Gene Summary

Gene:U2AF1; U2 small nuclear RNA auxiliary factor 1
Aliases: RN, FP793, U2AF35, U2AFBP, RNU2AF1
Summary:This gene belongs to the splicing factor SR family of genes. U2 auxiliary factor, comprising a large and a small subunit, is a non-snRNP protein required for the binding of U2 snRNP to the pre-mRNA branch site. This gene encodes the small subunit which plays a critical role in both constitutive and enhancer-dependent RNA splicing by directly mediating interactions between the large subunit and proteins bound to the enhancers. Alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Jul 2008]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:splicing factor U2AF 35 kDa subunit
Source:NCBIAccessed: 29 August, 2019


What does this gene/protein do?
Show (20)
Pathways:What pathways are this gene/protein implicaed in?
Show (1)

Cancer Overview

Research Indicators

Publications Per Year (1994-2019)
Graph generated 29 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.

  • DNA Sequence Analysis
  • DNA Mutational Analysis
  • Chronic Myelogenous Leukemia
  • Alternative Splicing
  • Repressor Proteins
  • RNA Splicing
  • Chronic Myelomonocytic Leukemia
  • Mutation Rate
  • Disease-Free Survival
  • Transcription
  • Single Nucleotide Polymorphism
  • Ribonucleoproteins
  • DNA-Binding Proteins
  • Follow-Up Studies
  • Genetic Association Studies
  • DNA Methylation
  • Neoplastic Cell Transformation
  • Acute Myeloid Leukaemia
  • Leukemic Gene Expression Regulation
  • Serine-Arginine Splicing Factors
  • Spliceosomes
  • Haematological Malignancies
  • Cohort Studies
  • U2AF1
  • Disease Progression
  • Chromosome 21
  • Cancer Gene Expression Regulation
  • Signal Transduction
  • Ribonucleoprotein, U2 Small Nuclear
  • Phosphoproteins
  • Epigenetics
  • RNA Splicing Factors
  • High-Throughput Nucleotide Sequencing
  • Base Sequence
  • Myelodysplastic Syndromes
  • Mutation
  • Adolescents
  • Nuclear Proteins
  • Childhood Cancer
  • Lung Cancer
  • Young Adult
  • Messenger RNA
Tag cloud generated 29 August, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (6)

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: U2AF1 (cancer-related)

Rudnicka K, Backert S, Chmiela M
Genetic Polymorphisms in Inflammatory and Other Regulators in Gastric Cancer: Risks and Clinical Consequences.
Curr Top Microbiol Immunol. 2019; 421:53-76 [PubMed] Related Publications
Helicobacter pylori infection is associated with the development of a chronic inflammatory response, which may induce peptic ulcers, gastric cancer (GC), and mucosa-associated lymphoid tissue (MALT) lymphoma. Chronic H. pylori infection promotes the genetic instability of gastric epithelial cells and interferes with the DNA repair systems in host cells. Colonization of the stomach with H. pylori is an important cause of non-cardia GC and gastric MALT lymphoma. The reduction of GC development in patients who underwent anti-H. pylori eradication schemes has also been well described. Individual susceptibility to GC development depends on the host's genetic predisposition, H. pylori virulence factors, environmental conditions, and geographical determinants. Biological determinants are urgently sought to predict the clinical course of infection in individuals with confirmed H. pylori infection. Possible candidates for such biomarkers include genetic aberrations such as single-nucleotide polymorphisms (SNPs) found in various cytokines/growth factors (e.g., IL-1β, IL-2, IL-6, IL-8, IL-10, IL-13, IL-17A/B, IFN-γ, TNF, TGF-β) and their receptors (IL-RN, TGFR), innate immunity receptors (TLR2, TLR4, CD14, NOD1, NOD2), enzymes involved in signal transduction cascades (PLCE1, PKLR, PRKAA1) as well as glycoproteins (MUC1, PSCA), and DNA repair enzymes (ERCC2, XRCC1, XRCC3). Bacterial determinants related to GC development include infection with CagA-positive (particularly with a high number of EPIYA-C phosphorylation motifs) and VacA-positive isolates (in particular s1/m1 allele strains). The combined genotyping of bacterial and host determinants suggests that the accumulation of polymorphisms favoring host and bacterial features increases the risk for precancerous and cancerous lesions in patients.

Bundgaard-Nielsen C, Baandrup UT, Nielsen LP, Sørensen S
The presence of bacteria varies between colorectal adenocarcinomas, precursor lesions and non-malignant tissue.
BMC Cancer. 2019; 19(1):399 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: A causal association has been suggested between certain bacteria and colorectal cancer (CRC). Only a few studies have, however, investigated the presence of these bacteria directly in colon tissue with conflicting results. It is thus uncertain which role they may have in prognosis and carcinogenesis of CRC.
METHODS: Formalin-fixed and paraffin-embedded (FFPE) colorectal tissue samples from patients diagnosed with colorectal cancer (CRC)(tumor and paired normal tissue, n = 99), adenomas (n = 96), or diverticular disease (n = 104) were tested for the presence and bacterial load of Streptococcus gallolyticus (S. gallolyticus), Fusobacterium nucleatum (F. nucleatum), and Bacteroides fragilis (B. fragilis) using quantitative PCR. A subsequent broader search was conducted on a subset of samples using 16S ribosomal RNA gene sequencing. Finally, to evaluate the prognostic value, the bacterial status was compared to patient outcome.
RESULTS: S. gallolyticus was not detected by qPCR in any of the investigated tissue samples and F. nucleatum and B. fragilis were found to be equally distributed in tumors, paired normal tissue, and diverticula, but significantly less present in adenomas compared to both tumors and diverticula. Neither, F. nucleatum nor B. fragilis status affected the five-year prognosis of the patients. The 16S rRNA gene sequencing data revealed that tumors were associated with the Prevotella genus while conversely adenomas and diverticula were associated with Acinetobacter genus.
CONCLUSION: These findings do not support a role of F. nucleatum or B. fragilis during colorectal beginning, while S. gallolyticus was not implicated in the colorectal tissue of a Danish population. A potential role of the bacterial genera Prevotella and Acinetobacter was indicated, and requires further investigations.

