Gene Summary

Gene:ZAP70; zeta chain of T cell receptor associated protein kinase 70
Aliases: SRK, STD, TZK, STCD, IMD48, ADMIO2, ZAP-70
Summary:This gene encodes an enzyme belonging to the protein tyrosine kinase family, and it plays a role in T-cell development and lymphocyte activation. This enzyme, which is phosphorylated on tyrosine residues upon T-cell antigen receptor (TCR) stimulation, functions in the initial step of TCR-mediated signal transduction in combination with the Src family kinases, Lck and Fyn. This enzyme is also essential for thymocyte development. Mutations in this gene cause selective T-cell defect, a severe combined immunodeficiency disease characterized by a selective absence of CD8-positive T-cells. Two transcript variants that encode different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:tyrosine-protein kinase ZAP-70
Source:NCBIAccessed: 01 September, 2019


What does this gene/protein do?
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Pathways:What pathways are this gene/protein implicaed in?
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Cancer Overview

Research Indicators

Publications Per Year (1994-2019)
Graph generated 01 September 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.

  • Leukemic Gene Expression Regulation
  • Immunoglobulin Heavy Chains
  • Receptors, Antigen, B-Cell
  • beta 2-Microglobulin
  • Case-Control Studies
  • Staging
  • ADP-ribosyl Cyclase 1
  • Biomarkers, Tumor
  • Survival Rate
  • Signal Transduction
  • Cancer Gene Expression Regulation
  • Membrane Glycoproteins
  • Trisomy
  • VDJ Recombinases
  • Messenger RNA
  • Mutation
  • Chromosome 2
  • Gene Expression Profiling
  • Protein-Tyrosine Kinases
  • MicroRNAs
  • Chromosome Deletion
  • Neoplasm Proteins
  • ZAP70
  • Genes, Immunoglobulin
  • Follow-Up Studies
  • Immunoglobulin Variable Region
  • B-Lymphocytes
  • Cohort Studies
  • Risk Factors
  • FISH
  • Flow Cytometry
  • Disease Progression
  • Genes, Immunoglobulin Heavy Chain
  • Immunophenotyping
  • Gene Expression
  • Apoptosis
  • Chronic Lymphocytic Leukemia
  • Chromosome Aberrations
  • Proto-Oncogene Proteins c-bcl-6
  • Oligonucleotide Array Sequence Analysis
Tag cloud generated 01 September, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (1)

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: ZAP70 (cancer-related)

Hou Y, Zhang Y, Qin L, et al.
Interferon-induced transmembrane protein-3 rs12252-CC is associated with low differentiation and progression of hepatocellular carcinoma.
Medicine (Baltimore). 2019; 98(2):e13996 [PubMed] Free Access to Full Article Related Publications
Interferon-induced transmembrane protein 3 (IFITM3) is a component of ISG (Interferon-Stimulated Gene) family. The association between IFITM3 and hepatocellular carcinoma (HCC) has been reported. While the relationship between this genetic variation and the progress of HCC remains unclear. To address this issue, we explore the relationship between the IFITM3-rs12252 genetic variants and the progression of HCC in this study.A total of 336 candidates were enrolled in the study, including 156 patients with HBV related HCC and 180 patients with chronic Hepatitis B infections or liver cirrhosis. Liver cirrhosis or chronic hepatitis B were diagnosed with clinical characteristics and staging, laboratory testing, and imaging results of viral infection and hepatic damage. Polymerase chain reaction (PCR) was employed to determine the gene polymorphism of IFITM3, and analyzed with the GraphPad Prism v 5.The patients with HCC had a significantly higher proportion of IFITM3 rs12252-CC as compared with the patients with chronic HBV infection or liver cirrhosis. Moreover, the distribution of CC genotype in HCC patients with low differentiation was significantly higher than that in those with high differentiation. Furthermore, the patients with CC genotype were found with bigger tumor size, higher percentage of vascular thrombosis, higher distribution of low differentiation and higher 5-year relapse rate than those with CT/TT genotypes.This study indicates a correlation between the IFITM3-rs12252 CC genotype and the progression of HCC.

Tari K, Shamsi Z, Reza Ghafari H, et al.
The role of the genetic abnormalities, epigenetic and microRNA in the prognosis of chronic lymphocytic leukemia.
Exp Oncol. 2018; 40(4):261-267 [PubMed] Related Publications
Chronic lymphocytic leukemia (CLL) is increased proliferation of B-cells with peripheral blood and bone marrow involvement, which is usually observed in older people. Genetic mutations, epigenetic changes and miRs play a role in CLL pathogenesis. Del 11q, del l17q, del 6q, trisomy 12, p53 and IgVH mutations are the most important genetic changes in CLL. Deletion of miR-15a and miR-16a can increase bcl2 gene expression, miR-29 and miR-181 deletions decrease the expression of TCL1, and miR-146a deletion prevents tumor metastasis. Epigenetic changes such as hypo- and hypermethylation, ubiquitination, hypo- and hyperacetylation of gene promoters involved in CLL pathogenesis can also play a role in CLL. Expression of CD38 and ZAP70, presence or absence of mutation in IgVH and P53 mutation are among the factors involved in CLL prognosis. Use of monoclonal antibodies against surface markers of B-cells like anti-CD20 as well as tyrosine kinase inhibitors are the most important therapeutic approaches for CLL.

