cell (WBC) count, mutations of SRSF2 were related with age, and mutations of FLT3-ITD, DNMT3A, IDH1, TET2 and SRSF2 were risk factors for overall survival. What's more, we discovered 15 novel mutations and difference of mutational incidence in 6 genes between Chinese and Caucasians AML. Bioinformatic analysis revealed some relationship between gene mutations and expressions as well as drug sensitivities.
CONCLUSIONS: We made an investigation on the mutation patterns of Chinese AML patients by NGS technique and revealed correlations between gene mutations and clinical features. Thus we recommend routine testing of suspected genes for better prognostic prediction and individualized treatment.

Wang P, Guo L, Li K, et al.
Serine/arginine rich splicing factor 2 expression and clinic pathological features indicating a prognostic factor in human hepatocellular carcinoma patients.
Cancer Biomark. 2018; 21(3):681-687 [PubMed] Related Publications
BACKGROUND: This research was aimed to study the expression of Serine/arginine rich splicing factor 2 (SRSF2) in tissues of hepatocellular carcinoma, and explore the relationship between the expression and the clinic pathological and prognosis of human hepatocellular carcinoma (HCC).
METHODS: One hundred and fifty-three pairs HCC tissues and adjacent normal tissue were collected from January 2010 to March 2013. The expression of SRSF2 gene was detected by immunohistochemistry, western blotting and real-time quantitative polymerase chain reaction (PCR), and the relationship between the expression and the clinic pathological and prognosis of HCC being analyzed.
RESULTS: In 153 cases of hepatocellular carcinoma, SRSF2 was highly expressed in 93 cases, low expression of 60 cases, immunohistochemistry score (6.50 ± 2.82), which was significantly higher than that in adjacent normal tissues (2.94 ± 1.23) (P< 0.05). The expression of SRSF2 in HCC was not associated with gender (χ2= 0.014, P= 0.906), age (χ2= 0.007, P= 0.931), tumor size (χ2= 3.566, P= 0.059) and T stage (χ2= 2.708, P= 0.100), and was significantly correlated with tumor differentiation (χ2= 9.687, P= 0.007), lymph node metastasis (χ2= 4.827, P= 0.028), distal metastasis (χ2= 9.235, P= 0.002), tumor, node, metastasis (TNM) stage (χ2= 3.978, P= 0.046), portal vein invasion and serum alpha-fetoprotein (χ2= 14.919, P= 0.000). The expression of SRSF2 protein in hepatocellular carcinoma was positively correlated (r = 0.704, P< 0.05) with serum alpha-fetoprotein through Pearson analysis. The survival rates of SRSF2 overexpressing hepatocellular carcinoma were 74.19%, 44.09%, 26.88%, 24.73% and 21.51% at 1 year, 2 years, 3 years, 4 years and 5 years respectively, which were lower than those of SRSF2 low expression group (93.33%, 71.67%, 56.67%, 51.67% and 50.00%).
CONCLUSION: SRSF2 is highly expressed in hepatocellular carcinoma and its expression increases with the degree of tumor differentiation and TNM staging. It is related to lymph node metastasis and metastasis of tumor cells, and is positively related to serum alpha fetoprotein content, and affects the postoperative survival time of HCC patients.