Smith MA, Choudhary GS, Pellagatti A, et al.
U2AF1 mutations induce oncogenic IRAK4 isoforms and activate innate immune pathways in myeloid malignancies.
Nat Cell Biol. 2019; 21(5):640-650 [PubMed] Free Access to Full Article Related Publications
Spliceosome mutations are common in myelodysplastic syndromes (MDS) and acute myeloid leukaemia (AML), but the oncogenic changes due to these mutations have not been identified. Here a global analysis of exon usage in AML samples revealed distinct molecular subsets containing alternative spliced isoforms of inflammatory and immune genes. Interleukin-1 receptor-associated kinase 4 (IRAK4) was the dominant alternatively spliced isoform in MDS and AML and is characterized by a longer isoform that retains exon 4, which encodes IRAK4-long (IRAK4-L), a protein that assembles with the myddosome, results in maximal activation of nuclear factor kappa-light-chain-enhancer of B cells (NF-κB) and is essential for leukaemic cell function. Expression of IRAK4-L is mediated by mutant U2 small nuclear RNA auxiliary factor 1 (U2AF1) and is associated with oncogenic signalling in MDS and AML. Inhibition of IRAK4-L abrogates leukaemic growth, particularly in AML cells with higher expression of the IRAK4-L isoform. Collectively, mutations in U2AF1 induce expression of therapeutically targetable 'active' IRAK4 isoforms and provide a genetic link to activation of chronic innate immune signalling in MDS and AML.

Palangat M, Anastasakis DG, Fei DL, et al.
The splicing factor U2AF1 contributes to cancer progression through a noncanonical role in translation regulation.
Genes Dev. 2019; 33(9-10):482-497 [PubMed] Article available free on PMC after 01/11/2019 Related Publications
Somatic mutations in the genes encoding components of the spliceosome occur frequently in human neoplasms, including myeloid dysplasias and leukemias, and less often in solid tumors. One of the affected factors, U2AF1, is involved in splice site selection, and the most common change, S34F, alters a conserved nucleic acid-binding domain, recognition of the 3' splice site, and alternative splicing of many mRNAs. However, the role that this mutation plays in oncogenesis is still unknown. Here, we uncovered a noncanonical function of U2AF1, showing that it directly binds mature mRNA in the cytoplasm and negatively regulates mRNA translation. This splicing-independent role of U2AF1 is altered by the S34F mutation, and polysome profiling indicates that the mutation affects translation of hundreds of mRNA. One functional consequence is increased synthesis of the secreted chemokine interleukin 8, which contributes to metastasis, inflammation, and cancer progression in mice and humans.

Pedersen IS, Thomassen M, Tan Q, et al.
Differential effect of surgical manipulation on gene expression in normal breast tissue and breast tumor tissue.
Mol Med. 2018; 24(1):57 [PubMed] Article available free on PMC after 01/11/2019 Related Publications
BACKGROUND: Gene expression profiles of normal and tumor tissue reflect both differences in biological processes taking place in vivo and differences in response to stress during surgery and sample handling. The effect of cold (room temperature) ischemia in the time interval between surgical removal of the specimen and freezing is described in a few studies. However, not much is known about the effect of warm (body temperature) ischemia during surgery.
METHODS: Three women with primary operable breast cancer underwent in situ biopsies from normal breast and tumor tissue prior to radical mastectomy. Ex vivo biopsies from normal and tumor tissue were collected immediately after surgical excision. The putative effects on gene expression of malignancy (tumor versus normal), surgical manipulation (post- versus pre-surgical) and interaction between the two (differences in effect of surgical manipulation on tumor and normal samples) were investigated simultaneously by Generalized Estimating Equation (GEE) analysis in this self-matched study.
RESULTS: Gene set enrichment analysis (GSEA) demonstrates a marked difference in effect of surgical manipulation on tumor compared to normal tissue. Interestingly, a large proportion of pathways affected by ischemia especially in tumor tissue are pathways considered to be specifically up regulated in tumor tissue compared to normal.
CONCLUSION: The results of this study suggest that a large contribution to this differential expression originates from altered response to stress in tumor cells rather than merely representing in vivo differences. It is important to bear this in mind when using gene-expression analysis to deduce biological function, and when collecting material for gene expression profiling.

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.