Kapelko-Słowik K, Dybko J, Grzymajło K, et al.
Expression of the PIM2 gene is associated with more aggressive clinical course in patients with chronic lymphocytic leukemia.
Adv Clin Exp Med. 2019; 28(3):391-396 [PubMed] Related Publications
BACKGROUND: The PIM2 gene belongs to the PIM family, which encodes serine/threonine kinases involved in cell survival and apoptosis. The relation between the expression of the PIM2 gene and the course of chronic lymphocytic leukemia (CLL) has not been fully determined.
OBJECTIVES: The aim of the study was to evaluate the role of the PIM2 gene as a marker of CLL malignancy and its importance as a predictive and prognostic factor.
MATERIAL AND METHODS: Sixty-seven patients, 35 females and 32 males, aged 49-90 years, with de novo CLL, and 14 healthy individuals were enrolled in the study. Expression of the PIM2 gene was analyzed using TaqMan RQ-PCR assay and western blot test.
RESULTS: Median PIM2 gene expression in CLL patients was higher than in controls. Patients with high expression of the PIM2 gene had shorter progression-free survival and time to first treatment than patients with low PIM2 expression. It was found that patients with CR had lower expression of the PIM2 gene than patients without complete remission (CR). Notably, associations between high PIM2 expression and rapid lymphocyte doubling time, the percentage of malignant lymphocytes with ZAP70 expression and the Rai stage were revealed.
CONCLUSIONS: We found that the PIM2 gene is associated with a more aggressive clinical course of CLL.

Filiú-Braga LDC, Serejo TRT, Lucena-Araujo AR, et al.
Unraveling KDM4 histone demethylase expression and its association with adverse cytogenetic findings in chronic lymphocytic leukemia.
Med Oncol. 2018; 36(1):3 [PubMed] Related Publications
The acquisition of complex karyotypes is related to the progression of chronic lymphocytic leukemia (CLL) and patients with this condition have a poor prognosis. Despite recent advances in the classification of prognosis in CLL patients, understanding of the molecular mechanisms that lead to genomic instability and progression of this disease remains inadequate. Interestingly, dysregulated expression of KDM4 members is involved in the progression of several cancer types and plays a role in the DNA damage response; however, the gene expression profile and the importance of KDM4 members in CLL are still unknown. Here, we assessed the gene expression profile of KDM4A, KDM4B, and KDM4C in 59 CLL samples and investigated whether these histone demethylases have any influence on the prognostic markers of this leukemia. KDM4A gene expression was higher in CLL patients as compared with control samples. In contrast, CLL samples showed decreased levels of the KDM4B transcript in relation to control cases, and no difference was detected in KDM4C expression. Furthermore, patients with positive expression of ZAP-70 had lower expression of KDM4B and KDM4C as compared with ZAP-70-negative patients. More importantly, patients with low expression of these histone demethylases had higher leukemic cell numbers and displayed adverse cytogenetic findings and the acquisition of a complex karyotype. The present data clearly show that the expression of KDM4 members is dysregulated in CLL and impact the prognosis of this leukemia. These findings are useful for a better understanding of the impact of epigenetics on CLL progression.

Mosaad Zaki E, Mohamed Zahran A, Abdelazeem Metwaly A, et al.
Impact of CD39 expression on CD4+ T lymphocytes and 6q deletion on outcome of patients with chronic lymphocytic leukemia.
Hematol Oncol Stem Cell Ther. 2019; 12(1):26-31 [PubMed] Related Publications
OBJECTIVE/BACKGROUND: Chronic lymphocytic leukemia is one of the commonest leukemias affecting adults. CD39 inhibits T-cell and Natural killer (NK) cell responses by hydrolyzing adenosine triphosphate and adenosine diphosphate, suppressing the immune system. We investigated expression of CD39 on CD4+ T Lymphocytes in chronic lymphocytic leukemia (CLL) patients and its relationship with deletion 6q, its association with disease stage and survival.
METHODS: Thirty CLL patients and 20 matched controls were included in the study. Bone marrow studies with immunophenotyping, CD39, CD38, and ZAP-70, and detection of del 6q by FISH were performed.
RESULTS: CD39+ CD4+ T helper cells in CLL patients were significantly expressed compared with the controls (p < .001). Levels of CD39+ CD4+ T cells were significantly expressed in high risk CLL patients. Del 6q was detected in 63.3% of patients and it correlated with CD39, CD38, and ZAP-70, and advanced stage disease. There was a significant relation between response to treatment and CD39 expression and del 6q, also there was a significant difference in overall survival (OS) between patients with and without Del 6q.
CONCLUSION: CD39 expression on CD4+ Tcells and del 6q act as prognostic markers in CLL. Blocking or inhibition of CD39 may be a target for new immune therapy for CLL.

Meyer HJ, Leifels L, Hamerla G, et al.
ADC-histogram analysis in head and neck squamous cell carcinoma. Associations with different histopathological features including expression of EGFR, VEGF, HIF-1α, Her 2 and p53. A preliminary study.
Magn Reson Imaging. 2018; 54:214-217 [PubMed] Related Publications
OBJECTIVE: Apparent diffusion coefficient (ADC) values derived from Diffusion-weighted images are able to reflect tumor microstructure, such as cellularity, extracellular matrix or proliferation potential. This present study sought to correlate prognostic relevant histopathologic parameters with ADC values derived from a whole lesion measurement in head and neck squamous cell carcinoma (HNSCC).
MATERIALS AND METHODS: Thirty-four patients with histological proven primary HNSCC were prospectively acquired. Histogram analysis was derived from ADC maps. In all cases, expression of Hif1-alpha, VEGF, EGFR, p53, p16, Her 2 were analyzed.
RESULTS: In the overall patient sample, ADCmax correlated with p53 expression (p = -0.446, p = 0.009) and ADCmode correlated with Her2-expression (p = -0.354, p = 0.047). In the p16 positive group there were several correlations. P25, P90 and entropy correlated with Hif1-alpha (p = -0.423, p = 0.05, p = -0.494, p = 0.019, p = 0.479, p = 0.024, respectively). Kurtosis correlated with P53 expression (p = -0.466, p = 0.029). For p16 negative carcinomas the following associations could be identified. Mode correlated with VEGF-expression (p = -0.657, p = 0.039). ADCmax, P75, P90, and Std correlated with p53-expression (p = -0.827, p = 0.002, p = -0.736, p = 0.01, p = -0.836, p = 0.001 and p = -0.70, p = 0.016, respectively). There were no statistically significant differences of ADC histogram parameters between p16 positive and p16 negative carcinomas.
CONCLUSION: ADC histogram values can reflect different histopathological features in HNSCC. Associations between ADC histogram analysis parameters and histopathology depend on p16 status.