Schuler E, Frank F, Hildebrandt B, et al.
Myelodysplastic syndromes without peripheral monocytosis but with evidence of marrow monocytosis share clinical and molecular characteristics with CMML.
Leuk Res. 2018; 65:1-4 [PubMed] Related Publications
MDS patients may present with monocytic marrow proliferation not fulfilling criteria for CMML. We analyzed MDS patients with or without a marrow monocytic proliferation by following up the amount of monocytic proliferation and characterizing their molecular profile. 315 MDS patients of Duesseldorf MDS registry were divided into two groups: A) 183 patients with monocytic esterase positive cells in marrow and monocytes between 101 and 900/μl in blood and B) 132 patients without monocytic esterase positive cells in marrow and monocytes in blood ≤100/μl. Twenty patients of each group were screened with regard to ASXL1, TET2, RUNX1, SETBP1, NRAS, and SRSF2 using Illumina myeloid panel. Group A patients were older, had significantly higher WBC, hemoglobin levels, neutrophils and platelets. CMML evolution rates were 4.9% and 1.5%, respectively (p=n.s.). TET2, NRAS and SRFS2 mutation frequencies were higher in group A and four patients had coexisting TET2 and SRFS2 mutation, which was shown to be characteristic but not specific for CMML. MDS patients with marrow monocytic proliferation have a more CMML-like pheno- and genotype and develop CMML more often. Those patients could potentially be very early stages of CMML or represent a CMML-like myeloid neoplasma with marrow adherence of the monocytic cell population.

Senín A, Fernández-Rodríguez C, Bellosillo B, et al.
Non-driver mutations in patients with JAK2V617F-mutated polycythemia vera or essential thrombocythemia with long-term molecular follow-up.
Ann Hematol. 2018; 97(3):443-451 [PubMed] Related Publications
JAK2V617F monitoring and NGS of non-driver genes was performed in 100 patients with polycythemia vera (PV) or essential thrombocythemia (ET) with long molecular follow-up. Patients who did not progress to myelofibrosis (MF) or acute myeloid leukemia (AML) after more than 10 years (n = 50) showed a low frequency of mutations at first sample (18%) and an incidence rate of 1.7 new mutations × 100 person-years. Mutations were detected at first sample in 83% of PV/ET patients who later progressed to AML (n = 12) with these patients having a rate of 25.6 mutations × 100 person-years. Presence of mutations at diagnosis was the unique risk factor for acquiring a new genetic event (HR 2.7, 95% CI 1.1-6.8, p = 0.03) after correction for age, PV diagnosis, and total duration of hydroxyurea (HU) exposure. Patients with additional mutation at first sample showed a higher probability of developing cytopenia under HU therapy and a higher risk of AML (HR 12.2, 95% CI 2.6-57.1, p = 0.001) with mutations in ASXL1 (p < 0.0001), TP53 (p = 0.01), SRSF2 (p < 0.0001), IDH1/2 (p < 0.0001), and RUNX1 (p < 0.0001) being associated with a higher probability of AML. Myelofibrotic transformation was more frequent in patients with additional mutations, especially in SF3B1 (p = 0.02) and IDH1/2 (p < 0.0001) although a persistently high or a progressive increase of the JAK2V617F allele burden while receiving cytoreduction was the strongest predictor of MF transformation (HR 10.8, 95% CI 2.4-49.1, p = 0.002). In conclusion, NGS may be useful to identify a minority of PV and ET patients with high genetic instability and increased risk of AML transformation.

Venton G, Courtier F, Charbonnier A, et al.
Impact of gene mutations on treatment response and prognosis of acute myeloid leukemia secondary to myeloproliferative neoplasms.
Am J Hematol. 2018; 93(3):330-338 [PubMed] Related Publications
Acute myeloid leukemias secondary (sAML) to myeloproliferative neoplasms (MPN) have variable clinical courses and outcomes, but remain almost always fatal. Large cohorts of sAML to MPN are difficult to obtain and there is very little scientific literature or prospective trials for determining robust prognostic markers and efficient treatments. We analyzed event-free survival (EFS) and overall survival (OS) of 73 patients with MPN who progressed to sAML, based on their epidemiological characteristics, the preexisting MPN, the different treatments received, the different prognostic groups and the responses achieved according to the ELN, and their mutational status determined by next-generation DNA sequencing (NGS). For 24 patients, we were able to do a comparative NGS analysis at both MPN and sAML phase. After acute transformation EFS and OS were respectively of 2.9 months (range: 0-48.1) and 4.7 months (range: 0.1-58.8). No difference in EFS or OS regarding the previous MPN, the ELN2017 prognostic classification, the first-line therapy or the response was found. After univariate analysis, three genes, TP53, SRSF2 and TET2, impacted pejoratively sAML prognosis at sAML time. In multivariate analysis, TP53 (P = .0001), TET2 (P = .011) and SRSF2 (P = .018) remained independent prognostic factors. Time to sAML transformation was shorter in SRSF2-mutated patients (51.2 months, range: 14.7-98) than in SRSF2-unmutated patients (133.8 months, range: 12.6-411.2) (P < .001). Conventional clinical factors (age, karyotype, ELN2017 prognostic classification, treatments received, treatments response, Allo-SCT…) failed to predict the patients' outcome. Only the mutational status appeared relevant to predict patients' prognosis at sAML phase.