Fei DL, Zhen T, Durham B, et al.
Impaired hematopoiesis and leukemia development in mice with a conditional knock-in allele of a mutant splicing factor gene
Proc Natl Acad Sci U S A. 2018; 115(44):E10437-E10446 [PubMed] Article available free on PMC after 01/11/2019 Related Publications
Mutations affecting the spliceosomal protein U2AF1 are commonly found in myelodysplastic syndromes (MDS) and secondary acute myeloid leukemia (sAML). We have generated mice that carry Cre-dependent knock-in alleles of

de Souza Timoteo AR, Gonçalves AÉMM, Sales LAP, et al.
A portrait of germline mutation in Brazilian at-risk for hereditary breast cancer.
Breast Cancer Res Treat. 2018; 172(3):637-646 [PubMed] Related Publications
PURPOSE: Knowledge about the germline mutational spectrum among Brazilian with hereditary breast and ovarian cancer (HBOC) is limited. Only five studies have performed comprehensive BRCA sequencing, corresponding to 1041 individuals among a Brazilian population of over 207 million people. Herein we aimed to determine the clinical and molecular characteristics of Brazilian patients who underwent oncogenetic counseling and genetic testing of a panel of high-risk and moderate-risk genes from 2009 to 2017.
METHODS: Massively parallel sequencing was applied in 157 individuals (132 breast cancer-affected and 25 breast cancer-unaffected individuals) selected according NCCN criteria for hereditary breast cancer. Analysis of mutation segregation in family members was performed by capillary bidirectional sequencing, clinical response after treament and survival analysis was estimated by Kaplan-Meier.
RESULTS: Nineteen germline variants were identified,15 pathogenic and 4 VUS (Variants of Uncertain Significance) in 27 individuals (27/157; 17% P < 0.0001) distributed among 7 genes. Sixty-eight percent of patients (13/19) harbor mutation in BRCA genes and 32% (6/19) in moderate risk genes. This is the first study reporting ATR deleterious germline mutation in association with hereditary breast cancer. Cancer-affected patients with moderate- risk mutation present a more aggressive phenotype, with bilateral cancer (25% vs. 13%, P = 0.0305), high-grade tumors (79.2% vs. 46.3%, P = 0.0001) and triple-negative (50% vs. 22.4%, P < 0.0001). However, no difference in the 5 years overall survival was observed between BRCA and moderate risk groups.
CONCLUSIONS: This work highlights the benefits of large-scale sequencing for oncogenetic counseling and extends our understanding about the genetics of hereditary breast cancer in the multi-ethnic Brazilian population.

Liao H, Zhu Z, Rong X, et al.
Hyponatremia is a potential predictor of progression in radiation-induced brain necrosis: a retrospective study.
BMC Neurol. 2018; 18(1):130 [PubMed] Article available free on PMC after 01/11/2019 Related Publications
BACKGROUND: To investigate the prognostic value of hyponatremia, defined as serum sodium level < 135 mEq/L, in radiation-induced brain necrosis (RN) patients.
METHODS: We performed a retrospective analysis of the RN patients (The patients included in our study had a history of primary cancers including nasopharyngeal carcinoma/glioma/oral cancer and received radiotherapy previously and then were diagnosed with RN) treated in Sun yat-sen Memorial Hospital from January 2013 to August 2015. Patients without cranial magnetic resonance imaging (MRI) scan and serum sodium data were excluded. Progression was identified when the increase of edema area ≥ 25% on the MRI taken in six months comparing with those taken at the baseline. Factors that might associate with prognosis of RN were collected. Multivariable logistic regression analyses were used to identify potential predictors.
RESULTS: We total included 135 patients, 32 (23.7%) of them with hyponatremia and 36 (26.7%) with RN progression. Percentage of progression was roughly three fold in hyponatremia patients compared with nonhyponatremia patients (53.1% versus 18.4%), translating into a 5-fold increased odds ratio (P <  0.001). Multivariable analyses identified hyponatremia as a potential predictor of progression (OR, 4.82; 95% CI [1.94-11.94]; P = 0.001).
CONCLUSIONS: Hyponatremia was identified as a potential predictor for the progression of patients with RN. Hyponatremia management in patients with RN should be paid much more concern in clinical practice.

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] Article available free on PMC after 01/11/2019 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.

Kim S, Park C, Jun Y, et al.
Integrative Profiling of Alternative Splicing Induced by
Mol Cells. 2018; 41(8):733-741 [PubMed] Article available free on PMC after 01/11/2019 Related Publications
Mutations in spliceosome components have been implicated in carcinogenesis of various types of cancer. One of the most frequently found is