Miyata-Takata T, Chuang SS, Takata K, et al.
Expression of T-cell receptor signalling pathway components in extranodal NK/T-cell lymphoma.
Histopathology. 2018; 73(6):1030-1038 [PubMed] Related Publications
AIMS: Although the neoplastic cells of extranodal natural killer (NK)/T-cell lymphoma (ENKTL) usually do not express T-cell antigens, the T-cell receptor (TCR) gene might be rearranged and TCR protein expressed. The aim is to elucidate the expression of the downstream TCR pathway components and their importance in ENKTL.
METHODS AND RESULTS: We used formalin-fixed paraffin-embedded tissues from 91 ENKTL samples to immunohistochemically characterise the expression of TCR pathway components. The following proteins were variably expressed: ZAP70 (94%; 83/88), GRAP2/GADS (68%; 60/88), DOK2 (42%; 38/90), LCK (35%; 31/88), and ITK (10%; 9/90). When these tumours were classified as being of T lineage (16%), NK lineage (45%), or indeterminate lineage (38%), the GRAP2/GADS expression rate was higher in T lineage tumours (versus NK, P = 0.0073; versus indeterminate, P = 0.00082). GRAP2/GADS-positive NK lineage tumours more frequently expressed DOK2 (P = 0.0073), and were more often confined to the nasal areas (P = 0.014). Furthermore, when these tumours were immunophenotypically classified into a T signature (42%) or NK signature (58%), the expression rates of GRAP2/GADS and ITK were higher in T signature tumours (P = 0.00074 and P = 0.067, respectively), whereas that of LCK was higher in NK-signature tumours (P = 0.10).
CONCLUSIONS: Although some ENTKL cases were polyclonal for TCR rearrangement and others lacked TCR expression, we speculate that the TCR pathway might be functioning in ENKTLs. A T signature versus a NK signature might be better for delineating the physiology of ENKTL than cellular lineage. Furthermore, ITK may represent a potential therapeutic target for patients with ITK-expressing tumours.

Zhang Y, Zhou X, Li Y, et al.
Inhibition of maternal embryonic leucine zipper kinase with OTSSP167 displays potent anti-leukemic effects in chronic lymphocytic leukemia.
Oncogene. 2018; 37(41):5520-5533 [PubMed] Related Publications
TP53 pathway defects contributed to therapy resistance and adverse clinical outcome in chronic lymphocytic leukemia (CLL), which represents an unmet clinical need with few therapeutic options. Maternal embryonic leucine zipper kinase (MELK) is a novel oncogene, which plays crucial roles in mitotic progression and stem cell maintenance. OTSSP167, an orally administrated inhibitor targeting MELK, is currently in a phase I/II clinical trial in patients with advanced breast cancer and acute myeloid leukemia. Yet, no investigation has been elucidated to date regarding the oncogenic role of MELK and effects of OTSSP167 in chronic lymphocytic leukemia (CLL). Previous studies confirmed MELK inhibition abrogated cancer cell survival via p53 signaling pathway. Thus, we aimed to determine the biological function of MELK and therapeutic potential of OTSSP167 in CLL. Herein, MELK over-expression was observed in CLL cells, and correlated with higher WBC count, advanced stage, elevated LDH, increased β2-MG level, unmutated IGHV, positive ZAP-70, deletion of 17p13 and inferior prognosis of CLL patients. In accordance with functional enrichment analyses in gene expression profiling, CLL cells with depletion or inhibition of MELK exhibited impaired cell proliferation, enhanced fast-onset apoptosis, induced G2/M arrest, attenuated cell chemotaxis and promoted sensitivity to fludarabine and ibrutinib. However, gain-of-function assay showed increased cell proliferation and cell chemotaxis. In addition, OTSSP167 treatment reduced phosphorylation of AKT and ERK1/2. It decreased FoxM1 phosphorylation, expression of FoxM1, cyclin B1 and CDK1, while up-regulating p53 and p21 expression. Taken together, MELK served as a candidate of therapeutic target in CLL. OTSSP167 exhibits potent anti-tumor activities in CLL cells, highlighting a novel molecule-based strategy for leukemic interventions.

Alves-Silva JC, de Carvalho JL, Rabello DA, et al.
GLP overexpression is associated with poor prognosis in Chronic Lymphocytic Leukemia and its inhibition induces leukemic cell death.
Invest New Drugs. 2018; 36(5):955-960 [PubMed] Related Publications
Background Heterodimeric methyltransferases GLP (EHMT1/KMT1D) and G9a (EHMT2/KMT1C) are two closely related enzymes that promote the monomethylation and dimethylation of histone H3 lysine 9. Dysregulation of their activity has been implicated in several types of human cancer. Patients and methods Here, in order to investigate whether GLP/G9a exerts any impact on Chronic Lymphocytic Leukemia (CLL), GLP/G9a expression levels were assessed in a cohort of 50 patients and the effects of their inhibition were verified for the viability of CLL cells. Also, qRT-PCR was used to investigate the transcriptional levels of GLP/G9a in CLL patients. In addition, patient samples were classified according to ZAP-70 protein expression by flow cytometry and according to karyotype integrity by cytogenetics analysis. Finally, a selective small molecule inhibitor for GLP/G9a was used to ascertain whether these methyltransferases influenced the viability of MEC-1 CLL cell lineage. Results mRNA analysis revealed that CLL samples had higher levels of GLP, but not G9a, when compared to non-leukemic controls. Interestingly, patients with unfavorable cytogenetics showed higher expression levels of GLP compared to patients with favorable karyotypes. More importantly, GLP/G9a inhibition markedly induced cell death in CLL cells. Conclusion Taken together, these results indicate that GLP is associated with a worse prognosis in CLL, and that the inhibition of GLP/G9a influences CLL cell viability. Altogether, the present data demonstrate that these methyltransferases can be potential markers for disease progression, as well as a promising epigenetic target for CLL treatment and the prevention of disease evolution.