Tefferi A, Lasho TL, Patnaik MM, et al.
Targeted next-generation sequencing in myelodysplastic syndromes and prognostic interaction between mutations and IPSS-R.
Am J Hematol. 2017; 92(12):1311-1317 [PubMed] Related Publications
A 27-gene panel was used for next-generation sequencing (NGS) in 179 patients (median age 73 years) with primary myelodysplastic syndromes (MDS); risk distribution according to the revised International Prognostic Scoring System (IPSS-R) was 11% very high, 18% high, 17% intermediate, 38% low and 16% very low. At least one mutation/variant was detected in 147 (82%) patients; 23% harbored three or more mutations/variants. The most frequent mutations/variants included ASXL1 (30%), TET2 (25%), SF3B1 (20%), U2AF1 (16%), SRSF2 (16%), TP53 (13%), RUNX1 (11%), and DNMT3A (10%). At a median follow up of 30 months, 148 (83%) deaths and 26 (15%) leukemic transformations were recorded. Multivariable analysis of mutations/variants identified ASXL1 (HR 1.7, 95% CI 1.2-2.5), SETBP1 (HR 4.1, 95% CI 1.6-10.2) and TP53 (HR 2.2, 95% CI 1.3-3.4) as risk factors for overall and SRSF2 (HR 3.9, 95% CI 1.5-10.2), IDH2 (HR 3.7, 95% CI 1.2-11.4), and CSF3R (HR 6.0, 95% CI 1.6-22.6) for leukemia-free survival. Addition of age to the multivariable model did not affect these results while accounting for IPSS-R weakened the significance of TP53 mutations/variants (P = .1). An apparently favorable survival impact of SF3B1 mutations was no longer evident after adjustment for IPSS-R. Approximately 41% and 20% of patients harbored at least one adverse mutation/variant for overall and leukemia-free survival, respectively. Number of mutations/variants did not provide additional prognostic value. The survival impact of adverse mutations was most evident in IPSS-R very low/low risk patients. These observations suggest that targeted NGS might assist in treatment decision-making in lower risk MDS.

Robertson AG, Shih J, Yau C, et al.
Integrative Analysis Identifies Four Molecular and Clinical Subsets in Uveal Melanoma.
Cancer Cell. 2017; 32(2):204-220.e15 [PubMed] Free Access to Full Article Related Publications
Comprehensive multiplatform analysis of 80 uveal melanomas (UM) identifies four molecularly distinct, clinically relevant subtypes: two associated with poor-prognosis monosomy 3 (M3) and two with better-prognosis disomy 3 (D3). We show that BAP1 loss follows M3 occurrence and correlates with a global DNA methylation state that is distinct from D3-UM. Poor-prognosis M3-UM divide into subsets with divergent genomic aberrations, transcriptional features, and clinical outcomes. We report change-of-function SRSF2 mutations. Within D3-UM, EIF1AX- and SRSF2/SF3B1-mutant tumors have distinct somatic copy number alterations and DNA methylation profiles, providing insight into the biology of these low- versus intermediate-risk clinical mutation subtypes.

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