de Sena LSB, da Silveira ÉJD, Batista AC, et al.
Immunoexpression of glucocorticoid receptor alpha (GRα) isoform and apoptotic proteins (Bcl-2 and Bax) in actinic cheilitis and lower lip squamous cell carcinoma.
J Oral Pathol Med. 2018; 47(8):788-795 [PubMed] Related Publications
BACKGROUND: Actinic cheilitis (AC) is a potentially malignant disorder that can progress to squamous cell carcinoma (SCC), but this process is not fully understood. This study evaluated the immunoexpression of glucocorticoid receptor alpha (GRα) isoform and apoptotic proteins (Bcl-2 and Bax) in AC and lower lip SCC (LLSCC).
METHODS: Twenty-two AC and 44 LLSCCs (22 with regional nodal metastasis and 22 without metastasis) were selected. The percentages of nuclear (GRα) and cytoplasmic (GRα, Bcl-2, and Bax) staining in epithelial cells were assessed and correlated with clinical (tumor size/extent and clinical stage) and histopathological parameters (risk of malignant transformation for AC and histopathological grade of malignancy for LLSCCs).
RESULTS: Expression of GRα was observed in all cases studied, with relatively high median percentages of positive staining. When compared to AC, LLSCCs exhibited lower nuclear expression and higher cytoplasmic expression of GRα (P < 0.05). Regarding clinicopathological parameters, significant differences were only found for cytoplasmic expression of GRα according to the histopathological grade of LLSCCs (P = 0.036). Higher expression of Bax compared to Bcl-2 was observed in AC and LLSCCs (P < 0.05). In LLSCCs, there was a positive correlation between nuclear and cytoplasmic expressions of GRα (P = 0.006).
CONCLUSION: Reduced nuclear translocation and increased cytoplasmic expression of GRα may be important events in lip carcinogenesis but are not involved in the progression of LLSCC. The role of GRα in lip cancer development does not seem to be primarily related to modulations in the expression of Bcl-2 or Bax.

Xu Y, Rong X, Hu W, et al.
Bevacizumab Monotherapy Reduces Radiation-induced Brain Necrosis in Nasopharyngeal Carcinoma Patients: A Randomized Controlled Trial.
Int J Radiat Oncol Biol Phys. 2018; 101(5):1087-1095 [PubMed] Related Publications
PURPOSE: Studies have shown that addition of bevacizumab to corticosteroids improves outcome against radiation-induced brain necrosis (RN). Here, we aimed to evaluate the effectiveness and safety of bevacizumab monotherapy on RN in nasopharyngeal carcinoma (NPC) patients.
METHODS AND MATERIALS: In this multicenter open-label study, patients with RN were randomly assigned (1:1) into a bevacizumab group (5 mg/kg intravenously every 2 weeks, for 4 cycles) or a corticosteroid group (methylprednisolone 500 mg/day intravenously for 3 consecutive days and then gradually tapered, followed by 10 mg/day oral prednisone, for 2 months in total). Magnetic resonance imaging (MRI) was performed pre- and post-treatment to define the radiographic response. The primary outcome was a 2-month response rate as determined by MRI and clinical symptoms. All of the patients were followed up with for 6 months. The trial was registered at www.clinicaltrials.gov (NCT01621880).
RESULTS: Of 121 patients screened, 112 patients met the entry criteria. Thirty-eight (65.5%) patients in the bevacizumab group showed response, which was significantly higher than that in the corticosteroid group (65.5% vs 31.5%, P < .001). The mean percentage decrease in RN volume seen on T1 post-gadolinium and T2-weighted fluid-attenuated inversion recovery (FLAIR) MRI was 25.5% and 51.8%, respectively, in the bevacizumab group, versus 5.0% and 19.3%, respectively, in the corticosteroid group. Moreover, 36 patients (62.1%) on bevacizumab and 23 patients (42.6%) on corticosteroids demonstrated clinical improvement (P = .039). During the 6-month follow up, fourteen patients on bevacizumab and 13 patients on corticosteroids showed RN recurrence. The most frequent adverse event in the bevacizumab group was hypertension (20.6%).
CONCLUSIONS: Our study indicate that compared with corticosteroids, bevacizumab offers improved symptomatic relief and radiographic response.

Peterle GT, Maia LL, Trivilin LO, et al.
PAI-1, CAIX, and VEGFA expressions as prognosis markers in oral squamous cell carcinoma.
J Oral Pathol Med. 2018; 47(6):566-574 [PubMed] Related Publications
BACKGROUND: In oral squamous cell carcinoma (OSCC), the HIF-1 complex promotes the expression of genes involved in specific mechanisms of cell survival under hypoxic conditions, such as plasminogen activator inhibitor-1 (PAI-1), carbonic anhydrase 9 (CAIX), and vascular endothelial growth factor A (VEGFA). The study aimed to investigate the presence and prognostic value of PAI-1, CAIX, and VEGFA in OSCC.
MATERIALS AND METHODS: Immunohistochemistry was used to analyze the expressions of these proteins in 52 tumoral tissue samples of patients with OSCC, surgically treated and followed by a minimum of 24 months after surgery. The correlations between protein expressions and clinicopathological parameters and prognosis were analyzed.
RESULTS: Positive PAI-1 membrane expression was significantly associated with local disease relapse (P = .027). Multivariate analysis revealed that the positive PAI-1 membrane expression is an independent marker for local disease relapse, with approximately 14-fold increased risk when compared to negative expression (OR = 14.49; CI = 1.40-150.01, P = .025). Strong PAI-1 cytoplasmic expression was significantly associated with the less differentiation grade (P = .027). Strong CAIX membrane expression was significantly associated with local disease-free survival (P = .038). Positive CAIX cytoplasmic expression was significantly associated with lymph node affected (P = .025) and with disease-specific survival (P = .022). Multivariate analysis revealed that the positive CAIX cytoplasmic expression is an independent risk factor for disease-related death, increasing their risk approximately 3-fold when compared to negative expression (HR = 2.84; CI = 1.02-7.87, P = .045). Positive VEGFA cytoplasmic expression was significantly associated with less differentiation grade (P = .035).
CONCLUSION: Our results suggest a potential role for these expressions profiles as tumor prognostic markers in OSCC patients.

