AICDA

Gene Summary

Gene:AICDA; activation induced cytidine deaminase
Aliases: AID, ARP2, CDA2, HIGM2, HEL-S-284
Location:12p13.31
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, HGNC, Ensembl, GeneCard, Gene
Protein:single-stranded DNA cytosine deaminase
Source:NCBIAccessed: 31 August, 2019

Ontology:

What does this gene/protein do?
Show (14)
Pathways:What pathways are this gene/protein implicaed in?
Show (1)

Cancer Overview

Research Indicators

Publications Per Year (1994-2019)
Graph generated 31 August 2019 using data from PubMed using criteria.

Literature Analysis

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

  • Tissue Array Analysis
  • Viral Core Proteins
  • Tumor Suppressor Proteins
  • Cancer RNA
  • Genetic Recombination
  • Risk Factors
  • Skin Cancer
  • Cytidine Deaminase
  • Up-Regulation
  • Tumor Necrosis Factor Receptor Superfamily, Member 7
  • TNF
  • Chronic Lymphocytic Leukemia
  • Molecular Sequence Data
  • Uridine
  • VDJ Exons
  • Pyrimidines
  • Translocation
  • Xeroderma Pigmentosum
  • Transcription
  • Proto-Oncogene Proteins c-bcl-6
  • Xenograft Models
  • Mutation
  • rho GTP-Binding Proteins
  • Signal Transduction
  • T-Lymphocytes
  • Transfection
  • Young Adult
  • Splenic Neoplasms
  • Sequence Homology, Nucleic Acid
  • RTPCR
  • Uracil
  • alpha-Fetoproteins
  • Survival Rate
  • Sequence Alignment
  • Messenger RNA
  • p53 Protein
  • Twist-Related Protein 1
  • Stomach Cancer
  • Chromosome 12
  • B-Lymphocytes
  • Somatic Hypermutation, Immunoglobulin
Tag cloud generated 31 August, 2019 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)

Roos A, Byron SA
Genomics-Enabled Precision Medicine for Cancer.
Cancer Treat Res. 2019; 178:137-169 [PubMed] Related Publications
Genomic information is increasingly being incorporated into clinical cancer care. Large-scale sequencing efforts have deepened our understanding of the genomic landscape of cancer and contributed to the expanding catalog of alterations being leveraged to aid in cancer diagnosis, prognosis, and treatment. Genomic profiling can provide clinically relevant information regarding somatic point mutations, copy number alterations, translocations, and gene fusions. Genomic features, such as mutational burden, can also be measured by more comprehensive sequencing strategies and have shown value in informing potential treatment options. Ongoing clinical trials are evaluating the use of molecularly targeted agents in genomically defined subsets of cancers within and across tumor histologies. Continued advancements in clinical genomics promise to further expand the application of genomics-enabled medicine to a broader spectrum of oncology patients.

Gatalica Z, Feldman R, Vranić S, Spetzler D
Immunohistochemistry-Enabled Precision Medicine.
Cancer Treat Res. 2019; 178:111-135 [PubMed] Related Publications
Immunohistochemistry (IHC) can be applied to diagnostic aspects of pathologic examination to provide aid in assignment of lineage and histologic type of cancer. Increasingly, however, IHC is widely used to provide prognostic and predictive (theranostic) information about the neoplastic disease. A refinement of theranostic application of IHC can be seen in the use of "genomic probing" where antibody staining results are directly correlated with an underlying genetic alteration in the tumor (somatic mutations) and/or the patient (germline constitution). All these aspects of IHC find their best use in guiding the oncologists in the optimal use of therapy for the patients.

