AICDA

Gene Summary

Gene:AICDA; activation-induced cytidine deaminase
Aliases: AID, ARP2, CDA2, HIGM2, HEL-S-284
Location:12p13
Summary:This gene encodes a RNA-editing deaminase that is a member of the cytidine deaminase family. The protein is involved in somatic hypermutation, gene conversion, and class-switch recombination of immunoglobulin genes. Defects in this gene are the cause of autosomal recessive hyper-IgM immunodeficiency syndrome type 2 (HIGM2). [provided by RefSeq, Feb 2009]
Databases:OMIM, VEGA, HGNC, Ensembl, GeneCard, Gene
Protein:single-stranded DNA cytosine deaminase
HPRD
Source:NCBIAccessed: 26 August, 2015

Ontology:

What does this gene/protein do?
Show (14)
Pathways:What pathways are this gene/protein implicaed in?
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Cancer Overview

Research Indicators

Publications Per Year (1990-2015)
Graph generated 26 August 2015 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.

  • Genetic Recombination
  • Molecular Sequence Data
  • TNF
  • VDJ Exons
  • Pyrimidines
  • B-Cell Lymphoma
  • Stomach Cancer
  • Transcription
  • Base Sequence
  • Survival Rate
  • Chromosome 12
  • Toll-Like Receptor 2
  • Tumor Markers
  • Cancer Gene Expression Regulation
  • Sequence Homology, Nucleic Acid
  • Virus Activation
  • Young Adult
  • Skin Cancer
  • Splenic Neoplasms
  • Up-Regulation
  • Uracil
  • Cytidine Deaminase
  • Risk Factors
  • alpha-Fetoproteins
  • Somatic Hypermutation, Immunoglobulin
  • Twist Transcription Factor
  • Neoplastic Cell Transformation
  • B-Lymphocytes
  • rho GTP-Binding Proteins
  • Viral Core Proteins
  • RTPCR
  • Immunoglobulin Class Switching
  • Sequence Alignment
  • Chronic Lymphocytic Leukemia
  • p53 Protein
  • Mutation
  • Translocation
  • Xenograft Models
  • Signal Transduction
  • Xeroderma Pigmentosum
Tag cloud generated 26 August, 2015 using data from PubMed, MeSH and CancerIndex

Specific Cancers (4)

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: AICDA (cancer-related)

Yoshizato T, Dumitriu B, Hosokawa K, et al.
Somatic Mutations and Clonal Hematopoiesis in Aplastic Anemia.
N Engl J Med. 2015; 373(1):35-47 [PubMed] Related Publications
BACKGROUND: In patients with acquired aplastic anemia, destruction of hematopoietic cells by the immune system leads to pancytopenia. Patients have a response to immunosuppressive therapy, but myelodysplastic syndromes and acute myeloid leukemia develop in about 15% of the patients, usually many months to years after the diagnosis of aplastic anemia.
METHODS: We performed next-generation sequencing and array-based karyotyping using 668 blood samples obtained from 439 patients with aplastic anemia. We analyzed serial samples obtained from 82 patients.
RESULTS: Somatic mutations in myeloid cancer candidate genes were present in one third of the patients, in a limited number of genes and at low initial variant allele frequency. Clonal hematopoiesis was detected in 47% of the patients, most frequently as acquired mutations. The prevalence of the mutations increased with age, and mutations had an age-related signature. DNMT3A-mutated and ASXL1-mutated clones tended to increase in size over time; the size of BCOR- and BCORL1-mutated and PIGA-mutated clones decreased or remained stable. Mutations in PIGA and BCOR and BCORL1 correlated with a better response to immunosuppressive therapy and longer and a higher rate of overall and progression-free survival; mutations in a subgroup of genes that included DNMT3A and ASXL1 were associated with worse outcomes. However, clonal dynamics were highly variable and might not necessarily have predicted the response to therapy and long-term survival among individual patients.
CONCLUSIONS: Clonal hematopoiesis was prevalent in aplastic anemia. Some mutations were related to clinical outcomes. A highly biased set of mutations is evidence of Darwinian selection in the failed bone marrow environment. The pattern of somatic clones in individual patients over time was variable and frequently unpredictable. (Funded by Grant-in-Aid for Scientific Research and others.).

Bettington ML, Chetty R
Traditional serrated adenoma: an update.
Hum Pathol. 2015; 46(7):933-8 [PubMed] Related Publications
Although recognized 25 years ago, the traditional serrated adenoma (TSA) remains an ongoing source of diagnostic and biologic debate. Recent research has greatly improved our understanding of the morphological and molecular aspects of these polyps. In particular, the recognition of ectopic crypt foci (ECFs) in combination with typical cytology and slitlike serrations improves diagnostic reproducibility. Awareness that many TSAs, particularly BRAF-mutated TSAs, arise in precursor microvesicular hyperplastic polyps and sessile serrated adenomas can aid in making this diagnosis and should not be confused with a sessile serrated adenoma with dysplasia. At a molecular level, TSAs can be divided into 2 groups based on their BRAF or KRAS mutation status. The development of overt cytologic dysplasia is accompanied by TP53 mutation, Wnt pathway activation, and, in some cases, silencing of CDKN2A. Importantly, however, mismatch repair enzyme function is retained. Thus, the TSA is an important precursor of aggressive molecular subtypes of colorectal carcinoma.