Avanzato D, Pupo E, Ducano N, et al.
High USP6NL Levels in Breast Cancer Sustain Chronic AKT Phosphorylation and GLUT1 Stability Fueling Aerobic Glycolysis.
Cancer Res. 2018; 78(13):3432-3444 [PubMed] Related Publications
USP6NL, also named RN-tre, is a GTPase-activating protein involved in control of endocytosis and signal transduction. Here we report that USP6NL is overexpressed in breast cancer, mainly of the basal-like/integrative cluster 10 subtype. Increased USP6NL levels were accompanied by gene amplification and were associated with worse prognosis in the METABRIC dataset, retaining prognostic value in multivariable analysis. High levels of USP6NL in breast cancer cells delayed endocytosis and degradation of the EGFR, causing chronic AKT (protein kinase B) activation. In turn, AKT stabilized the glucose transporter GLUT1 at the plasma membrane, increasing aerobic glycolysis. In agreement, elevated USP6NL sensitized breast cancer cells to glucose deprivation, indicating that their glycolytic capacity relies on this protein. Depletion of USP6NL accelerated EGFR/AKT downregulation and GLUT1 degradation, impairing cell proliferation exclusively in breast cancer cells that harbored increased levels of USP6NL. Overall, these findings argue that USP6NL overexpression generates a metabolic rewiring that is essential to foster the glycolytic demand of breast cancer cells and promote their proliferation.

Cavalcante RB, Nonaka CFW, Santos HBP, et al.
Assessment of CTNNB1 gene mutations and β-catenin immunoexpression in salivary gland pleomorphic adenomas and adenoid cystic carcinomas.
Virchows Arch. 2018; 472(6):999-1005 [PubMed] Related Publications
β-Catenin exerts multiple functions in several neoplasms, playing a major role in cell signaling and tumor progression. This study analyzed possible CTNNB1 mutations in salivary gland pleomorphic adenomas (PAs) and adenoid cystic carcinomas (ACCs), and determined possible differences in β-catenin immunoexpression in relation to these mutations, as well as histopathological aspects of these tumors. Twenty-four PAs (15 cell-rich and 9 cell-poor tumors) and 24 ACCs (10 tubular, 8 cribriform, and 6 solid tumors) were selected for the analysis of β-catenin distribution and cellular localization. Furthermore, β-catenin expression was evaluated using the H-score scoring system. Mutations in CTNNB1 exon 3 were investigated by the single-strand conformational polymorphism test. Diffuse β-catenin expression was more frequently observed in ACCs compared to PAs (P = 0.008). No significant difference in β-catenin cellular localization was observed between these tumors (P = 0.098). Comparisons between PA and ACC cases revealed a higher median H-score in the latter (P = 0.036). Cell-rich PAs exhibited a trend for higher H-score than cell-poor tumors (P = 0.060), whereas lower H-scores were observed in cribriform ACCs when compared to tubular and solid ACCs (P = 0.042). Mutations in CTNNB1 were observed in 6 PAs and 7 ACCs, with no significant difference in H-scores for β-catenin according to mutation status (P = 0.135). β-Catenin is important in the pathogenesis of salivary gland PAs and ACCs. In addition, CTNNB1 exon 3 mutations do not seem to significantly influence β-catenin cytoplasmic/membranous expression or nuclear translocation in these tumors.

Eisfeld AK, Kohlschmidt J, Mrózek K, et al.
Mutation patterns identify adult patients with de novo acute myeloid leukemia aged 60 years or older who respond favorably to standard chemotherapy: an analysis of Alliance studies.
Leukemia. 2018; 32(6):1338-1348 [PubMed] Article available free on PMC after 01/11/2019 Related Publications
Thus far, only 5-15% of AML patients aged ≥60 years are cured with chemotherapy. Identification of patients who are less (more) likely to respond to standard chemotherapy might enable early risk stratification toward alternative treatment regimens. We used a next-generation sequencing panel of 80 cancer- and/or leukemia-associated genes to profile molecularly 423 older patients with de novo AML. Using variables identified in multivariable models and co-occurring mutations in NPM1-mutated AML, we classified the patients into good-, intermediate-, and poor-risk groups for complete remission (CR) attainment, disease-free (DFS), and overall survival (OS). Whereas 81% of good-risk patients (comprising NPM1-mutated patients harboring mutations in chromatin remodeling, cohesin complex, methylation-related, spliceosome, and/or RAS pathway genes, FLT3-TKD, and/or patients without FLT3-ITD) achieved a CR, only 32% of poor-risk patients (with U2AF1, WT1 mutations and/or complex karyotype) did. Intermediate-risk patients had a 50% CR rate. Similarly, using NPM1 co-mutation patterns and SF1 mutation status, we identified patients with favorable DFS and OS 3-year rates of 46% and 45%, respectively. Patients with adverse genetic features had DFS and OS rates of only 2% and 4%. We show that application of our proposed criteria may refine the 2017 European LeukemiaNet classification for older patients treated with chemotherapy.