Bins S, Basak EA, El Bouazzaoui S, et al.
Association between single-nucleotide polymorphisms and adverse events in nivolumab-treated non-small cell lung cancer patients.
Br J Cancer. 2018; 118(10):1296-1301 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Treatment with PD-1 inhibitors can be hampered by severe auto-immune-related toxicities. Our objective was to identify single-nucleotide polymorphisms (SNPs) in genes previously associated with auto-immunity, which are associated with toxicities in nivolumab-treated NSCLC patients. This was in order to identify patients prone to develop severe toxicities and to gain more insight into the underlying pathobiology.
METHODS: We analysed 322 nivolumab-treated patients and assessed the association with toxicities for seven SNPs in four genes, which are considered contributors to PD-1-directed T-cell responses, i.e., PDCD1, PTPN11, ZAP70 and IFNG. Every SNP was tested for its association with toxicity endpoints. Significant associations were tested in a validation cohort.
RESULTS: A multivariable analysis in the exploration cohort showed that homozygous variant patients for PDCD1 804C>T (rs2227981) had decreased odds for any grade treatment-related toxicities (n = 96; OR 0.4; 95% CI 0.2-1.0; p = 0.039). However, this result could not be validated (n = 85; OR 0.9; 95% CI 0.4-1.9; p = NS).
CONCLUSIONS: Our results show that it is unlikely that the investigated SNPs have a clinical implication in predicting toxicity. A finding, even though negative, that is considered timely and instructive towards further research in biomarker development for checkpoint inhibitor treatments.

Liu Y, Wang Y, Yang J, et al.
ZAP-70 in chronic lymphocytic leukemia: A meta-analysis.
Clin Chim Acta. 2018; 483:82-88 [PubMed] Related Publications
BACKGROUND: Recent studies have reported that zeta-chain-associated protein kinase 70 (ZAP-70) expression plays a prognostic role in chronic lymphocytic leukemia (CLL). However, these results remain controversial. Thus, we performed a meta-analysis to clarify the prognostic value of ZAP-70 expression in CLL.
MATERIALS AND METHODS: Relevant studies were searched in PubMed, Embase, Cochrane library, and Web of Science up to January 2018. Clinicopathological features and prognostic data were extracted from the studies. We pooled estimates and 95% confidence intervals (CIs) and estimated the heterogeneity of studies using Mantel-Haenszel or DerSimonian and Laird method.
RESULTS: Twelve studies that included 1956 patients with CLL were eligible for inclusion. The pooled results revealed that increased ZAP-70 expression was significantly associated with poor overall survival (hazard ratio [HR] = 2.48, 95% CI: 1.72-3.59, P = 0.019, I
CONCLUSIONS: Our findings indicated that ZAP-70 was a strong prognostic biomarker for patients with CLL.

Ali AY, Wu X, Eissa N, et al.
Distinct roles for phosphoinositide 3-kinases γ and δ in malignant B cell migration.
Leukemia. 2018; 32(9):1958-1969 [PubMed] Free Access to Full Article Related Publications
The PI 3-kinases (PI3K) are essential mediators of chemokine receptor signaling necessary for migration of chronic lymphocytic leukemia (CLL) cells and their interaction with tissue-resident stromal cells. While the PI3Kδ-specific inhibitor idelalisib shows efficacy in treatment of CLL and other B cell malignancies, the function of PI3Kγ has not been extensively studied in B cells. Here, we assess whether PI3Kγ has non-redundant functions in CLL migration and adhesion to stromal cells. We observed that pharmaceutical PI3Kγ inhibition with CZC24832 significantly impaired CLL cell migration, while dual PI3Kδ/γ inhibitor duvelisib had a greater impact than single isoform-selective inhibitors. Knockdown of PI3Kγ reduced migration of CLL cells and cell lines. Expression of the PI3Kγ subunits increased in CLL cells in response to CD40L/IL-4, whereas BCR cross-linking had no effect. Overexpression of PI3Kγ subunits enhanced cell migration in response to SDF1α/CXCL12, with the strongest effect observed within ZAP70 + CLL samples. Microscopic tracking of cell migration within chemokine gradients revealed that PI3Kγ functions in gradient sensing and impacts cell morphology and F-actin polarization. PI3Kγ inhibition also reduced CLL adhesion to stromal cells to a similar extent as idelalisib. These findings provide the first evidence that PI3Kγ has unique functions in malignant B cells.

Sun Y, Hu B, Wang Q, et al.
Long non-coding RNA HOTTIP promotes BCL-2 expression and induces chemoresistance in small cell lung cancer by sponging miR-216a.
Cell Death Dis. 2018; 9(2):85 [PubMed] Free Access to Full Article Related Publications
Despite progress in treatment of small cell lung cancer (SCLC), its multidrug chemoresistance and poor prognosis still remain. Recently, we globally assessed long non-coding RNAs (lncRNAs) for contributions to SCLC chemoresistance using microarray data, in vitro and in vivo assays. Here we reported that HOTTIP, encoding a lncRNA that is frequently amplified in SCLC, was associated with SCLC cell chemosensitivity, proliferation, and poor prognosis of SCLC patients. Moreover, mechanistic investigations showed that HOTTIP functioned as an oncogene in SCLC progression by binding miR-216a and abrogating its tumor-suppressive function in this setting. On the other hand, HOTTIP increased the expression of anti-apoptotic factor BCL-2, another important target gene of miR-216a, and jointly enhanced chemoresistance of SCLC by regulating BCL-2. Taken together, our study established a role for HOTTIP in SCLC progression and chemoresistance suggest its candidacy as a new diagnostic and prognostic biomarker for clinical management of SCLC.

