Research IndicatorsGraph generated 31 August 2019 using data from PubMed using criteria.
Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic. Tag cloud generated 31 August, 2019 using data from PubMed, MeSH and CancerIndex
Specific Cancers (5)
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).
OMIM, Johns Hopkin University
Referenced article focusing on the relationship between phenotype and genotype.
International Cancer Genome Consortium.
Summary of gene and mutations by cancer type from ICGC
Cancer Genome Anatomy Project, NCI
COSMIC, Sanger Institute
Somatic mutation information and related details
GEO Profiles, NCBI
Search the gene expression profiles from curated DataSets in the Gene Expression Omnibus (GEO) repository.
Latest Publications: DOK2 (cancer-related)
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
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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.
DNA methylation aberrations have been implicated in acquired resistance to platinum drugs in ovarian cancer. In this study, we elucidated an epigenetic signature associated with platinum drug resensitization that may offer utility in predicting the outcomes of patients who are coadministered a DNA methyltransferase inhibitor. The ovarian cancer specimens we analyzed were derived from a recent clinical trial that compared the responses of patients with recurrent platinum-resistant ovarian cancer who received carboplatin plus the DNA methyltransferase inhibitor guadecitabine or a standard-of-care chemotherapy regimen selected by the treating physician. Tumor biopsies or malignant ascites were collected from patients before treatment (day 1, cycle 1) or after treatment (after 2 cycles) for epigenomic and transcriptomic profiling using the Infinium HumanMethylation450 BeadChip (HM450). We defined 94 gene promoters that were hypomethylated significantly by guadecitabine, with 1,659 genes differentially expressed in pretreatment versus posttreatment tumors. Pathway analysis revealed that the experimental regimen significantly altered immune reactivation and DNA repair pathways. Progression-free survival correlated with baseline expression levels of 1,155 genes involved in 25 networks. In functional investigations in ovarian cancer cells, engineered upregulation of certain signature genes silenced by promoter methylation (
Transgenic mice expressing the tax gene from human T-cell leukemia virus type 1 (HTLV-I) genome developed T-cell leukemia or histiocytic sarcoma after at least 12 months. The transgenic mice showed low expression of the downstream of tyrosine kinase (DOK) family members, DOK1, DOK2 and DOK3, which were recently reported to be tumor suppressor genes. Mice showed low DOK2 expression at 5-6 months of age, before disease onset. The expression of DOK1 and DOK3 was not significantly reduced at any age tested. These results suggest that downregulation of DOK2 by the expression of the viral tax gene is the first step in the development of T-cell leukemia or histiocytic sarcoma.
Deshpande RP, Chandra Sekhar YBVK, Panigrahi M, Babu PPRegion-Specific Dok2 Overexpression Associates with Poor Prognosis in Human Astrocytoma.
Mol Neurobiol. 2018; 55(1):402-408 [PubMed
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Astrocytoma is the most frequent malignancies of the brain. Despite present clinical advancements, median survival time in malignant forms remains poor. Downstream of kinase protein 2 (Dok2) is adaptor protein known to modulate the effect of tyrosine kinase. Previously, Dok2 is shown to be marker of poor prognosis in colorectal and gastric cancer, and reduced levels of Dok2 were reported in lung adenocarcinoma and gastric cancer. The aim of the present study was to evaluate prognostic significance of pDok2 expression in surgically resected astrocytoma tissue samples. In the present study, 47 numbers of tissue samples were collected from patients who underwent surgery for astrocytoma. Temporal lobe epilepsy tissues were used as control. Real-time PCR was used to study transcript expression while protein expression was studied by western blotting and immunohistochemistry. The pDok2 expression was categorized as pDok2 positive and pDok2 negative on the basis of intensity of protein expression. This observation was confirmed by two independent pathologists. Control and few GII tissues were used as reference on account for low expression of pDok2 protein. Basic information of patients as anatomic origin of tumor and follow-up details were retrieved from hospital registry. Kaplan-Meier test was used to analyze the association of pDok2 expression and survival outcome in clinical cases. Real-time PCR signifies pDok2 is overexpressed in high-grade (GIII + GIV) tissue samples compared with low-grade (GII) and control brain tissue samples (p < 0.005). Western blotting and immunohistochemistry analysis signifies overexpression of pDok2 protein expression in tumor tissue samples as compared with control brain tissues. Clinico-pathological analysis reveals 83% of high-grade astrocytoma (GIII + GIV) and 30% of low-grade (GII) tissue samples which were detected with pDok2 expression. Tumor location was found to be predominant at the frontal and temporal lobes. Survival studies underline prognostic importance of pDok2 protein. Median survival of 20 months was reported with patients with positive pDok2 expression (95% CI 0.083 to 0.49). Taken together, pDok2 protein overexpression is associated with poor prognosis in astrocytoma clinical cases and appears to be an attractive target for therapeutic intervention. Noticeable anatomic origin at the frontal and temporal lobe suggests site-specific role of developmental factors in tumor occurrence.