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.

Li Y, Huang X, Jiang J, et al.
Clinical Variables for Prediction of the Therapeutic Effects of Bevacizumab Monotherapy in Nasopharyngeal Carcinoma Patients With Radiation-Induced Brain Necrosis.
Int J Radiat Oncol Biol Phys. 2018; 100(3):621-629 [PubMed] Related Publications
PURPOSE: To identify the predictive and prognostic factors for a decrease or recurrence of brain edema in patients who developed radiation-induced brain necrosis (RN) after radiation therapy for nasopharyngeal carcinoma (NPC) and who received bevacizumab monotherapy.
METHODS AND MATERIALS: This was a retrospective study. The charts of 50 patients who were diagnosed with RN after radiation therapy for NPC, treated with bevacizumab, and followed up for 6 months were reviewed. Clinical data of these patients were collected, and their brain edema volume before bevacizumab administration, after bevacizumab administration, at 3-month follow-up, and at 6-month follow-up was evaluated on the basis of brain magnetic resonance imaging findings. The baseline serum vascular endothelial growth factor levels of 15 patients were measured by enzyme-linked immunosorbent assay. A random forests model was developed for statistical analysis.
RESULTS: The median percentage of decrease in RN volume shown on T2-weighted fluid-attenuated inversion recovery images at the end of bevacizumab therapy was 72.6% (interquartile range, 34.5% to 89.5%; P < .001). Twelve of these 50 patients (24.0%) did not have an effective response, and 38 patients (76.0%) showed an effective response after bevacizumab administration. Fifteen of the 38 patients showed RN recurrence. According to the random forests model the maximum radiation dose of the temporal lobe (D
CONCLUSIONS: Prediction models for the therapeutic effect of bevacizumab in RN patients were developed, using the random forests model. Bevacizumab might be more effective in patients with a lower maximum radiation dose to the temporal lobe.

Kostas M, Haugsten EM, Zhen Y, et al.
Protein Tyrosine Phosphatase Receptor Type G (PTPRG) Controls Fibroblast Growth Factor Receptor (FGFR) 1 Activity and Influences Sensitivity to FGFR Kinase Inhibitors.
Mol Cell Proteomics. 2018; 17(5):850-870 [PubMed] Article available free on PMC after 01/11/2019 Related Publications
Recently, FGFR1 was found to be overexpressed in osteosarcoma and represents an important target for precision medicine. However, because targeted cancer therapy based on FGFR inhibitors has so far been less efficient than expected, a detailed understanding of the target is important. We have here applied proximity-dependent biotin labeling combined with label-free quantitative mass spectrometry to identify determinants of FGFR1 activity in an osteosarcoma cell line. Many known FGFR interactors were identified (

Cavalcante GHO, de Araújo JMG, Fernandes JV, Lanza DCF
A seminested PCR assay for detection and typing of human papillomavirus based on E1 gene sequences.
Diagn Microbiol Infect Dis. 2018; 91(1):20-26 [PubMed] Related Publications
HPV infection is considered one of the leading causes of cervical cancer in the world. To date, more than 180 types of HPV have been described and viral typing is critical for defining the prognosis of cancer. In this work, a seminested PCR which allow fast and inexpensively detection and typing of HPV is presented. The system is based on the amplification of a variable length region within the viral gene E1, using three primers that potentially anneal in all HPV genomes. The amplicons produced in the first step can be identified by high resolution electrophoresis or direct sequencing. The seminested step includes nine specific primers which can be used in multiplex or individual reactions to discriminate the main types of HPV by amplicon size differentiation using agarose electrophoresis, reducing the time spent and cost per analysis.

Medeiros Tavares Marques JC, Cornélio DA, Nogueira Silbiger V, et al.
Identification of new genes associated to senescent and tumorigenic phenotypes in mesenchymal stem cells.
Sci Rep. 2017; 7(1):17837 [PubMed] Article available free on PMC after 01/11/2019 Related Publications
Although human mesenchymal stem cells (hMSCs) are a powerful tool for cell therapy, prolonged culture times result in replicative senescence or acquisition of tumorigenic features. To identify a molecular signature for senescence, we compared the transcriptome of senescent and young hMSCs with normal karyotype (hMSCs/n) and with a constitutional inversion of chromosome 3 (hMSC/inv). Senescent and young cells from both lineages showed differentially expressed genes (DEGs), with higher levels in senescent hMSCs/inv. Among the 30 DEGs in senescent hMSC/inv, 11 are new candidates for biomarkers of cellular senescence. The functional categories most represented in senescent hMSCs were related to cellular development, cell growth/proliferation, cell death, cell signaling/interaction, and cell movement. Mapping of DEGs onto biological networks revealed matrix metalloproteinase-1, thrombospondin 1, and epidermal growth factor acting as topological bottlenecks. In the comparison between senescent hMSCs/n and senescent hMSCs/inv, other functional annotations such as segregation of chromosomes, mitotic spindle formation, and mitosis and proliferation of tumor lines were most represented. We found that many genes categorized into functional annotations related to tumors in both comparisons, with relation to tumors being highest in senescent hMSCs/inv. The data presented here improves our understanding of the molecular mechanisms underlying the onset of cellular senescence as well as tumorigenesis.