Ren FH, Yang H, He RQ, et al.
Analysis of microarrays of miR-34a and its identification of prospective target gene signature in hepatocellular carcinoma.
BMC Cancer. 2018; 18(1):12 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Currently, some studies have demonstrated that miR-34a could serve as a suppressor of several cancers including hepatocellular carcinoma (HCC). Previously, we discovered that miR-34a was downregulated in HCC and involved in the tumorigenesis and progression of HCC; however, the mechanism remains unclear. The purpose of this study was to estimate the expression of miR-34a in HCC by applying the microarray profiles and analyzing the predicted targets of miR-34a and their related biological pathways of HCC.
METHODS: Gene expression omnibus (GEO) datasets were conducted to identify the difference of miR-34a expression between HCC and corresponding normal tissues and to explore its relationship with HCC clinicopathologic features. The natural language processing (NLP), gene ontology (GO), pathway and network analyses were performed to analyze the genes associated with the carcinogenesis and progression of HCC and the targets of miR-34a predicted in silico. In addition, the integrative analysis was performed to explore the targets of miR-34a which were also relevant to HCC.
RESULTS: The analysis of GEO datasets demonstrated that miR-34a was downregulated in HCC tissues, and no heterogeneity was observed (Std. Mean Difference(SMD) = 0.63, 95% confidence intervals(95%CI):[0.38, 0.88], P < 0.00001; P
CONCLUSION: Our results may lead researchers to understand the molecular mechanism of miR-34a in the diagnosis, prognosis and therapy of HCC. Therefore, the interaction between miR-34a and its targets may promise better prediction and treatment for HCC. And the experiments in vivo and vitro will be conducted by our group to identify the specific mechanism of miR-34a in the progress and deterioration of HCC.

Till KJ, Allen JC, Talab F, et al.
Lck is a relevant target in chronic lymphocytic leukaemia cells whose expression variance is unrelated to disease outcome.
Sci Rep. 2017; 7(1):16784 [PubMed] Free Access to Full Article Related Publications
Pathogenesis of chronic lymphocytic leukaemia (CLL) is contingent upon antigen receptor (BCR) expressed by malignant cells of this disease. Studies on somatic hypermutation of the antigen binding region, receptor expression levels and signal capacity have all linked BCR on CLL cells to disease prognosis. Our previous work showed that the src-family kinase Lck is a targetable mediator of BCR signalling in CLL cells, and that variance in Lck expression associated with ability of BCR to induce signal upon engagement. This latter finding makes Lck similar to ZAP70, another T-cell kinase whose aberrant expression in CLL cells also associates with BCR signalling capacity, but also different because ZAP70 is not easily pharmacologically targetable. Here we describe a robust method of measuring Lck expression in CLL cells using flow cytometry. However, unlike ZAP70 whose expression in CLL cells predicts prognosis, we find Lck expression and disease outcome in CLL are unrelated despite observations that its inhibition produces effects that biologically resemble the egress phenotype taken on by CLL cells treated with idelalisib. Taken together, our findings provide insight into the pathobiology of CLL to suggest a more complex relationship between expression of molecules within the BCR signalling pathway and disease outcome.

Gladkikh AA, Potashnikova DM, Tatarskiy V, et al.
Comparison of the mRNA expression profile of B-cell receptor components in normal CD5-high B-lymphocytes and chronic lymphocytic leukemia: a key role of ZAP70.
Cancer Med. 2017; 6(12):2984-2997 [PubMed] Free Access to Full Article Related Publications
The B-cell receptor (BCR) signaling pathway is of great importance for B-cell survival and proliferation. The BCR expressed on malignant B-CLL cells contributes to the disease pathogenesis, and its signaling pathway is currently the target of several therapeutic strategies. Although various BCR alterations have been described in B-CLL at the protein level, the mRNA expression levels of tyrosine kinases in B-CLL compared to that in normal CD5-high and CD5-low B-lymphocytes remain unknown. In the current study, we measured the mRNA expression levels of CD79A, CD79B, LYN, SYK, SHP1, and ZAP70 in purified populations of CD5-high B-CLL cells, CD5-low B-cells from the peripheral blood of healthy donors, and CD5-high B-cells from human tonsils. Here, we report a clear separation in the B-CLL dataset between the ZAP70-high and ZAP70-low subgroups. Each subgroup has a unique expression profile of BCR signaling components that might reflect the functional status of the BCR signaling pathway. Moreover, the ZAP70-low subgroup does not resemble either CD5-high B-lymphocytes from the tonsils or CD5-low lymphocytes from PBMC (P < 0.05). We also show that ZAP70 is the only gene that is differentially expressed in CD5-high and CD5-low normal B-lymphocytes, confirming the key role of Zap-70 tyrosine kinase in BCR signaling alterations in B-CLL.

Martínez-Trillos A, Pinyol M, Delgado J, et al.
The mutational landscape of small lymphocytic lymphoma compared to non-early stage chronic lymphocytic leukemia.
Leuk Lymphoma. 2018; 59(10):2318-2326 [PubMed] Related Publications
Small lymphocytic lymphoma (SLL) is considered as the non-leukemic form of presentation of chronic lymphocytic leukemia (CLL). We have compared the features, genomic alterations, and outcome of 890 patients with CLL and SLL. One hundred and thirteen patients presented as SLL and more frequently had unmutated-IGHV, CD38

Zakrzewska E, Pirog M, Purkot J, Giannopoulos K
Novel prognostic molecular factors: a quantum leap in the field of chronic lymphocytic leukemia.
Folia Histochem Cytobiol. 2017; 55(3):95-106 [PubMed] Related Publications
Cytogenetic lesions do not completely explain clinical heterogeneity of chronic lymphocytic leukemia (CLL). The 2016 revision of the World Health Organization classification 2008 indicated that molecular lesions of TP53, NOTCH1, SF3B1 and BIRC3 have potential clinical relevance and could be integrated into an updated risk profile. The negative clinical implications of TP53 disruptions are well constituted and patients with these mutations should be considered for novel, small molecule signal transduction inhibitors therapies. Mutations of NOTCH1, SF3B1 and BIRC3 are associated with poor prognosis. Patients with mutated SF3B1 or NOTCH1 genes present shorter time to first treatment compared to unmutated group. NOTCH1 mutations are related to a high risk of Richter's syndrome transformation, especially in case of TP53 disruptions' coexistence. Large studies on MYD88 mutations in CLL have not explained clearly their clinical importance.The aim of this paper is to provide a comprehensive review on novel molecular aberrations identified in CLL.