Ohsugi T, Wakamiya M, Morikawa S, Fujita MExpression of DOK1, 2, and 3 genes in HTLV-1-infected T cells.
Acta Virol. 2016; 60(2):211-3 [PubMed
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Human T-cell leukemia virus type 1 (HTLV-1) can cause an aggressive malignancy known as adult T-cell leukemia/lymphoma (ATLL). The Tax protein encoded by the pX region of the HTLV-1 genome appears to be a key element in the early stage of ATLL development. In this study, we examined the expression of the downstream of tyrosine kinase (DOK) family members DOK1, DOK2 and DOK3, recently reported to be tumor suppressors, in HTLV-1-transformed T cells (MT-2 and HUT-102) and TL-Om1 cells derived from ATLL leukemic cells. DOK2 and DOK3 expression was significantly reduced in MT-2, HUT-102, and TL-Om1 cells compared with their expression in uninfected T cells, and the expression of DOK3 was reduced by the induction of Tax expression in T cells.
Agostinelli C, Rizvi H, Paterson J, et al.Intracellular TCR-signaling pathway: novel markers for lymphoma diagnosis and potential therapeutic targets.
Am J Surg Pathol. 2014; 38(10):1349-59 [PubMed
] Related Publications
Despite the immunologic functions of T-cell receptor signaling molecules being extensively investigated, their potential as immunohistochemical markers has been poorly explored. With this background, we evaluated the expression of 5 intracellular proteins-GADS, DOK2, SKAP55, ITK, and PKCα-involved in T-cell receptor signaling in normal and neoplastic hematologic tissue samples, using antibodies raised against fixation-resistant epitopes of the 5 molecules. All 5 antibodies were associated with normal T-cell differentiation. GADS, DOK2, SKAP55, and ITK turned out to be T-cell lineage-specific markers in the setting of lymphoid and myeloid precursor neoplasms but showed differential expression in peripheral T-cell lymphoma (PTCL) subtypes, being detected in PTCL/not otherwise specified (NOS) and angioimmunoblastic T-cell lymphoma but negative in anaplastic large cell lymphoma (ALCL). Peripheral B-cell lymphomas were consistently negative for ITK, with occasional cases showing expression of DOK2 and SKAP55, and a proportion (47%) of hairy cell leukemias were GADS. Notably, PKCα highlighted a defective antigen in both PTCL/NOS (6%) and angioimmunoblastic T-cell lymphoma (10%), mostly negative in ALCL, and was aberrantly expressed in classical Hodgkin lymphoma (65%), Burkitt lymphoma (48%), and plasma cell myeloma (48%). In conclusion, all five molecules evaluated play a role in T-cell differentiation in normal and neoplastic tissues. They can be applied confidently to routine sections contributing primarily to assignment of T-lineage differentiation in the setting of hematopoietic precursor neoplasms (GADS/DOK2/SKAP55/ITK) and for the differential diagnosis between ALCL and PTCL/NOS (GADS/DOK2/SKAP55/ITK) or classical Hodgkin lymphoma (PKCα). Finally, association with specific tumor subtypes may have therapeutic potential.