De Araújo RF, Pessoa JB, Cruz LJ, et al.
Apoptosis in human liver carcinoma caused by gold nanoparticles in combination with carvedilol is mediated via modulation of MAPK/Akt/mTOR pathway and EGFR/FAAD proteins.
Int J Oncol. 2018; 52(1):189-200 [PubMed] Related Publications
In cancers, apoptosis signaling pathways and cell survival and growth pathways responsible for resistance to conventional treatments, such as Pi3K/Akt/mTOR and mitogen-activated protein kinase (MAPK) become dysregulated. Recently, alternative treatments to promote tumor cell death have become important. The present study reports on the antitumor and cytoprotective action of gold nanoparticles (GNPs) and carvedilol in combination and in isolated application. Apoptosis was analyzed by FITC/propidium iodide staining flow cytometry; caspase-3, caspase-8, Bcl-2 and MAPK/ERK activity by immunofluorescence microscopy; gene expression of proteins related to cell death as Akt, mTOR, EGFR, MDR1, survivin, FADD and Apaf, by the real-time PCR; and western blot analysis for MAPK/ERK, Akt and mTOR. Oxidative stress evaluation was performed by reduced glutathione (GSH) and malondialdehyde (MDA) levels. Intracellular GNPs targets were identified by transmission electron microscopy. After exposure to a combination of GNPs (6.25 µg/ml) and carvedilol (3 µM), death as promoted by apoptosis was detected using flow cytometry, for expression of pro-apoptotic proteins FADD, caspase-3, caspase-8 and sub-regulation of anti-apoptotic MAPK/ERK, Akt, mTOR, EGFR and MDR1 resistance. Non-tumor cell cytoprotection with GSH elevation and MDA reduction levels was detected. GNPs were identified within the cell near to the nucleus when combined with carvedilol. The combination of GNP and carvedilol promoted downregulation of anti-apoptotic and drug resistance genes, over-regulation of pro-apoptotic proteins in tumor cells, as well as cytoprotection of non-tumor cells with reduction of apoptosis and oxidative stress.

Huang H, Ji Y, Zhang J, et al.
Aberrant DNA methylation in radon and/or cigarette smoke-induced malignant transformation in BEAS-2B human lung cell line.
J Toxicol Environ Health A. 2017; 80(23-24):1321-1330 [PubMed] Related Publications
It is well known that cigarette smoking (CS) and/or radon (Rn) induce malignant transformation in lung cells. To investigate the mechanisms underlying lung carcinogenesis induced by CS, Rn; or Rn followed by CS using BEAS-2B cell line derived from human bronchial epithelial cells. BEAS-2B cells were exposed to either Rn (20,000 Bq/m

Rong X, Yin J, Wang H, et al.
Statin treatment may lower the risk of postradiation epilepsy in patients with nasopharyngeal carcinoma.
Epilepsia. 2017; 58(12):2172-2177 [PubMed] Related Publications
OBJECTIVE: This study aimed to clarify the effect of statins on preventing the risk of postradiation epilepsy.
METHODS: We performed a retrospective analysis of neurological nasopharyngeal carcinoma patients with a history of radiotherapy. Patients with a history of epilepsy before radiation and those who received prophylactically antiepileptic treatment were excluded. The demographic and clinical data of these patients were collected through chart review. We used Kaplan-Meier analysis (log-rank test) to examine the effect of statins on epilepsy-free survival. Cox regression analysis was utilized to identify independent predictive variables.
RESULTS: Our study included 532 patients (405 males and 127 females) with a mean follow-up of 28.1 months. During follow-up, 471 (88.5%) patients developed radiation-induced brain necrosis (RN). Within a mean latency of 24.1 months, 88 (16.5%) patients experienced epilepsy, of whom 27 (27 of 88, 30.7%) patients suffered from epilepsy before the diagnosis of RN. Thirty-six (36 of 88, 40.9%) cases of epilepsy occurred after RN onset, and in 22 cases (22 of 88, 25.0%) epilepsy was the first presentation of RN. Three patients suffered from epilepsy but did not have RN. Eighty-eight patients in our cohort were treated with statins because of hyperlipidemia or prevention of cardiocerebrovascular diseases, of whom six (6.8%) developed epilepsy, whereas in those without statin, the epileptic rate was 18.5%. Log-rank test found that there was a significant difference in epilepsy-free survival between patients who used statins and those who did not (p = 0.016). After adjusting for confounding variables, multivariate Cox regression analysis revealed that statin use could still significantly reduce the risk of epilepsy after radiation (hazard ratio = 0.36, 95% confidence interval = 0.15-0.82, p = 0.015). However, for the patients who already suffered from RN, statin treatment did not lower the risk of post-RN epilepsy.
SIGNIFICANCE: Early statin use may reduce the risk of postradiotherapy epilepsy in patients with nasopharyngeal carcinoma.