Carabia J, Carpio C, Abrisqueta P, et al.
Microenvironment regulates the expression of miR-21 and tumor suppressor genes PTEN, PIAS3 and PDCD4 through ZAP-70 in chronic lymphocytic leukemia.
Sci Rep. 2017; 7(1):12262 [PubMed] Free Access to Full Article Related Publications
Chronic lymphocytic leukemia (CLL) cells are highly dependent on microenvironment, being the BCR pathway one key player in this crosstalk. Among proteins participating, ZAP-70 enhances response to microenvironmental stimuli. MicroRNA-21 (miR-21) is overexpressed in diverse neoplasias including CLL, where it has been associated to refractoriness to fludarabine and to shorter time to progression and survival. To further elucidate the role of ZAP-70 in the biology of CLL, we studied its involvement in miR-21 regulation. MiR-21 expression was higher in CLL cells with high ZAP-70. Ectopic expression of ZAP-70 induced transcription of miR-21 via MAPK and STAT3, which subsequently induced downregulation of tumor suppressors targeted by miR-21. The co-culture of primary CLL cells mimicking the microenvironment induced ZAP-70 and miR-21 expression, as well as downregulation of miR-21 targets. Interestingly, the increase in miR-21 after co-culture was significantly impaired by ibrutinib, indicating that the BCR signaling pathway is involved in its regulation. Finally, survival of CLL cells induced by the co-culture correlated with miR-21 upregulation. In conclusion, stimuli from the microenvironment regulate miR-21 and its targeted tumor suppressor genes via a signaling pathway involving ZAP-70, thus contributing to the cytoprotection offered by the microenvironment particularly observed in CLL cells expressing ZAP-70.

Lin X, Gu Y, Kapoor A, et al.
Overexpression of MUC1 and Genomic Alterations in Its Network Associate with Prostate Cancer Progression.
Neoplasia. 2017; 19(11):857-867 [PubMed] Free Access to Full Article Related Publications
We investigate the association of MUC1 with castration-resistant prostate cancer (CRPC), bone metastasis, and PC recurrence. MUC1 expression was studied in patient-derived bone metastasis and CRPCs produced by prostate-specific PTEN

Aubatin A, Sako N, Decrouy X, et al.
IL4-induced gene 1 is secreted at the immune synapse and modulates TCR activation independently of its enzymatic activity.
Eur J Immunol. 2018; 48(1):106-119 [PubMed] Related Publications
Amino-acid catabolizing enzymes produced by mononuclear phagocytes play a central role in regulating the immune response. The mammalian phenylalanine-catabolizing enzyme IL4-induced gene 1 (IL4I1) inhibits effector T lymphocyte proliferation and facilitates regulatory T-cell development. IL4I1 expression by macrophages of various human tumors may affect patient prognosis as it facilitates tumor escape from the T-cell response in murine models. Its enzymatic activity appears to participate in its effects, but some actions of IL4I1 remain unclear. Here, we show that the presence of IL4I1 during T-cell activation decreases early signaling events downstream of TCR stimulation, resulting in global T-cell inhibition which is more pronounced when there is CD28 costimulation. Surprisingly, the enzymatic activity of IL4I1 is not involved. Focal secretion of IL4I1 into the immune synaptic cleft and its binding to CD3

Habashy DM, Eissa DS, Aboelez MM
Turk J Haematol. 2018; 35(3):168-174 [PubMed] Free Access to Full Article Related Publications
Objective: Traditional prognostic factors have proved insufficient to account for heterogeneity in the clinical behavior of chronic lymphocytic leukemia (CLL). 
Materials and Methods: A total of 100 CLL patients at diagnosis were studied for 

Carvalho Alves-Silva J, do Amaral Rabello D, Oliveira Bravo M, et al.
Aberrant levels of SUV39H1 and SUV39H2 methyltransferase are associated with genomic instability in chronic lymphocytic leukemia.
Environ Mol Mutagen. 2017; 58(9):654-661 [PubMed] Related Publications
Chromosomal alterations are commonly detected in patients with chronic lymphocytic leukemia (CLL) and impact disease pathogenesis, prognosis, and progression. Telomerase expression (hTERT), its activity and the telomere length are other important predictors of survival and multiple outcomes in CLL. SUV39H and SUV420H enzymes are histone methyltransferases (HMTases) involved in several cellular processes, including regulation of telomere length, heterochromatin organization, and genome stability. Here, we investigated whether SUV39H1, SUV39H2, SUV420H1, SUV420H2, and hTERT are associated with genomic instability of CLL. SUV39H (1/2), SUV420H (1/2), and hTERT expression was determined in 59 CLL samples by real time PCR. In addition, ZAP-70 protein expression was evaluated by Flow Cytometry and patients' karyotype was defined by Cytogenetic Analysis. Low expression of SUV39H1 was associated with the acquisition of altered and complex karyotypes. Conversely, high expression of SUV39H2 correlated with cytogenetic abnormalities in CLL patients. The pattern of karyotypic alterations differed in samples with detectable or undetectable hTERT expression. Furthermore, hTERT expression in CLL showed a correlation with transcript levels of SUV39H2, which, in part, can explain the association between SUV39H2 expression and cytogenetic abnormalities. Moreover, SUV39H1 correlated with SUV420H1 expression while SUV420H2 was associated with all other investigated HMTases. Our data show that the differential expression of SUV39H1 and SUV39H2 is associated with genomic instability and that the modulation of these HMTases can be an attractive approach to prevent CLL evolution. Environ. Mol. Mutagen. 58:654-661, 2017. © 2017 Wiley Periodicals, Inc.