Ge YZ, Xu LW, Xu Z, et al.
Expression Profiles and Clinical Significance of MicroRNAs in Papillary Renal Cell Carcinoma: A STROBE-Compliant Observational Study.
Medicine (Baltimore). 2015; 94(16):e767 [PubMed] Related Publications
Papillary renal cell carcinoma (pRCC) is the second most prevalent subtype of kidney cancers. In the current study, we analyzed the global microRNA (miRNA) expression profiles in pRCC, with the aim to evaluate the relationship of miRNA expression with the progression and prognosis of pRCC.A total of 163 treatment-naïve primary pRCC patients were identified from the Cancer Genome Atlas dataset and included in this retrospective observational study. The miRNA expression profiles were graded by tumor-node-metastasis information, and compared between histologic subtypes. Furthermore, the training-validation approach was applied to identify miRNAs of prognostic values, with the aid of Kaplan-Meier survival, and univariate and multivariate Cox regression analyses. Finally, the online DAVID (Database for Annotation, Visualization, and Integrated Discover) program was applied for the pathway enrichment analysis with the target genes of prognosis-associated miRNAs, which were predicted by 3 computational algorithms (PicTar, TargetScan, and Miranda).In the progression-related miRNA profiles, 26 miRNAs were selected for pathologic stage, 28 for pathologic T, 16 for lymph node status, 3 for metastasis status, and 32 for histologic types, respectively. In the training stage, the expression levels of 12 miRNAs (mir-134, mir-379, mir-127, mir-452, mir-199a, mir-200c, mir-141, mir-3074, mir-1468, mir-181c, mir-1180, and mir-34a) were significantly associated with patient survival, whereas mir-200c, mir-127, mir-34a, and mir-181c were identified by multivariate Cox regression analyses as potential independent prognostic factors in pRCC. Subsequently, mir-200c, mir-127, and mir-34a were confirmed to be significantly correlated with patient survival in the validation stage. Finally, target gene prediction analysis identified a total of 113 target genes for mir-200c, 37 for mir-127, and 180 for mir-34a, which further generated 15 molecular pathways.Our results identified the specific miRNAs associated with the progression and aggressiveness of pRCC, and 3 miRNAs (mir-200c, mir-127, and mir-34a) as promising prognostic factors of pRCC.

Berget E, Molven A, Løkeland T, et al.
IGHV gene usage and mutational status in follicular lymphoma: Correlations with prognosis and patient age.
Leuk Res. 2015; 39(7):702-8 [PubMed] Related Publications
Follicular lymphoma (FL) is a heterogeneous disease with some patients developing progressively or transformed disease early, whereas others follow an indolent clinical course. We evaluated the prognostic value of immunoglobulin heavy chain variable (IGHV) gene usage and mutational status in FL patients. One hundred and four IGH sequences were obtained in tumour samples from 99 patients. The IGHV3 subgroup had the highest usage frequency (57.7%) with IGHV3-23 being the most common sequence. Patients with the IGHV5 subgroup or IGHV sequences from more than one subgroup had significantly less favourable prognosis with an estimated 5-year survival of 62.5 and 50.0%, respectively, as compared with a 5-year survival of 95.1% for patients with other IGHV subgroups (P=0.013 and P<0.001, log-rank). The poor survival associated with IGHV5 or >1 IGHV subgroup usage was an independent prognostic factor in Cox multivariate analysis (P=0.005). IGHV genes were unmutated showing >98% homology in 15.2% of cases. Contrasting the situation in chronic lymphocytic leukaemia (CLL), the presence of unmutated sequences did not yield prognostic information, although unmutated sequences were associated with age at diagnosis >60 years (P=0.022, Fisher's exact). In conclusion, our results indicate that analysis of IGHV gene usage might aid in predicting prognosis for FL patients.

Choi CH, Chung JY, Park HS, et al.
Pancreatic adenocarcinoma up-regulated factor expression is associated with disease-specific survival in cervical cancer patients.
Hum Pathol. 2015; 46(6):884-93 [PubMed] Related Publications
Pancreatic adenocarcinoma up-regulated factor (PAUF) is a novel soluble protein involved in tumor development and metastases. This study was to investigate the PAUF expression and its prognostic value in cervical cancer patients. The expression of PAUF was immunohistochemically determined in 345 formalin-fixed, paraffin-embedded cervical cancer tissues and 107 normal cervical epitheliums. Subsequently, its associations with clinicopathological characteristics and patient survival were assessed. PAUF protein was expressed both in cytoplasm and nucleus, and cytoplasmic expression was more frequent in cancers than normal tissues (32% versus 17%, P = .002), and the difference was prominent in glandular cells. Notably, the expression was more frequent in adenocarcinoma than in squamous cell carcinoma (57% versus 25%, respectively; P < .001), and the differential expression was also seen at the messenger RNA level (P = .014). Cox regression analysis showed that the cytoplasmic expression of PAUF protein was independently associated with poor disease-free (hazard ratio = 2.3; 95% confidence interval, 1.2-4.3; P = .008) and overall survival (hazard ratio = 2.9; 95% confidence interval, 1.2-7.5; P = .020). Detection of PAUF expression may aid current evaluation of prognosis in cervical adenocarcinoma.

Reis GF, Pekmezci M, Hansen HM, et al.
CDKN2A loss is associated with shortened overall survival in lower-grade (World Health Organization Grades II-III) astrocytomas.
J Neuropathol Exp Neurol. 2015; 74(5):442-52 [PubMed] Article available free on PMC after 01/05/2016 Related Publications
Lower-grade (World Health Organization Grades II and III) gliomas vary widely in clinical behavior and are classified as astrocytic, oligodendroglial, or mixed. Anaplasia depends greatly on mitotic activity, with CDKN2A loss considered as the most common mechanism for cell cycle dysregulation. We investigated whether loss of the CDKN2A gene is associated with overall survival across pathologically and genetically defined glioma subtypes. After adjustment for IDH mutation, sex, and age, CDKN2A deletion was strongly associated with poorer overall survival in astrocytomas but not in oligodendrogliomas or oligoastrocytomas. Molecular classification of astrocytomas by IDH mutation, TP53 mutation, and /or ATRX loss of expression revealed that CDKN2A loss in IDH/TP53 mutated tumors was strongly associated with worse overall survival. CDKN2A loss in IDH mutated tumors with ATRX loss was only weakly associated with worse overall survival. These findings suggest that CDKN2A testing may provide further clinical aid in lower-grade glioma substratification beyond IDH mutation and 1p19q codeletion status, particularly in IDH/TP53 mutated astrocytomas.