Somatic mutations in the EGFR proto-oncogene occur in ~15% of human lung adenocarcinomas and the importance of EGFR mutations for the initiation and maintenance of lung cancer is well established from mouse models and cancer therapy trials in human lung cancer patients. Recently, we identified DOK2 as a lung adenocarcinoma tumor suppressor gene. Here we show that genomic loss of DOK2 is associated with EGFR mutations in human lung adenocarcinoma, and we hypothesized that loss of DOK2 might therefore cooperate with EGFR mutations to promote lung tumorigenesis. We tested this hypothesis using genetically engineered mouse models and find that loss of Dok2 in the mouse accelerates lung tumorigenesis initiated by oncogenic EGFR, but not that initiated by mutated Kras. Moreover, we find that DOK2 participates in a negative feedback loop that opposes mutated EGFR; EGFR mutation leads to recruitment of DOK2 to EGFR and DOK2-mediated inhibition of downstream activation of RAS. These data identify DOK2 as a tumor suppressor in EGFR-mutant lung adenocarcinoma.
Maternal obesity is associated with a variety of common diseases in the offspring. One possible underlying mechanism could be maternal obesity induced alterations in DNA methylation. However, this hypothesis is yet to be tested. We performed epigenomic mapping of cord blood among 308 Black mother-infant pairs delivered at term at the Boston Medical Center using the Illumina HumanMethylation27 BeadChip. Linear regression and pathway analyses were conducted to evaluate the associations between DNA methylation levels and prepregnancy maternal BMI (<25, 25-30, ≥30 kg/m(2) ). The methylation levels of 20 CpG sites were associated with maternal BMI at a significance level of P-value <10(-4) in the overall sample, and boys and girls, separately. One CpG site remained statistically significant after correction for multiple comparisons (FDR corrected P-value = 0.04) and was annotated to a potential cancer gene, ZCCHC10. Some of the other CpG site annotated genes appear to be critical to the development of cancers and cardiovascular diseases (i.e., WNT16, C18orf8, ANGPTL2, SAPCD2, ADCY3, PRR16, ERBB2, DOK2, PLAC1). Significant findings from pathway analysis, such as infectious and inflammatory and lipid metabolism pathways, lends support for the potential impact of maternal BMI on the above stated disorders. This study demonstrates that prepregnancy maternal BMI might lead to alterations in offspring DNA methylation in genes relevant to the development of a range of complex chronic diseases, providing evidence of trans-generational influence on disease susceptibility via epigenetic mechanism.
Our goal of this study was to reconstruct a "genome-scale co-expression network" and find important modules in lung adenocarcinoma so that we could identify the genes involved in lung adenocarcinoma. We integrated gene mutation, GWAS, CGH, array-CGH and SNP array data in order to identify important genes and loci in genome-scale. Afterwards, on the basis of the identified genes a co-expression network was reconstructed from the co-expression data. The reconstructed network was named "genome-scale co-expression network". As the next step, 23 key modules were disclosed through clustering. In this study a number of genes have been identified for the first time to be implicated in lung adenocarcinoma by analyzing the modules. The genes EGFR, PIK3CA, TAF15, XIAP, VAPB, Appl1, Rab5a, ARF4, CLPTM1L, SP4, ZNF124, LPP, FOXP1, SOX18, MSX2, NFE2L2, SMARCC1, TRA2B, CBX3, PRPF6, ATP6V1C1, MYBBP1A, MACF1, GRM2, TBXA2R, PRKAR2A, PTK2, PGF and MYO10 are among the genes that belong to modules 1 and 22. All these genes, being implicated in at least one of the phenomena, namely cell survival, proliferation and metastasis, have an over-expression pattern similar to that of EGFR. In few modules, the genes such as CCNA2 (Cyclin A2), CCNB2 (Cyclin B2), CDK1, CDK5, CDC27, CDCA5, CDCA8, ASPM, BUB1, KIF15, KIF2C, NEK2, NUSAP1, PRC1, SMC4, SYCE2, TFDP1, CDC42 and ARHGEF9 are present that play a crucial role in cell cycle progression. In addition to the mentioned genes, there are some other genes (i.e. DLGAP5, BIRC5, PSMD2, Src, TTK, SENP2, PSMD2, DOK2, FUS and etc.) in the modules.
Lum E, Vigliotti M, Banerjee N, et al.Loss of DOK2 induces carboplatin resistance in ovarian cancer via suppression of apoptosis.
Gynecol Oncol. 2013; 130(2):369-76 [PubMed
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OBJECTIVE: Ovarian cancers are highly heterogeneous and while chemotherapy is the preferred treatment many patients are intrinsically resistant or quickly develop resistance. Furthermore, all tumors that recur ultimately become resistant. Recent evidence suggests that epigenetic deregulation may be a key factor in the onset and maintenance of chemoresistance. We set out to identify epigenetically silenced genes that affect chemoresistance.