Albero-González R, Hernández-Llodrà S, Juanpere N, et al.
Immunohistochemical expression of mismatch repair proteins (MSH2, MSH6, MLH1, and PMS2) in prostate cancer: correlation with grade groups (WHO 2016) and ERG and PTEN status.
Virchows Arch. 2019; 475(2):223-231 [PubMed] Related Publications
The role of DNA MMR genes in prostate cancer (PrCa) is controversial, as genetic alterations leading to microsatellite instability are incompletely defined in these tumors. ERG rearrangements and PTEN loss are concomitant events in PrCa. The aim of this study has been to analyze the immunohistochemical (IHC) expression of MSH2, MSH6, MLH1, PMS2, ERG, and PTEN and their potential association with the grade group (GG) grading system (WHO 2016) and PSA recurrence in a series of 200 PrCa (PSMAR-Biobank, Barcelona, Spain). MSH2, MLH1, PMS2, and PTEN losses were documented in 8%, 5%, 2%, and 36.5%, respectively. ERG expression was found in 48%. MSH6 showed an increase of expression with respect to basal levels in 42.1% of the cases. A statistical association between MSH6 overexpression and GG5 was found (p = 0.0281). ERG-wild-type cases were associated with single MSH2 loss (p = 0.024), and MSH2 and/or MLH1 loss (p = 0.019). The percentage of cases with PTEN loss was 20.5% (8/39) in GG1, 37.6% (53/141) of clustered GG2 to 4, and 60% (12/20) of GG5 (chi-square test, p = 0.01). Thus, PTEN expression loss was statistically more frequent in the upper-grade tumors. PMS2 loss was an infrequent event, but it was statistically associated with shorter time to PSA recurrence (p = 0.011). These results suggest the existence of an alternative non-ERG pathway associated with MSH2 or MLH1 expression loss. MSH6 overexpression could be a marker of aggressiveness in PrCa. The IHC assessment of DNA MMR proteins, ERG and PTEN, could identify different altered PrCa pathways, which could aid patient stratification.

Henrik Heiland D, Ravi VM, Behringer SP, et al.
Tumor-associated reactive astrocytes aid the evolution of immunosuppressive environment in glioblastoma.
Nat Commun. 2019; 10(1):2541 [PubMed] Free Access to Full Article Related Publications
Reactive astrocytes evolve after brain injury, inflammatory and degenerative diseases, whereby they undergo transcriptomic re-programming. In malignant brain tumors, their function and crosstalk to other components of the environment is poorly understood. Here we report a distinct transcriptional phenotype of reactive astrocytes from glioblastoma linked to JAK/STAT pathway activation. Subsequently, we investigate the origin of astrocytic transformation by a microglia loss-of-function model in a human organotypic slice model with injected tumor cells. RNA-seq based gene expression analysis of astrocytes reveals a distinct astrocytic phenotype caused by the coexistence of microglia and astrocytes in the tumor environment, which leads to a large release of anti-inflammatory cytokines such as TGFβ, IL10 and G-CSF. Inhibition of the JAK/STAT pathway shifts the balance of pro- and anti-inflammatory cytokines towards a pro-inflammatory environment. The complex interaction of astrocytes and microglia cells promotes an immunosuppressive environment, suggesting that tumor-associated astrocytes contribute to anti-inflammatory responses.

Jung YY, Woo HY, Kim HS
Targeted Genomic Sequencing Reveals Novel
Anticancer Res. 2019; 39(6):2883-2889 [PubMed] Related Publications
BACKGROUND/AIM: High-grade serous carcinoma (HGSC) is the most common histological subtype of ovarian carcinoma. Somatic mutation of tumor protein 53 (TP53) is a hallmark of tubo-ovarian HGSC and is observed in almost all such cases. Highly sensitive targeted genomic sequencing can be used to identify novel mutations that may become potential druggable targets and aid in therapeutic decisions. The aim of this study was to describe the clinicopathological and molecular characteristics of HGSCs with novel somatic TP53 mutations identified by next-generation sequencing (NGS).
MATERIALS AND METHODS: A commercial NGS panel comprising 170 genes, including TP53, was used to analyze the genetic profiles of 132 ovarian carcinoma cases. The clinicopathological characteristics and p53 immunostaining results of two HGSCs exhibiting novel TP53 mutations were investigated.
RESULTS: Eighty-eight (66.7%) out of 132 ovarian carcinoma cases were diagnosed as HGSC. Novel TP53 in-frame deletion mutations c.719_727delGTTCCTGCA (p53 p.Ser240_Cys242del) and c.634_642delTTTCGACAT (p53 p.F212_H214del) were detected in a single case of HGSC each. Both patients were postmenopausal women. Imaging and laboratory studies revealed peritoneal carcinomatosis and elevated levels of serum tumor markers. The patients underwent primary debulking surgery and were diagnosed as having stage IIIC HGSC. In both cases, p53 immunostaining revealed uniform nuclear immunoreactivity in 90% or more of tumor cells at a very strong intensity.
CONCLUSION: Targeted genomic sequencing revealed novel in-frame deletion mutations of TP53 leading to p53 overexpression in tubo-ovarian HGSC. This discovery of previously unreported somatic TP53 mutations provides insight into the translation of NGS technology into personalized medicine and identifies new potential targets for therapeutic applications.