Bhatia P, Deniwar A, Friedlander P, et al.
Diagnostic potential of ancillary molecular testing in differentiation of benign and malignant thyroid nodules.
Anticancer Res. 2015; 35(3):1237-41 [PubMed] Related Publications
Fine needle aspiration (FNA) cytology, being the mainstay to diagnose thyroid nodules, does not provide definitive results in a subset of patients. The use of molecular markers testing has been described as a useful aid in differentiation of thyroid nodules that present with an indeterminate cytodiagnosis. Molecular tests, such as the Afirma gene classifier, mutational assay and immunohistochemical markers have been increasingly used to further increase the accuracy and defer unnecessary surgeries for benign thyroid nodules. However, in light of the current literature, their emerging roles in clinical practice are limited due to financial and technical limitations. Nevertheless, their synergistic implementation can predict the risk of malignancy and yield an accurate diagnosis. This review discusses the clinical utility of various molecular tests done on FNA indeterminate nodules to avoid diagnostic thyroidectomies and warrant the need of future multi-Institutional studies.

Heineman TE, Joshi R, Cohen MA, et al.
In silico analysis of RET variants in medullary thyroid cancer: from the computer to the bedside.
Otolaryngol Head Neck Surg. 2015; 152(4):650-4 [PubMed] Related Publications
OBJECTIVE: The American Thyroid Association (ATA) medullary thyroid cancer (MTC) guidelines group RET variants, in the setting of familial medullary thyroid cancer and multiple endocrine neoplasia type 2, into 4 classes of severity based on epidemiological data. The aim of this study was to determine if genotype correlates with phenotype in RET missense mutations.
STUDY DESIGN: In silico mutational tolerance prediction.
SETTING: Academic research hospital.
SUBJECTS AND METHODS: We analyzed all RET variants currently listed in the ATA guidelines for the management of MTC using 2 computer-based (in silico) mutation tolerance prediction approaches: PolyPhen-2 HumVar and PolyPhen-2 HumDiv. Our analysis also included 27 different RET single-nucleotide polymorphisms resulting in missense variants.
RESULTS: There was a statistically significant difference in the overall HumDiv score between ATA groups A and B (P = .025) and a statistically significant different HumVar score between benign polymorphisms and ATA group A (P = .023). Overall, RET variants associated with a less aggressive clinical phenotype generally had a lower Hum Div/Var score.
CONCLUSIONS: Polyphen-2 Hum Div/Var may provide additional clinical data to help distinguish benign from MEN2/familial medullary thyroid carcinoma-causing RET variants as well as less aggressive phenotypes (ATA A) from more aggressive ones (ATA B-C). In silico genetic analyses, with proper validation, may predict the phenotypic severity of RET variants, providing clinicians with a tool to aid clinical decision making in cases in which the RET variant is currently unknown or little epidemiological data are available.

Cescon DW, Haibe-Kains B, Mak TW
APOBEC3B expression in breast cancer reflects cellular proliferation, while a deletion polymorphism is associated with immune activation.
Proc Natl Acad Sci U S A. 2015; 112(9):2841-6 [PubMed] Article available free on PMC after 01/05/2016 Related Publications
Genomic sequencing studies of breast and other cancers have identified patterns of mutations that have been attributed to the endogenous mutator activity of APOBEC3B (A3B), a member of the AID/APOBEC family of cytidine deaminases. A3B gene expression is increased in many cancers, but its upstream drivers remain undefined. Furthermore, there exists a common germ-line deletion polymorphism (A3B(del)), which has been associated with a paradoxical increase in breast cancer risk. To examine causes and consequences of A3B expression and its constitutive absence in breast cancer, we analyzed two large clinically annotated genomic datasets [The Cancer Genome Atlas (TCGA) and the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC)]. We confirmed that A3B expression is associated with aggressive clinicopathologic characteristics and adverse outcomes and show that A3B expression is highly correlated with proliferative features (mitosis and cell cycle-related gene expression) in breast and 15 of 16 other solid tumor types. However, breast cancers arising in homozygous A3B(del) individuals with A3B absent did not differ in these features, indicating that A3B expression is a reflection rather than a direct cause of increased proliferation. Using gene set enrichment analysis (GSEA), we detected a pattern of immune activation in A3B(del) breast cancers, which seems to be related to hypermutation arising in A3B(del) carriers. Together, these results provide an explanation for A3B overexpression and its prognostic effect, giving context to additional study of this mutator as a cancer biomarker or putative drug target. In addition, although immune features of A3B(del) require additional study, these findings nominate the A3B(del) polymorphism as a potential predictor for cancer immunotherapy.

Hershkovitz-Rokah O, Modai S, Pasmanik-Chor M, et al.
Restoration of miR-424 suppresses BCR-ABL activity and sensitizes CML cells to imatinib treatment.
Cancer Lett. 2015; 360(2):245-56 [PubMed] Related Publications
MicroRNAs (miRNAs) are small noncoding RNAs that participate in many biological processes by posttranscriptionally regulating gene expression. Dysregulation of miRNA expression has been shown to be typical of many neoplasms. Chronic myeloid leukemia (CML) is a disorder of hematopoietic stem cells carrying the Philadelphia (Ph) chromosome and an oncogenic BCR-ABL tyrosine kinase fusion gene. While the development of tyrosine kinase inhibitors (TKIs) like imatinib has revolutionized treatment of CML, it has become increasingly clear in recent years that TKI treatment alone will not be curative in many cases. Thus, further dissection of the regulatory networks that drive BCR-ABL-induced malignant transformation may help to identify other novel therapeutic approaches that complement TKI treatment. In this study we demonstrate that the expression of miR-424 is markedly low in CML cell lines and patient samples at time of diagnosis. With the aid of bioinformatics analysis we revealed a conserved target site for miR-424 in the 3'-untranslated region (UTR) of the ABL gene. Via luciferase assays, we showed that miR-424 directly targets BCR-ABL. Overexpression of miR-424 was shown to suppress proliferation and induce apoptosis of K562 cells as well as sensitize these cells to imatinib treatment. These findings strongly suggest that miR-424 acts as a tumor suppressor by downregulating BCR-ABL expression. Up-regulation of miR-424 in CML cells may therefore have a therapeutic effect against this disease.