METHODS: The epigenomes of a total of 45 ovarian samples were analyzed to identify epigenetically altered genes that segregate with platinum response, and further filtered with expression data to identify genes that were suppressed. A tissue culture carboplatin resistance screen was utilized to functionally validate this set of candidate platinum resistance genes.
RESULTS: Our screen correctly identified 19 genes that when suppressed altered the chemoresistance of the cells in culture. Of the genes identified in the screen we further characterized one gene, docking protein 2 (DOK2), an adapter protein downstream of tyrosine kinase, to determine if we could elucidate the mechanism by which it increased resistance. The loss of DOK2 decreased the level of apoptosis in response to carboplatin. Furthermore, in cells with reduced DOK2, the level of anoikis was decreased.
CONCLUSIONS: We have developed a screening methodology that analyzes the epigenome and informatically identifies candidate genes followed by in vitro culture screening of the candidate genes. To validate our screening methodology we further characterized one candidate gene, DOK2, and showed that loss of DOK2 induces chemotherapy resistance by decreasing the level of apoptosis in response to treatment.
INTRODUCTION: Increasing evidence has shown that immune surveillance is compromised in a tumor-promoting microenvironment for patients with non-small cell lung cancer (NSCLC), and can be restored by appropriate chemotherapy.
METHODS: To test this hypothesis, we analyzed microarray gene expression profiles of peripheral blood mononuclear cells from 30 patients with newly-diagnosed advanced stage NSCLC, and 20 age-, sex-, and co-morbidity-matched healthy controls. All the patients received a median of four courses of chemotherapy with cisplatin and gemcitabine for a 28-day cycle as first line treatment.
RESULTS: Sixty-nine differentially expressed genes between the patients and controls, and 59 differentially expressed genes before and after chemotherapy were identified. The IL4 pathway was significantly enriched in both tumor progression and chemotherapy signatures. CXCR4 and IL2RG were down-regulated, while DOK2 and S100A15 were up-regulated in the patients, and expressions of all four genes were partially or totally reversed after chemotherapy. Real-time quantitative RT-PCR for the four up-regulated (S100A15, DOK2) and down-regulated (TLR7, TOP1MT) genes in the patients, and the six up-regulated (TLR7, CRISP3, TOP1MT) and down-regulated (S100A15, DOK2, IL2RG) genes after chemotherapy confirmed the validity of the microarray results. Further immunohistochemical analysis of the paraffin-embedded lung cancer tissues identified strong S100A15 nuclear staining not only in stage IV NSCLC as compared to stage IIIB NSCLC (p = 0.005), but also in patients with stable or progressive disease as compared to those with a partial response (p = 0.032). A high percentage of S100A15 nuclear stained cells (HR 1.028, p = 0.01) was the only independent factor associated with three-year overall mortality.
CONCLUSIONS: Our results suggest a potential role of the IL4 pathway in immune surveillance of advanced stage NSCLC, and immune potentiation of combination chemotherapy. S100A15 may serve as a potential biomarker for tumor staging, and a predictor of poor prognosis in NSCLC.
BACKGROUND: Leukemia is a heterogeneous disease commonly associated with recurrent chromosomal translocations that involve tyrosine kinases including BCR-ABL, TEL-PDGFRB and TEL-JAK2. Most studies on the activated tyrosine kinases have focused on proximal signaling events, but little is known about gene transcription regulated by these fusions.
METHODS: Oligonucleotide microarray was performed to compare mRNA changes attributable to BCR-ABL, TEL-PDGFRB and TEL-JAK2 after 1 week of activation of each fusion in Ba/F3 cell lines. Imatinib was used to control the activation of BCR-ABL and TEL-PDGFRB, and TEL-JAK2-mediated gene expression was examined 1 week after Ba/F3-TEL-JAK2 cells were switched to factor-independent conditions.