Iida-Norita R, Kawamura M, Suzuki Y, et al.
Vasohibin-2 plays an essential role in metastasis of pancreatic ductal adenocarcinoma.
Cancer Sci. 2019; 110(7):2296-2308 [PubMed] Free Access to Full Article Related Publications
Vasohibin-2 (VASH2) is expressed in various cancers and promotes their progression. We recently reported that pancreatic cancer patients with higher VASH2 expression show poorer prognosis. Herein, we sought to characterize the role of VASH2 in pancreatic cancer. We used LSL-Kras

Penault-Llorca F, Rudzinski ER, Sepulveda AR
Testing algorithm for identification of patients with TRK fusion cancer.
J Clin Pathol. 2019; 72(7):460-467 [PubMed] Free Access to Full Article Related Publications
The neurotrophic tyrosine receptor kinase (

Wang C, Gao F, Giannakis GB, et al.
Efficient proximal gradient algorithm for inference of differential gene networks.
BMC Bioinformatics. 2019; 20(1):224 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Gene networks in living cells can change depending on various conditions such as caused by different environments, tissue types, disease states, and development stages. Identifying the differential changes in gene networks is very important to understand molecular basis of various biological process. While existing algorithms can be used to infer two gene networks separately from gene expression data under two different conditions, and then to identify network changes, such an approach does not exploit the similarity between two gene networks, and it is thus suboptimal. A desirable approach would be clearly to infer two gene networks jointly, which can yield improved estimates of network changes.
RESULTS: In this paper, we developed a proximal gradient algorithm for differential network (ProGAdNet) inference, that jointly infers two gene networks under different conditions and then identifies changes in the network structure. Computer simulations demonstrated that our ProGAdNet outperformed existing algorithms in terms of inference accuracy, and was much faster than a similar approach for joint inference of gene networks. Gene expression data of breast tumors and normal tissues in the TCGA database were analyzed with our ProGAdNet, and revealed that 268 genes were involved in the changed network edges. Gene set enrichment analysis identified a significant number of gene sets related to breast cancer or other types of cancer that are enriched in this set of 268 genes. Network analysis of the kidney cancer data in the TCGA database with ProGAdNet also identified a set of genes involved in network changes, and the majority of the top genes identified have been reported in the literature to be implicated in kidney cancer. These results corroborated that the gene sets identified by ProGAdNet were very informative about the cancer disease status. A software package implementing the ProGAdNet, computer simulations, and real data analysis is available as Additional file 1.
CONCLUSION: With its superior performance over existing algorithms, ProGAdNet provides a valuable tool for finding changes in gene networks, which may aid the discovery of gene-gene interactions changed under different conditions.

Liang W, Guo M, Pan Z, et al.
Association between certain non-small cell lung cancer driver mutations and predictive markers for chemotherapy or programmed death-ligand 1 inhibition.
Cancer Sci. 2019; 110(6):2014-2021 [PubMed] Free Access to Full Article Related Publications
This study aimed to analyze the association between driver mutations and predictive markers for some anti-tumor agents in non-small cell lung cancer (NSCLC). A cohort of 785 Chinese patients with NSCLC who underwent resection from March 2016 to November 2017 in the First Affiliated Hospital of Guangzhou Medical University was investigated. The specimens were subjected to hybridization capture and sequence of 8 important NSCLC-related driver genes. In addition, the slides were tested for PD-L1, excision repair cross-complementation group 1 (ERCC1), ribonucleotide reductase subunit M1 (RRM1), thymidylate synthase (TS) and β-tubulin III by immunohistochemical staining. A total of 498 (63.4%) patients had at least 1 driver gene alteration. Wild-type, EGFR rare mutation (mut), ALK fusion (fus), RAS mut, RET fus and MET mut had relatively higher proportions of lower ERCC1 expression. EGFR 19del, EGFR L858R, EGFR rare mut, ALK fus, HER2 mut, ROS1 fus and MET mut were more likely to have TS low expression. Wild-type, EGFR L858R, EGFR rare mut and BRAF mut were associated with lower β-tubulin III expression. In addition, wild-type, RAS mut, ROS1 fus, BRAF and MET mut had higher proportion of PD-L1 high expression. As a pilot validation, 21 wild-type patients with advanced NSCLC showed better depth of response and response rate to taxanes compared with pemetrexed/gemcitabine (31.2%/60.0% vs 26.6%/45.5%). Our study may aid in selecting the optimal salvage regimen after targeted therapy failure, or the chemo-regimen where targeted therapy has not been a routine option. Further validation is warranted.