Hsu L, Jeon J, Brenner H, et al.
A model to determine colorectal cancer risk using common genetic susceptibility loci.
Gastroenterology. 2015; 148(7):1330-9.e14 [PubMed] Article available free on PMC after 01/06/2016 Related Publications
BACKGROUND & AIMS: Risk for colorectal cancer (CRC) can be greatly reduced through screening. To aid in the development of screening strategies, we refined models designed to determine risk of CRC by incorporating information from common genetic susceptibility loci.
METHODS: By using data collected from more than 12,000 participants in 6 studies performed from 1990 through 2011 in the United States and Germany, we developed risk determination models based on sex, age, family history, genetic risk score (number of risk alleles carried at 27 validated common CRC susceptibility loci), and history of endoscopic examinations. The model was validated using data collected from approximately 1800 participants in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial, conducted from 1993 through 2001 in the United States.
RESULTS: We identified a CRC genetic risk score that independently predicted which patients in the training set would develop CRC. Compared with determination of risk based only on family history, adding the genetic risk score increased the discriminatory accuracy from 0.51 to 0.59 (P = .0028) for men and from 0.52 to 0.56 (P = .14) for women. We calculated age- and sex-specific 10-year CRC absolute risk estimates based on the number of risk alleles, family history, and history of endoscopic examinations. A model that included a genetic risk score better determined the recommended starting age for screening in subjects with and without family histories of CRC. The starting age for high-risk men (family history of CRC and genetic risk score, 90%) was 42 years, and for low-risk men (no family history of CRC and genetic risk score, 10%) was 52 years. For men with no family history and a high genetic risk score (90%), the starting age would be 47 years; this is an intermediate value that is 5 years earlier than it would be for men with a genetic risk score of 10%. Similar trends were observed in women.
CONCLUSIONS: By incorporating information on CRC risk alleles, we created a model to determine the risk for CRC more accurately. This model might be used to develop screening and prevention strategies.

Puls F, Niblett A, Clarke J, et al.
YAP1-TFE3 epithelioid hemangioendothelioma: a case without vasoformation and a new transcript variant.
Virchows Arch. 2015; 466(4):473-8 [PubMed] Related Publications
Epithelioid hemangioendothelioma is a rare vascular tumor of borderline malignancy characterized by recurrent WWTR1-CAMTA1 gene fusions in approximately 90 % of cases. In addition, a recurrent YAP1-TFE3 gene fusion has been identified in WWTR1-CAMTA1 negative epithelioid hemangioendotheliomas. This subset has been reported as having a distinct morphology with more obvious vasoformation, voluminous eosinophilic cytoplasm, and TFE3 positivity on immunohistochemistry. We report a case of a YAP1-TFE3 translocated epithelioid hemangioendothelioma arising in a groin lymph node in a 29-year-old male. Plump spindle cell morphology and absence of vasoformation made correct diagnosis particularly difficult. Immunohistochemistry showed nuclear positivity for both ERG and TFE3, fluorescence in situ hybridization showed break apart for TFE3 and RT-PCR identified a YAP1 exon1 to TFE3 exon 6 transcript, a previously unreported fusion variant. Awareness of this solid morphology and variant fusion will aid in identification of future cases of this rare vascular tumor.

Kitamura J, Uemura M, Kurozumi M, et al.
Chronic lung injury by constitutive expression of activation-induced cytidine deaminase leads to focal mucous cell metaplasia and cancer.
PLoS One. 2015; 10(2):e0117986 [PubMed] Article available free on PMC after 01/06/2016 Related Publications
Activation-induced cytidine deaminase (AID) is an enzyme required for antibody diversification, and it causes DNA mutations and strand breaks. Constitutive AID expression in mice invariably caused lung lesions morphologically similar to human atypical adenomatous hyperplasia (AAH), which can be a precursor of bronchioloalveolar carcinoma. Similar to AAH, mouse AAH-like lesion (MALL) exhibited signs of alveolar differentiation, judging from the expression of alveolar type II (AT2) cell marker surfactant protein C (SP-C). However, electron microscopy indicated that MALL, which possessed certain features of a mucous cell, is distinct from an AAH or AT2 cell. Although MALL developed in all individuals within 30 weeks after birth, lung tumors occurred in only 10%; this suggests that the vast majority of MALLs fail to grow into visible tumors. MALL expressed several recently described markers of lung alveolar regeneration such as p63, keratin 5, keratin 14, leucine-rich repeat containing G protein-coupled receptor 5 (Lgr5), and Lgr6. Increased cell death was observed in the lungs of AID transgenic mice compared with wild-type mice. Based on these observations, we speculate that MALL is a regenerating tissue compensating for cellular loss caused by AID cytotoxicity. AID expression in such regenerating tissue should predispose cells to malignant transformation via its mutagenic activity.

Russo A, Okur MN, Bosland M, O'Bryan JP
Phosphatidylinositol 3-kinase, class 2 beta (PI3KC2β) isoform contributes to neuroblastoma tumorigenesis.
Cancer Lett. 2015; 359(2):262-8 [PubMed] Article available free on PMC after 10/04/2016 Related Publications
Phosphatidylinositol 3-kinases (PI3Ks) play important roles in human tumorigenesis. Activation of the PI3K target AKT is frequent in neuroblastoma (NB) and correlates with poor prognosis. PI3K pan-inhibitors reduce NB tumor formation but present severe toxicity, which limits their therapeutic potential. Therefore, defining the importance of specific PI3K isoforms may aid in developing more effective therapeutic strategies. We previously demonstrated that PI3K Class IIβ (PI3KC2β) and its regulator intersectin 1 (ITSN1) are highly expressed in primary NB tumors and cell lines. Silencing ITSN1 dramatically reduced the tumorigenic potential of NB cells. Interestingly, overexpression of PI3KC2β rescued the anchorage-independent growth of ITSN1-silenced cells suggesting that PI3KC2β mediates ITSN1's function in NB cells. To address the importance of PI3KC2β in NBs, we generated PI3KC2β-silenced lines and examined their biologic activity. Herein, we demonstrate that PI3KC2β-silencing inhibits early stages of NB tumorigenic growth. We also show that loss of endogenous PI3KC2β or ITSN1 reduces AKT activation but does not impact ERK-MAPK activation. These data reveal a novel role for PI3KC2β in human NB tumorigenesis.