Zhang TJ, Lin J, Zhou JD, et al.
High bone marrow miR-19b level predicts poor prognosis and disease recurrence in de novo acute myeloid leukemia.
Gene. 2018; 640:79-85 [PubMed] Related Publications
Oncogenic role of miR-19 family has been identified in human cancers especially in lymphoid malignancies. However, to date, little studies investigated the role of miR-19 family in myeloid malignancies. Herein, we examined miR-19a/b expression and explored its clinical significance in de novo acute myeloid leukemia (AML). The detection of miR-19a/b expression was performed by real-time quantitative PCR in bone marrow mononuclear cells of 113 patients and 42 healthy donors. Both miR-19a/b levels were significantly increased in AML patients in contrast to controls. Patients with miR-19a/b overexpression were more frequently occurred in female, and had an older age. Moreover, cases with miR-19a overexpression had a higher frequency of U2AF1, C-KIT and CEBPA mutations, whereas miR-19b overexpressed cases harbored U2AF1 and IDH1/2 mutations. There was no significant association of miR-19a overexpression with complete remission (CR) rate and overall survival (OS) among whole-cohort AML, non-M3 AML, and cytogenetically normal AML (CN-AML). However, although miR-19b overexpression was not correlated with CR rate, patients with miR-19b overexpression presented significantly shorter OS in whole-cohort AML and a trend in non-M3 AML and CN-AML patients. Importantly, our data also showed that miR-19a/b expression level at CR phase was lower than diagnosis time, and was returned to primary level even higher when at relapse phase. Our findings revealed that miR-19a/b overexpression were frequent events in de novo AML patients. Moreover, up-regulation of miR-19b expression was associated with poor prognosis and disease recurrence in AML.

Gade IL, Brækkan S, Næss IA, et al.
Epidemiology of venous thromboembolism in hematological cancers: The Scandinavian Thrombosis and Cancer (STAC) cohort.
Thromb Res. 2017; 158:157-160 [PubMed] Related Publications
INTRODUCTION: Venous thromboembolism (VTE) is an important cause of morbidity and mortality in cancer patients, however the risk of VTE differs according to cancer type. Hematological cancers have varying phenotypes. Incidence rates (IR) of VTE in different hematological cancer types have not been investigated in a cancer-exposed subset of the general population.
METHODS: In a population-based cohort, we estimated incidence rates of VTE among patients with six subtypes of hematological cancer and among age and sex matched reference subjects.
RESULTS: During a mean follow-up of 4.8years, 30 objectively confirmed first-time symptomatic VTEs occurred among 838 subjects with hematological cancer. The IR of VTE was higher in all types of cancer except for indolent lymphoma but including chronic lymphocytic leukemia compared with reference subjects both during the first year after cancer diagnosis and 1-5years after diagnosis. IR of VTE for indolent lymphoma was not higher than controls.
CONCLUSION: The IRs of VTE were increased in all types of hematological cancer (including chronic lymphocytic leukemia) compared with reference subjects except indolent lymphomas.

Herdt O, Neumann A, Timmermann B, Heyd F
The cancer-associated U2AF35 470A>G (Q157R) mutation creates an in-frame alternative 5' splice site that impacts splicing regulation in Q157R patients.
RNA. 2017; 23(12):1796-1806 [PubMed] Article available free on PMC after 01/11/2019 Related Publications
Recent work has identified cancer-associated U2AF35 missense mutations in two zinc-finger (ZnF) domains, but little is known about Q157R/P substitutions within the second ZnF. Surprisingly, we find that the c.470A>G mutation not only leads to the Q157R substitution, but also creates an alternative 5' splice site (ss) resulting in the deletion of four amino acids (Q157Rdel). Q157P, Q157R, and Q157Rdel control alternative splicing of distinct groups of exons in cell culture and in human patients, suggesting that missplicing of different targets may contribute to cellular aberrations. Our data emphasize the importance to explore missense mutations beyond altered protein sequence.

Zhang TJ, Wu DH, Zhou JD, et al.
Overexpression of miR-216b: Prognostic and predictive value in acute myeloid leukemia.
J Cell Physiol. 2018; 233(4):3274-3281 [PubMed] Related Publications
Accumulating studies have shown that miR-216b acted as a tumor suppressor and was down-regulated in solid tumors. However, little studies revealed the role or clinical implication of miR-216b in blood cancers. Herein, we reported miR-216b expression and its clinical significance in patients with acute myeloid leukemia (AML). In the current study, we analyzed bone marrow (BM) miR-216b expression in 115 de novo AML patients examined by real-time quantitative PCR. Notably, BM miR-216b expression was significantly up-regulated in AML patients, and could serve as a potential biomarker distinguishing AML from controls. No significant correlations of BM miR-216 expression were found with sex, age, white blood cells, hemoglobin, platelets, BM blasts, French-American-British classifications, and karyotypes. Significantly, patients with high miR-216b expression tended to have a lower frequency of FLT3-ITD mutation and higher incidence of U2AF1 and IDH1/2 mutations. Moreover, complete remission (CR) rate and overall survival were negatively affected by BM miR-216b overexpression among cytogenetically normal AML (CN-AML). Cox regression analyses showed that high BM miR-216b expression may act as an independent risk factor in CN-AML patients. Among the follow-up patients, BM miR-216b level in CR phase was markedly lower than in diagnosis time, and was returned in relapse phase. Collectively, our findings indicated that miR-216b overexpression was a frequent event in de novo AML, and independently conferred a poor prognosis in CN-AML. Moreover, miR-216b expression was a valuable biomarker correlated with disease recurrence in AML.

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.

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