RESULTS: Microarray analysis revealed between 800 to 2000 genes induced or suppressed by two-fold or greater by each tyrosine kinase, with a subset of these genes commonly induced or suppressed among the three fusions. Validation by Quantitative PCR confirmed that eight genes (Dok2, Mrvi1, Isg20, Id1, gp49b, Cxcl10, Scinderin, and collagen Vα1(Col5a1)) displayed an overlapping regulation among the three tested fusion proteins. Stat1 and Gbp1 were induced uniquely by TEL-PDGFRB.
CONCLUSIONS: Our results suggest that BCR-ABL, TEL-PDGFRB and TEL-JAK2 regulate distinct and overlapping gene transcription profiles. Many of the genes identified are known to be involved in processes associated with leukemogenesis, including cell migration, proliferation and differentiation. This study offers the basis for further work that could lead to an understanding of the specificity of diseases caused by these three chromosomal translocations.
Miyagaki H, Yamasaki M, Takahashi T, et al.DOK2 as a marker of poor prognosis of patients with gastric adenocarcinoma after curative resection.
Ann Surg Oncol. 2012; 19(5):1560-7 [PubMed
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BACKGROUND: DOK2 is known as the substrate of chmeric p210bcr/abl oncoprotein characterizing chronic myelogenous leukemia with Philadelphia chromosome. Reduced DOK2 expression was recently reported in lung adenocarcinoma, suggesting that this protein acts as a tumor suppressor in solid tumors. The purpose of this study was to determine the significance of DOK2 in gastric cancer.
METHODS: The study subjects were 118 patients who underwent curative surgery for gastric cancer, as well as 7 gastric cancer cell lines. The tissues and cell lines were analyzed for DOK2 gene and protein expressions by histopathology and immunohistochemistry, and also using a microsatellite marker for loss of heterozygosity. Correlation of survival with clinicopathological parameters was investigated by univariate and multivariate analyses.
RESULTS: DOK2 expression was confirmed in the normal gastric mucosa. Considerable differences in the gene expression were noted among the gastric cell lines. Positive DOK2 expression was noted in the noncancerous regions of all pathological specimens, whereas 59 (50.0%) specimens of 118 patients were negatively stained in the tumor. Loss of heterozygosity was observed in 54.5% of DOK2(-) cases. DOK2(-) patients were more likely to develop recurrence than DOK2(+) and showed poorer 5-year overall survival (59.1%) than DOK2(+) (76.4%, P = .0403). Multivariate analysis identified pT (hazard ratio [HR] = 2.748, 95% confidence interval [95% CI] = 1.061-8.927, P = .0361), pN (HR = 2.486, 95% CI = 1.264-4.932, P = .0086), and DOK2(-) (HR = 2.343, 95% CI = 1.211-4.727, P = .0112) as significant and independent determinants of poor survival.
CONCLUSIONS: Our data suggest the potential usefulness of DOK2 as a marker of poor prognosis in patients with gastric cancer after curative resection.
It was originally proposed that tumour suppressor genes (TSGs) act in a recessive manner. Instead, numerous TSGs, including p53 and PTEN, exhibit haplo-insufficiency as a consequence of the dose-dependency of TSG function. Due to the challenges of identifying haplo-insufficient TSGs by human genetics analysis alone, mouse models play a pivotal role in firmly establishing the haplo-insufficiency of a gene, as in the recent identification of DOK2 as a haplo-insufficient lung TSG. In many cases, TSGs exhibit conditional or compound haplo-insufficiency, in which loss of one TSG allele is functionally important only in certain settings or after compound loss of other genes. The 5q deletion syndrome (5q(-) ) is a paradigm of compound haplo-insufficiency and demonstrates the importance of combinatorial interactions to elicit specific phenotypes. These concepts must be integrated into basic science studies to avoid delay in the identification of important TSGs. In the clinical realm, the challenges for molecular pathologists are the development of quantitative measures that can accurately and systematically ascertain the status of haplo-insufficient genes in tumour biopsies, and the use of this information to accurately predict prognosis and response to therapy.