Wu Q, Ni X
ROS-mediated DNA methylation pattern alterations in carcinogenesis.
Curr Drug Targets. 2015; 16(1):13-9 [PubMed] Related Publications
Elevated levels of both reactive oxygen species (ROS) and DNA methylation are characteristic of various types of cancer cells. However, the relation between these two is not well understood. Here we will discuss the cause-consequence relationship between ROS and DNA methylation. Cancer research reveals that disregulation of DNA methylation results in regional CpG island hypermethylation and generalized genomic hypomethylation. ROS-induced oxidative stress is associated with both aberrant hypermethylation of tumor suppressor gene (TSG) promoter regions and global hypomethylation. The DNA oxidation structure, 8-hydroxy-2'-deoxyguanosine (8-OHdG), can induce DNA hypomethylation by inhibiting DNA methylation at nearby cytosine bases, while another DNA oxidation structure, 5-hydroxymethylcytosine (5hmC), may achieve active DNA demethylation processes, thus, causing DNA hypomethylation. Recently, it has been found that ROS can function as catalysts of DNA methylation, further accounting for TSG promoter hypermethylation. Moreover, ROS may induce site-specific hypermethylation via either the up-regulation of expression of DNA methyltransferases (DNMTs) or the formation of a new DNMT containing complex. In addition, these ROS-induced DNA methylation pattern alterations have been implicated with not only malignant transformation, but also the progression of numerous tumors. In conclusion, ROS can influence both aspects of DNA methylation changes through different mechanisms, which play an important role of epigenetic regulation in cancer cells. Therefore, the comprehension of mechanisms leading to epigenetic modifications associated with ROS may help better understand the carcinogenesis and progression, as well as aid in the development of potential biomarkers for better cancer diagnostics and novel therapeutic strategies.

Yang W, Yoshigoe K, Qin X, et al.
Identification of genes and pathways involved in kidney renal clear cell carcinoma.
BMC Bioinformatics. 2014; 15 Suppl 17:S2 [PubMed] Article available free on PMC after 10/04/2016 Related Publications
BACKGROUND: Kidney Renal Clear Cell Carcinoma (KIRC) is one of fatal genitourinary diseases and accounts for most malignant kidney tumours. KIRC has been shown resistance to radiotherapy and chemotherapy. Like many types of cancers, there is no curative treatment for metastatic KIRC. Using advanced sequencing technologies, The Cancer Genome Atlas (TCGA) project of NIH/NCI-NHGRI has produced large-scale sequencing data, which provide unprecedented opportunities to reveal new molecular mechanisms of cancer. We combined differentially expressed genes, pathways and network analyses to gain new insights into the underlying molecular mechanisms of the disease development.
RESULTS: Followed by the experimental design for obtaining significant genes and pathways, comprehensive analysis of 537 KIRC patients' sequencing data provided by TCGA was performed. Differentially expressed genes were obtained from the RNA-Seq data. Pathway and network analyses were performed. We identified 186 differentially expressed genes with significant p-value and large fold changes (P < 0.01, |log(FC)| > 5). The study not only confirmed a number of identified differentially expressed genes in literature reports, but also provided new findings. We performed hierarchical clustering analysis utilizing the whole genome-wide gene expressions and differentially expressed genes that were identified in this study. We revealed distinct groups of differentially expressed genes that can aid to the identification of subtypes of the cancer. The hierarchical clustering analysis based on gene expression profile and differentially expressed genes suggested four subtypes of the cancer. We found enriched distinct Gene Ontology (GO) terms associated with these groups of genes. Based on these findings, we built a support vector machine based supervised-learning classifier to predict unknown samples, and the classifier achieved high accuracy and robust classification results. In addition, we identified a number of pathways (P < 0.04) that were significantly influenced by the disease. We found that some of the identified pathways have been implicated in cancers from literatures, while others have not been reported in the cancer before. The network analysis leads to the identification of significantly disrupted pathways and associated genes involved in the disease development. Furthermore, this study can provide a viable alternative in identifying effective drug targets.
CONCLUSIONS: Our study identified a set of differentially expressed genes and pathways in kidney renal clear cell carcinoma, and represents a comprehensive computational approach to analysis large-scale next-generation sequencing data. The pathway and network analyses suggested that information from distinctly expressed genes can be utilized in the identification of aberrant upstream regulators. Identification of distinctly expressed genes and altered pathways are important in effective biomarker identification for early cancer diagnosis and treatment planning. Combining differentially expressed genes with pathway and network analyses using intelligent computational approaches provide an unprecedented opportunity to identify upstream disease causal genes and effective drug targets.

Liu H, Lin F
Application of immunohistochemistry in thyroid pathology.
Arch Pathol Lab Med. 2015; 139(1):67-82 [PubMed] Related Publications
CONTEXT: Accurate classification of follicular-patterned thyroid lesions is not always an easy task on routine surgical hematoxylin-eosin-stained or cytologic fine-needle aspiration specimens. The diagnostic challenges are partially due to differential diagnostic criteria that are often subtle and subjective. In the past decades, tremendous advances have been made in molecular gene profiling of tumors and diagnostic immunohistochemistry, aiding in diagnostic accuracy and proper patient management.
OBJECTIVE: To evaluate the diagnostic utility of the most commonly studied immunomarkers in the field of thyroid pathology by review of the literature, using the database of indexed articles in PubMed (US National Library of Medicine) from 1976-2013.
DATA SOURCES: Literature review, authors' research data, and personal practice experience.
CONCLUSIONS: The appropriate use of immunohistochemistry by applying a panel of immunomarkers and using a standardized technical and interpretational method may complement the morphologic assessment and aid in the accurate classification of difficult thyroid lesions.

Miremami J, Kyprianou N
The promise of novel molecular markers in bladder cancer.
Int J Mol Sci. 2014; 15(12):23897-908 [PubMed] Article available free on PMC after 10/04/2016 Related Publications
Bladder cancer is the fourth most common malignancy in the US and is associated with the highest cost per patient. A high likelihood of recurrence, mandating stringent surveillance protocols, has made the development of urinary markers a focus of intense pursuit with the hope of decreasing the burden this disease places on patients and the healthcare system. To date, routine use of markers is not recommended for screening or diagnosis. Interests include the development of a single urinary marker that can be used in place of or as an adjunct to current screening and surveillance techniques, as well identifying a molecular signature for an individual's disease that can help predict progression, prognosis, and potential therapeutic response. Markers have shown potential value in improving diagnostic accuracy when used as an adjunct to current modalities, risk-stratification of patients that could aid the clinician in determining aggressiveness of surveillance, and allowing for a decrease in invasive surveillance procedures. This review discusses the current understanding of emerging biomarkers, including miRNAs, gene signatures and detection of circulating tumor cells in the blood, and their potential clinical value in bladder cancer diagnosis, as prognostic indicators, and surveillance tools, as well as limitations to their incorporation into medical practice.