Morandi L, Gissi D, Tarsitano A, et al.
CpG location and methylation level are crucial factors for the early detection of oral squamous cell carcinoma in brushing samples using bisulfite sequencing of a 13-gene panel.
Clin Epigenetics. 2017; 9:85 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Oral squamous cell carcinoma (OSCC) is usually diagnosed at an advanced stage and is commonly preceded by oral premalignant lesions. The mortality rates have remained unchanged (50% within 5 years after diagnosis), and it is related to tobacco smoking and alcohol intake. Novel molecular markers for early diagnosis are urgently needed. The purpose of this study was to evaluate the diagnostic value of methylation level in a set of 18 genes by bisulfite next-generation sequencing.
METHODS: With minimally invasive oral brushing, 28 consecutive OSCC, one squamous cell carcinoma with sarcomatoid features, six high-grade squamous intraepithelial lesions (HGSIL), 30 normal contralateral mucosa from the same patients, and 65 healthy donors were evaluated for DNA methylation analyzing 18 target genes by quantitative bisulfite next-generation sequencing. We further evaluated an independent cohort (validation dataset) made of 20 normal donors, one oral fibroma, 14 oral lichen planus (OLP), three proliferative verrucous leukoplakia (PVL), and two OSCC.
RESULTS: Comparing OSCC with normal healthy donors and contralateral mucosa in 355 CpGs, we identified the following epigenetically altered genes:
CONCLUSIONS: Our data highlight the importance of CpG location and correct estimation of DNA methylation level for highly accurate early diagnosis of OSCC.

Piccaluga PP, Agostinelli C, Righi S, et al.
IFI16 reduced expression is correlated with unfavorable outcome in chronic lymphocytic leukemia.
APMIS. 2017; 125(6):511-522 [PubMed] Related Publications
Chronic lymphocytic leukemia (CLL) is the most common leukemia in adults. Its clinical course is typically indolent; however, based on a series of pathobiological, clinical, genetic, and phenotypic parameters, patient survival varies from less than 5 to more than 20 years. In this paper, we show for the first time that the expression of the interferon-inducible DNA sensor IFI16, a member of the PYHIN protein family involved in proliferation inhibition and apoptosis regulation, is associated with the clinical outcome in CLL. We studied 99 CLLs cases by immunohistochemistry and 10 CLLs cases by gene expression profiling. We found quite variable degrees of IFI16 expression among CLLs cases. Noteworthy, we observed that a reduced IFI16 expression was associated with a very poor survival, but only in cases with ZAP70/CD38 expression. Furthermore, we found that IFI16 expression was associated with a specific gene expression signature. As IFI16 can be easily detected by immunohistochemistry or flow cytometry, it may become a part of phenotypic screening in CLL patients if its prognostic role is confirmed in independent series.

Putowski M, Podgórniak M, Piróg M, et al.
Prognostic impact of NOTCH1, MYD88, and SF3B1 mutations in Polish patients with chronic lymphocytic leukemia.
Pol Arch Intern Med. 2017; 127(4):238-244 [PubMed] Related Publications
INTRODUCTION    Currently available prognostic factors determining the course of chronic lymphocytic leukemia (CLL) are not fully efficient, especially for newly diagnosed patients. Investigation of molecular changes may help clarify the reasons for the heterogeneity of the disease. Apart from already confirmed TP53 mutations, the novel candidates: NOTCH1, SF3B1, and MYD88 might represent clinically relevant biomarkers. OBJECTIVES    The aim of this study was to evaluate the mutational status of NOTCH1, MYD88, and SF3B1 and to compare the results with confirmed prognostic factors: ZAP‑70, CD38, and immunoglobulin heavy‑chain variable region (IGHV) mutation in CLL. The study assessed also prognostic significance in terms of the time to first treatment (TTFT) and subset analysis. PATIENTS AND METHODS The study was conducted on samples of 370 newly diagnosed patients with CLL. The analysis was performed using high‑resolution melting, Sanger sequencing, and polymerase chain reaction methods. RESULTS    Patients harboring the NOTCH1 mutation were significantly more often found among patients with an unmutated IGHV gene status and high expression of CD38 and ZAP‑70. The MYD88 mutation was equally distributed in patients with mutated and unmutated IGHV status (5 vs 7 patients). For MYD88 and SF3B1, there were no significant differences in the levels of CD38 and ZAP‑70 expression. The tendency for lower median TTFT was revealed in patients with mutated SF3B1 (P = 0.08). The analysis showed the presence of 14 different types of the subsets of IGHV in 50 of 345 patients (14.5%). The most frequent were subsets #1 and #2. CONCLUSIONS    The NOTCH1 and SF3B1 mutations accompany biological markers of unfavorable prognosis in patients with CLL. The mutations may contribute to the identification of patients with high‑risk CLL.

Xu X, Wu K, Zhao Y, Mei L
Stage I lung adenocarcinoma: the value of quantitative CT in differentiating pathological subtypes and predicting growth of subsolid nodules.
Medicine (Baltimore). 2017; 96(16):e6595 [PubMed] Free Access to Full Article Related Publications
The aim of this study was to investigate feasibility of quantitative computed tomography (CT) measurements in predicting invasiveness and growth of nodular ground glass opacities (nGGOs).A set of 203 patients (group A) with nGGOs that were confirmed stage-I adenocarcinomas and 79 patients (group B) with nGGOs that were completely followed up were included. Lesions diameters, volume (VOL), maximum (MAX), mean (MEN), and standard deviation (STD) of CT attenuation were measured. P53 labeling index (LI) was evaluated through immunohistochemistry in group-A patients. Multivariate linear stepwise regressions were performed based on group-A lesions to calculate P53-LI prediction from CT measurements. The receiver operating characteristic (ROC) curve analyses were performed to assess the performance of P53-LI prediction in predicting invasiveness and growth of nGGOs. The Cox regression analysis was conducted to identify correlation between P53-LI Prediction and volume doubling time (VDT) of lesions in group B.Diameter, VOL, MEN, STD, and the P53 LI showed significant differences between lesions of different pathological invasiveness (P < .01). By multivariate linear regressions, MEN and STD were identified as independent variables indicating P53 LI (P < .001); thus, an equation was established to calculate P53-LI Prediction as: P53LI Prediction = 0.013 ×  MEN + 0.024 × STD + 9.741 (R square = 0.411, P < .001). The P53-LI Prediction showed good performance, similar as the actual one, in differentiating pathological invasiveness of nGGOs. In addition, the P53-LI Prediction demonstrated excellent performance in predicting growth of nGGOs (AUC = 0.833, P < .001) and independently forecasted VDT of nGGOs (β = 1.773, P < .001).The P53-LI Prediction that was calculated from preoperative quantitative CT measurements of nGGOs indicates lesions' invasiveness and allows for predicting growth of nGGOs.