Genome-wide analyses of human lung adenocarcinoma have identified regions of consistent copy-number gain or loss, but in many cases the oncogenes and tumor suppressors presumed to reside in these loci remain to be determined. Here we identify the downstream of tyrosine kinase (Dok) family members Dok1, Dok2 and Dok3 as lung tumor suppressors. Single, double or triple compound loss of these genes in mice results in lung cancer, with penetrance and latency dependent on the number of lost Dok alleles. Cancer development is preceded by an aberrant expansion and signaling profile of alveolar type II cells and bronchioalveolar stem cells. In human lung adenocarcinoma, we identify DOK2 as a target of copy-number loss and mRNA downregulation and find that DOK2 suppresses lung cancer cell proliferation in vitro and in vivo. Given the genomic localization of DOK2, we propose it as an 8p21.3 haploinsufficient human lung tumor suppressor.
Lamkin TJ, Chin V, Yen AAll-trans retinoic acid induces p62DOK1 and p56DOK2 expression which enhances induced differentiation and G0 arrest of HL-60 leukemia cells.
Am J Hematol. 2006; 81(8):603-15 [PubMed
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p62(DOK1) (DOK1) and p56(DOK2) (DOK2) are sequence homologs that act as docking proteins downstream of receptor or nonreceptor tyrosine kinases. Originally identified in chronic myelogenous leukemia cells as a highly phosphorylated substrate for the chimeric p210(bcr-abl) protein, DOK1 was suspected to play a role in leukemogenesis. However, p62(DOK1-/-) fibroblast knockout cells were found to have enhanced MAPK signaling and proliferation due to growth factors, suggesting negative regulatory capabilities for DOK1. The role of DOK1 and DOK2 in leukemogeneis thus is enigmatic. The data in this report show that both the DOK1 and the DOK2 adaptor proteins are constitutively expressed in the myelomonoblastic leukemia cell line, HL-60, and that expression of both proteins is induced by the chemotherapeutic differentiation causing agents, all-trans retinoic acid (atRA) and 1,25-dihydroxyvitamin D3 (VD3). Ectopic expression of either protein enhances atRA- or VD3-induced growth arrest, differentiation, and G(0)/G(1) cell cycle arrest and results in increased ERK1/2 phosphorylation. DOK1 and DOK2 are similarly effective in these capabilities. The data provide evidence that DOK1 and DOK2 proteins have a similar role in regulating cell proliferation and differentiation and are positive regulators of the MAPK signaling pathway in this context.
Wang J, Ni H, Chen L, et al.Preparation and analysis of cSNP chip on hepatocellular carcinoma-related genes.
Hepatobiliary Pancreat Dis Int. 2005; 4(3):398-402 [PubMed
] Related Publications
BACKGROUND: The understanding of cSNPs of cancer-related genes harboring in high frequency loss regions of tumor chromosomes can advance the disclosure of genetic and variant mechanisms of tumorigenesis, and the investigation of cancer susceptibility. In preparing a gene chip for detecting polymorphisms on coding region of genes in hepatocellular carcinoma tissues, some cSNPs are of interest for their potential links with phenotype.
METHODS: The genes harboring in loss regions with high frequency of hepatocellular carcinoma (HCC) were selected, the related information of cSNP sequences was obtained from the SNP database (dbSNP) of the National Center for Biotechnology Information (NCBI). Then appropriate primers and oligonucleotide probes were designed according to the SNP sites, and a gene chip for the detection of SNPs was constructed. The chip included 48 cSNPs of 25 hepatocellular carcinoma-related genes. The PCR products labeled by Dig-dUTP were hybridized with the cSNP chip.
RESULTS: The sensitivity, influence by probe concentration, and reiteration of the chip were detected, with a high sensitivity of 6X10(-3) ng/mul. The signal of hybridization was reduced with a lower concentration of probe. Seven polymorphisms of caspase 9 (rs2308941)C-->T and DOK2(rs2242241) T-->G, 6 of polymorphisms of EGFL3 (rs947345)A -->G, caspase 9 ( rs2308938) C-->G and PHGDH(rs1801955)T-->A, 5 of polymorphisms of E2F2(rs3218170) G-->A,4 of polymorphisms of MUTYH(rs1140507)T-->C and BNIP3L(rs1055806)G-->T, and 1 of polymorphism of TNFRSF1B (rs1061622)T-->G were detected by the chip in the tissues of 10 HCC. Samples of caspase 9 (rs2308941G) and (rs2308941A) were verified by PCR-SSCP and sequencing.
CONCLUSION: The cSNP chip of hepatocellular carcinoma-related genes can accelerate the discovery of polymorphic markers on hepatocellular carcinoma.