Foster JG, Wong SC, Sharp TV
The hypoxic tumor microenvironment: driving the tumorigenesis of non-small-cell lung cancer.
Future Oncol. 2014; 10(16):2659-74 [PubMed] Related Publications
Since the application of molecular biology in cancer biology, lung cancer research has classically focused on molecular drivers of disease. One such pathway, the hypoxic response pathway, is activated by reduced local oxygen concentrations at the tumor site. Hypoxia-driven gene and protein changes enhance epithelial-to-mesenchymal transition, remodel the extracellular matrix, drive drug resistance, support cancer stem cells and aid evasion from immune cells. However, it is not the tumor cells alone which drive this response to hypoxia, but rather their interaction with a complex milieu of supporting cells. This review will focus on recent advances in our understanding of how these cells contribute to the tumor response to hypoxia in non-small-cell lung cancer.

Holmes TD, Wilson EB, Black EV, et al.
Licensed human natural killer cells aid dendritic cell maturation via TNFSF14/LIGHT.
Proc Natl Acad Sci U S A. 2014; 111(52):E5688-96 [PubMed] Article available free on PMC after 10/04/2016 Related Publications
Interactions between natural killer (NK) cells and dendritic cells (DCs) aid DC maturation and promote T-cell responses. Here, we have analyzed the response of human NK cells to tumor cells, and we identify a pathway by which NK-DC interactions occur. Gene expression profiling of tumor-responsive NK cells identified the very rapid induction of TNF superfamily member 14 [TNFSF14; also known as homologous to lymphotoxins, exhibits inducible expression, and competes with HSV glycoprotein D for HVEM, a receptor expressed by T lymphocytes (LIGHT)], a cytokine implicated in the enhancement of antitumor responses. TNFSF14 protein expression was induced by three primary mechanisms of NK cell activation, namely, via the engagement of CD16, by the synergistic activity of multiple target cell-sensing NK-cell activation receptors, and by the cytokines IL-2 and IL-15. For antitumor responses, TNFSF14 was preferentially produced by the licensed NK-cell population, defined by the expression of inhibitory receptors specific for self-MHC class I molecules. In contrast, IL-2 and IL-15 treatment induced TNFSF14 production by both licensed and unlicensed NK cells, reflecting the ability of proinflammatory conditions to override the licensing mechanism. Importantly, both tumor- and cytokine-activated NK cells induced DC maturation in a TNFSF14-dependent manner. The coupling of TNFSF14 production to tumor-sensing NK-cell activation receptors links the tumor immune surveillance function of NK cells to DC maturation and adaptive immunity. Furthermore, regulation by NK cell licensing helps to safeguard against TNFSF14 production in response to healthy tissues.

Samarasinghe S, Chaiboonchoe A
Neural networks and Fuzzy clustering methods for assessing the efficacy of microarray based intrinsic gene signatures in breast cancer classification and the character and relations of identified subtypes.
Methods Mol Biol. 2015; 1260:285-317 [PubMed] Related Publications
In the classification of breast cancer subtypes using microarray data, hierarchical clustering is commonly used. Although this form of clustering shows basic cluster patterns, more needs to be done to investigate the accuracy of clusters as well as to extract meaningful cluster characteristics and their relations to increase our confidence in their use in a clinical setting. In this study, an in-depth investigation of the efficacy of three reported gene subsets in distinguishing breast cancer subtypes was performed using four advanced computational intelligence methods-Self-Organizing Maps (SOM), Emergent Self-Organizing Maps (ESOM), Fuzzy Clustering by Local Approximation of Memberships (FLAME), and Fuzzy C-means (FCM)-each differing in the way they view data in terms of distance measures and fuzzy or crisp clustering. The gene subsets consisted of 71, 93, and 71 genes reported in the literature from three comprehensive experimental studies for distinguishing Luminal (A and B), Basal, Normal breast-like, and HER2 subtypes. Given the costly procedures involved in clinical studies, the proposed 93-gene set can be used for preliminary classification of breast cancer. Then, as a decision aid, SOM can be used to map the gene signature of a new patient to locate them with respect to all subtypes to get a comprehensive view of the classification. These can be followed by a deeper investigation in the light of the observations made in this study regarding overlapping subtypes. Results from the study could be used as the base for further refining the gene signatures from later experiments and from new experiments designed to separate overlapping clusters as well as to maximally separate all clusters.

King-Spohn K, Pilarski R
Beyond BRCA1 and BRCA2.
Curr Probl Cancer. 2014 Nov-Dec; 38(6):235-48 [PubMed] Related Publications
A hereditary breast cancer syndrome can present in a variety of ways ranging from an index case of early-onset breast cancer to an incidental finding during an endoscopy or a dermatological examination. A comprehensive review of the patient’s personal and family history is essential to accurately assess the risk for a hereditary cancer syndrome. Clinicians should be aware of the wide variety of hereditary breast cancer syndromes beyond BRCA1 and BRCA2-associated HBOC. Failure to identify a rare hereditary breast cancer syndrome can lead to additional cancer diagnoses in the patient or relatives that might have been prevented with appropriately aggressive management and screening. Effective identification and management of patients with a hereditary breast cancer syndrome requires a team approach. The use of cancer gene panels, although they can be beneficial in many cases, may also reveal incidental information, unexpected diagnoses, and inconclusive findings. Patients should be offered comprehensive counseling about the potential impact of this type of genetic testing before deciding to pursue a gene panel test. This counseling should include information about the numerous genetic syndromes analyzed. When performed in the context of thorough pretest and posttest counseling, genetic testing is a powerful tool that can aid the patient, his or her family members, and their physicians in making appropriate medical management decisions.