Miller CR, Ruppert AS, Fobare S, et al.
The long noncoding RNA, treRNA, decreases DNA damage and is associated with poor response to chemotherapy in chronic lymphocytic leukemia.
Oncotarget. 2017; 8(16):25942-25954 [PubMed] Free Access to Full Article Related Publications
The study of long noncoding RNAs (lncRNAs) is an emerging area of cancer research, in part due to their ability to serve as disease biomarkers. However, few studies have investigated lncRNAs in chronic lymphocytic leukemia (CLL). We have identified one particular lncRNA, treRNA, which is overexpressed in CLL B-cells. We measured transcript expression in 144 CLL patient samples and separated samples into high or low expression of treRNA relative to the overall median. We found that high expression of treRNA is significantly associated with shorter time to treatment. High treRNA also correlates with poor prognostic indicators such as unmutated IGHV and high ZAP70 protein expression. We validated these initial findings in samples collected in a clinical trial comparing the nucleoside analog fludarabine alone or in combination with the alkylating agent cyclophosphamide in untreated CLL samples collected prior to starting therapy (E2997). High expression of treRNA was independently prognostic for shorter progression free survival in patients receiving fludarabine plus cyclophosphamide. Given these results, in order to study the role of treRNA in DNA damage response we generated a model cell line system where treRNA was over-expressed in the human B-CLL cell line OSU-CLL. Relative to the vector control line, there was less cell death in OSU-CLL over-expressing treRNA after exposure to fludarabine and mafosfamide, due in part to a reduction in DNA damage. Therefore, we suggest that treRNA is a novel biomarker in CLL associated with aggressive disease and poor response to chemotherapy through enhanced protection against cytotoxic mediated DNA damage.

Witkowska M, Majchrzak A, Cebula-Obrzut B, et al.
The distribution and potential prognostic value of SMAD protein expression in chronic lymphocytic leukemia.
Tumour Biol. 2017; 39(3):1010428317694551 [PubMed] Related Publications
The SMAD proteins are responsible for transducing signals from activated transforming growth factor-beta. This is the first study assessing the expression of SMAD-1/8, SMAD-2/3, SMAD-4, and SMAD-7 in chronic lymphocytic leukemia cells with regard to their clinical significance and potential prognostic value. Overexpression of SMAD-1/8 was observed in 160 chronic lymphocytic leukemia patients compared to 42 healthy volunteers (p = 0.023) and was associated with a more progressive course of the disease (p = 0.016). Moreover, the high expression of SMAD-1/8 correlated with other, well-established prognostic factors, including clinical stage (p = 0.010) and lymphocyte doubling time (p = 0.021). The expression of SMAD-4 was lower in chronic lymphocytic leukemia patients compared with the control group (p = 0.003). Importantly, lower SMAD-4 levels correlated with longer progression-free survival (p = 0.009), progressive course of the disease (p = 0.002), advanced clinical stage (p = 0.0004), elevated beta-2-microglobulin and lactate dehydrogenase levels (p < 0.05), shorter lymphocyte doubling time (p = 0.009), and CD38 antigen expression (p = 0.039). In addition, lower SMAD-4 expression correlated with lower apoptotic index (p = 0.0007) and lower expression of receptors for vascular endothelial growth factors VEGFR-1 and VEGFR-2. A significant association was found between the low expression of inhibitory protein SMAD-7 and both zeta-chain-associated protein kinase 70-negative cells (p = 0.04) and lower apoptotic index (p = 0.004). No differences were observed in SMAD-2/3 expression. In conclusion, our results demonstrate a significant correlation between greater SMAD-1/8 and lower SMAD-4 expression in chronic lymphocytic leukemia cells, as well as more progressive outcome and poor prognosis. These data provide supporting evidence that the expression of SMAD proteins plays an important role in disease development and may be considered as a novel, biologic prognostic factor in this disease.

Gomes LC, Evangelista FCG, Sousa LP, et al.
Prognosis biomarkers evaluation in chronic lymphocytic leukemia.
Hematol Oncol Stem Cell Ther. 2017; 10(2):57-62 [PubMed] Related Publications
OBJECTIVE/BACKGROUND: From clinical and biological points of view, chronic lymphocytic leukemia (CLL) is a heterogeneous disease characterized by a progressive accumulation of lymphocytes in the peripheral blood, bone marrow, and lymphoid organs. New prognostic markers in CLL may be useful to clinicians for predicting outcome and in clinical decision-making. The aim of this study was to evaluate the potential prognostic value of the apoptotic/survival-controlling proteins and protein tyrosine kinase ZAP-70 gene expression in CLL patients and control individuals, correlating such findings with patients' clinical data.
METHODS: Fifty-three patients diagnosed with CLL attending the hematology service of a clinical hospital, and 24 healthy individuals with no history of leukemia (Control group) were enrolled in this study. Analyses of apoptotic/survival-controlling proteins were performed by western blot and ZAP-70 gene expression was evaluated by real-time polymerase chain reaction.
RESULTS: Significant differences were observed for the p-p38, Mcl-1 long, and Mcl-1 short proteins when patients were compared with CLL and controls. A positive correlation between the results for Mcl-1 short and Mcl-1 long and lymphocyte count was observed, corroborating the hypothesis of an imbalance between proteins of cell survival pathways/apoptosis in CLL.
CONCLUSION: ZAP-70 gene expression was not detected as a discriminant biomarker in these CLL patients. An imbalance between apoptosis-related proteins was observed in the present study, corroborating the hypothesis of increased survival of lymphocytes in CLL patients.

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