Kumar A, Rao A, Bhavani S, et al.
Automated analysis of immunohistochemistry images identifies candidate location biomarkers for cancers.
Proc Natl Acad Sci U S A. 2014; 111(51):18249-54 [PubMed] Article available free on PMC after 10/04/2016 Related Publications
Molecular biomarkers are changes measured in biological samples that reflect disease states. Such markers can help clinicians identify types of cancer or stages of progression, and they can guide in tailoring specific therapies. Many efforts to identify biomarkers consider genes that mutate between normal and cancerous tissues or changes in protein or RNA expression levels. Here we define location biomarkers, proteins that undergo changes in subcellular location that are indicative of disease. To discover such biomarkers, we have developed an automated pipeline to compare the subcellular location of proteins between two sets of immunohistochemistry images. We used the pipeline to compare images of healthy and tumor tissue from the Human Protein Atlas, ranking hundreds of proteins in breast, liver, prostate, and bladder based on how much their location was estimated to have changed. The performance of the system was evaluated by determining whether proteins previously known to change location in tumors were ranked highly. We present a number of candidate location biomarkers for each tissue, and identify biochemical pathways that are enriched in proteins that change location. The analysis technology is anticipated to be useful not only for discovering new location biomarkers but also for enabling automated analysis of biomarker distributions as an aid to determining diagnosis.

Pettersen HS, Galashevskaya A, Doseth B, et al.
AID expression in B-cell lymphomas causes accumulation of genomic uracil and a distinct AID mutational signature.
DNA Repair (Amst). 2015; 25:60-71 [PubMed] Related Publications
The most common mutations in cancer are C to T transitions, but their origin has remained elusive. Recently, mutational signatures of APOBEC-family cytosine deaminases were identified in many common cancers, suggesting off-target deamination of cytosine to uracil as a common mutagenic mechanism. Here we present evidence from mass spectrometric quantitation of deoxyuridine in DNA that shows significantly higher genomic uracil content in B-cell lymphoma cell lines compared to non-lymphoma cancer cell lines and normal circulating lymphocytes. The genomic uracil levels were highly correlated with AID mRNA and protein expression, but not with expression of other APOBECs. Accordingly, AID knockdown significantly reduced genomic uracil content. B-cells stimulated to express endogenous AID and undergo class switch recombination displayed a several-fold increase in total genomic uracil, indicating that B cells may undergo widespread cytosine deamination after stimulation. In line with this, we found that clustered mutations (kataegis) in lymphoma and chronic lymphocytic leukemia predominantly carry AID-hotspot mutational signatures. Moreover, we observed an inverse correlation of genomic uracil with uracil excision activity and expression of the uracil-DNA glycosylases UNG and SMUG1. In conclusion, AID-induced mutagenic U:G mismatches in DNA may be a fundamental and common cause of mutations in B-cell malignancies.

Tothill RW, Shi F, Paiman L, et al.
Development and validation of a gene expression tumour classifier for cancer of unknown primary.
Pathology. 2015; 47(1):7-12 [PubMed] Related Publications
Accurate identification of the primary tumour in cancer of unknown primary (CUP) is required for effective treatment selection and improved patient outcomes. The aim of this study was to develop and validate a gene expression tumour classifier and integrate it with histopathology to identify the likely site of origin in CUP.RNA was extracted from 450 formalin fixed, paraffin embedded samples of known origin comprising 18 tumour groups. Whole genome expression analysis was performed using a bead-based array. Classification of the tumours made use of a binary support vector machine, together with recursive feature elimination. A hierarchical tumour classifier was developed and incorporated with conventional histopathology to identify the origins of metastatic tumours.The classifier demonstrated an accuracy of 88% for correctly predicting the tumour type on a validation set of known tumours (n = 94). For CUP samples (n = 49) having a final clinical diagnosis, the classifier improved the accuracy of histology alone for both single and multiple predictions. Furthermore, where histology alone could not suggest any specific diagnosis, the classifier was able to correctly predict the primary site of origin.We demonstrate the integration of gene expression profiling with conventional histopathology to aid the investigation of CUP.

Qian J, Wang Q, Dose M, et al.
B cell super-enhancers and regulatory clusters recruit AID tumorigenic activity.
Cell. 2014; 159(7):1524-37 [PubMed] Article available free on PMC after 18/12/2015 Related Publications
The antibody gene mutator activation-induced cytidine deaminase (AID) promiscuously damages oncogenes, leading to chromosomal translocations and tumorigenesis. Why nonimmunoglobulin loci are susceptible to AID activity is unknown. Here, we study AID-mediated lesions in the context of nuclear architecture and the B cell regulome. We show that AID targets are not randomly distributed across the genome but are predominantly grouped within super-enhancers and regulatory clusters. Unexpectedly, in these domains, AID deaminates active promoters and eRNA(+) enhancers interconnected in some instances over megabases of linear chromatin. Using genome editing, we demonstrate that 3D-linked targets cooperate to recruit AID-mediated breaks. Furthermore, a comparison of hypermutation in mouse B cells, AID-induced kataegis in human lymphomas, and translocations in MEFs reveals that AID damages different genes in different cell types. Yet, in all cases, the targets are predominantly associated with topological complex, highly transcribed super-enhancers, demonstrating that these compartments are key mediators of AID recruitment.

Kohashi K, Yamada Y, Hotokebuchi Y, et al.
ERG and SALL4 expressions in SMARCB1/INI1-deficient tumors: a useful tool for distinguishing epithelioid sarcoma from malignant rhabdoid tumor.
Hum Pathol. 2015; 46(2):225-30 [PubMed] Related Publications
ERG is immunoexpressed in vascular endothelial tumors, blastic extramedullary myeloid tumors, and tumors with ERG-involved translocation, such as prostate carcinoma or Ewing sarcoma. Recently, ERG immunoexpression was reported in an epithelioid sarcoma, which is a SMARCB1/INI1-deficient tumor, although epithelioid sarcoma is not associated with chromosomal translocations involving ERG and is categorized as a tumor with uncertain differentiation. SALL4 is essential for a proliferation and stabilization of embryonic stem cells. It was reported that SALL4 expression may aid in distinguishing epithelioid sarcoma from malignant rhabdoid tumor. We analyzed the frequency of ERG and SALL4 expressions in 80 SMARCB1/INI1-deficient tumors, including 45 epithelioid sarcomas (conventional-type, 24; proximal-type, 20), 17 malignant rhabdoid tumors, 5 atypical teratoid/rhabdoid tumors, 6 undifferentiated/unclassified sarcomas, 5 myoepithelial tumors, and 4 extraskeletal myxoid chondrosarcomas. We found that ERG expression was present in 18 of the epithelioid sarcomas (41%), including 13 conventional-type (54%) and 5 proximal-type (25%), whereas all 17 of the malignant rhabdoid tumors exhibited negative immunoreactivity. One atypical teratoid/rhabdoid tumor (20%), 1 myoepithelial carcinoma (20%), 1 undifferentiated/unclassified sarcoma (17%), and no extraskeletal myxoid chondrosarcomas (0%) also showed ERG expression. SALL4 expression was recognized in 5 epithelioid sarcomas (11%), 12 malignant rhabdoid tumors (71%), 2 atypical teradoid/rhabdoid tumors (40%), 4 undifferentiated/unclassified sarcomas (67%), 1 myoepithelial tumor (20%), and none of the extraskeletal myxoid chondrosarcomas (0%). Therefore, the evaluation of ERG and SALL4 immunoexpressions may be a useful diagnostic tool to distinguish epithelioid sarcoma, especially proximal type, from malignant rhabdoid tumor.

Wishart GC, Rakha E, Green A, et al.
Inclusion of KI67 significantly improves performance of the PREDICT prognostication and prediction model for early breast cancer.
BMC Cancer. 2014; 14:908 [PubMed] Article available free on PMC after 18/12/2015 Related Publications
BACKGROUND: PREDICT (http://www.predict.nhs.uk) is a prognostication and treatment benefit tool for early breast cancer (EBC). The aim of this study was to incorporate the prognostic effect of KI67 status in a new version (v3), and compare performance with the Predict model that includes HER2 status (v2).
METHODS: The validation study was based on 1,726 patients with EBC treated in Nottingham between 1989 and 1998. KI67 positivity for PREDICT is defined as >10% of tumour cells staining positive. ROC curves were constructed for Predict models with (v3) and without (v2) KI67 input. Comparison was made using the method of DeLong.
RESULTS: In 1274 ER+ patients the predicted number of events at 10 years increased from 196 for v2 to 204 for v3 compared to 221 observed. The area under the ROC curve (AUC) improved from 0.7611 to 0.7676 (p=0.005) in ER+ patients and from 0.7546 to 0.7595 (p=0.0008) in all 1726 patients (ER+ and ER-).
CONCLUSION: Addition of KI67 to PREDICT has led to a statistically significant improvement in the model performance for ER+ patients and will aid clinical decision making in these patients. Further studies should determine whether other markers including gene expression profiling provide additional prognostic information to that provided by PREDICT.

Hao Q, Cho WC
Battle against cancer: an everlasting saga of p53.
Int J Mol Sci. 2014; 15(12):22109-27 [PubMed] Article available free on PMC after 18/12/2015 Related Publications
Cancer is one of the most life-threatening diseases characterized by uncontrolled growth and spread of malignant cells. The tumor suppressor p53 is the master regulator of tumor cell growth and proliferation. In response to various stress signals, p53 can be activated and transcriptionally induces a myriad of target genes, including both protein-encoding and non-coding genes, controlling cell cycle progression, DNA repair, senescence, apoptosis, autophagy and metabolism of tumor cells. However, around 50% of human cancers harbor mutant p53 and, in the majority of the remaining cancers, p53 is inactivated through multiple mechanisms. Herein, we review the recent progress in understanding the molecular basis of p53 signaling, particularly the newly identified ribosomal stress-p53 pathway, and the development of chemotherapeutics via activating wild-type p53 or restoring mutant p53 functions in cancer. A full understanding of p53 regulation will aid the development of effective cancer treatments.

Golden EB, Cho HY, Jahanian A, et al.
Chloroquine enhances temozolomide cytotoxicity in malignant gliomas by blocking autophagy.
Neurosurg Focus. 2014; 37(6):E12 [PubMed] Related Publications
OBJECT: In a recent clinical trial, patients with newly diagnosed glioblastoma multiforme benefited from chloroquine (CQ) in combination with conventional therapy (resection, temozolomide [TMZ], and radiation therapy). In the present study, the authors report the mechanism by which CQ enhances the therapeutic efficacy of TMZ to aid future studies aimed at improving this therapeutic regimen.
METHODS: Using in vitro and in vivo experiments, the authors determined the mechanism by which CQ enhances TMZ cytotoxicity. They focused on the inhibition-of-autophagy mechanism of CQ by knockdown of the autophagy-associated proteins or treatment with autophagy inhibitors. This mechanism was tested using an in vivo model with subcutaneously implanted U87MG tumors from mice treated with CQ in combination with TMZ.
RESULTS: Knockdown of the autophagy-associated proteins (GRP78 and Beclin) or treatment with the autophagy inhibitor, 3-methyl adenine (3-MA), blocked autophagosome formation and reduced CQ cytotoxicity, suggesting that autophagosome accumulation precedes CQ-induced cell death. In contrast, blocking autophagosome formation with knockdown of GRP78 or treatment with 3-MA enhanced TMZ cytotoxicity, suggesting that the autophagy pathway protects from TMZ-induced cytotoxicity. CQ in combination with TMZ significantly increased the amounts of LC3B-II (a marker for autophagosome levels), CHOP/GADD-153, and cleaved PARP (a marker for apoptosis) over those with untreated or individual drug-treated glioma cells. These molecular mechanisms seemed to take place in vivo as well. Subcutaneously implanted U87MG tumors from mice treated with CQ in combination with TMZ displayed higher levels of CHOP/GADD-153 than did untreated or individual drug-treated tumors.
CONCLUSIONS: Taken together, these results demonstrate that CQ blocks autophagy and triggers endoplasmic reticulum stress, thereby increasing the chemosensitivity of glioma cells to TMZ.

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