Benstead-Hume G, Chen X, Hopkins SR, et al.
Predicting synthetic lethal interactions using conserved patterns in protein interaction networks.
PLoS Comput Biol. 2019; 15(4):e1006888 [PubMed] Free Access to Full Article Related Publications
In response to a need for improved treatments, a number of promising novel targeted cancer therapies are being developed that exploit human synthetic lethal interactions. This is facilitating personalised medicine strategies in cancers where specific tumour suppressors have become inactivated. Mainly due to the constraints of the experimental procedures, relatively few human synthetic lethal interactions have been identified. Here we describe SLant (Synthetic Lethal analysis via Network topology), a computational systems approach to predicting human synthetic lethal interactions that works by identifying and exploiting conserved patterns in protein interaction network topology both within and across species. SLant out-performs previous attempts to classify human SSL interactions and experimental validation of the models predictions suggests it may provide useful guidance for future SSL screenings and ultimately aid targeted cancer therapy development.

Tian S
Identification of monotonically differentially expressed genes for non-small cell lung cancer.
BMC Bioinformatics. 2019; 20(1):177 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Monotonically expressed genes (MEGs) are genes whose expression values increase or decrease monotonically as a disease advances or time proceeds. Non-small cell lung cancer (NSCLC) is a multistage progression process resulting from genetic sequences mutations, the identification of MEGs for NSCLC is important.
RESULTS: With the aid of a feature selection algorithm capable of identifying MEGs - the MFSelector method - two sets of potential MEGs were selected in this study: the MEGs across the different pathologic stages and the MEGs across the risk levels of death for the NSCLC patients at early stages. For the lung adenocarcinoma (AC) subtypes no statistically significant MEGs were identified across pathologic stages, however dozens of MEGs were identified across the risk levels of death. By contrast, for the squamous cell lung carcinoma (SCC) there were no statistically significant MEGs as either stage or risk level advanced.
CONCLUSIONS: The pathologic stage of non-small cell lung cancer patients at early stages has no prognostic value, making the identification of prognostic gene signatures for them more meaningful and highly desirable.

Luo Q, Cui M, Deng Q, Liu J
Comprehensive analysis of differentially expressed profiles and reconstruction of a competing endogenous RNA network in papillary renal cell carcinoma.
Mol Med Rep. 2019; 19(6):4685-4696 [PubMed] Free Access to Full Article Related Publications
Long noncoding RNAs (lncRNAs) function as competing endogenous RNAs (ceRNAs). ceRNA networks may serve important roles in various tumors, as demonstrated by an increasing number of studies; however, papillary renal cell carcinoma (PRCC)‑associated ceRNA networks mediated by lncRNAs remain unknown. Increased knowledge of ceRNA networks in PRCC may aid the identification of novel targets and biomarkers in the treatment of PRCC. In the present study, a comprehensive investigation of mRNA, lncRNA, and microRNA (miRNA) expression in PRCC was conducted using sequencing data from The Cancer Genome Atlas. Differential expression (DE) profiles of mRNAs, lncRNAs and miRNAs were evaluated, with 1,970 mRNAs, 1,201 lncRNAs and 96 miRNAs identified as genes with significantly different expression between PRCC and control paracancerous tissues. Based on the identified DEmRNAs, a protein‑protein interaction network was generated using the STRING database. Furthermore, a ceRNA network for PRCC was determined using a targeted assay combined with the DE of miRNAs, mRNAs and lncRNAs, enabling the identification of important lncRNA‑miRNA and miRNA‑mRNA pairs. Analysis of the ceRNA network led to the extraction of a subnetwork and the identification of lncRNA maternally expressed 3 (MEG3), lncRNA PWRN1, miRNA (miR)‑508, miR‑21 and miR519 as important genes. Reverse transcription‑quantitative polymerase chain reaction analysis was conducted to validate the results of the bioinformatics analyses; it was revealed that lncRNA MEG3 expression levels were downregulated in PRCC tumor tissues compared with adjacent non‑tumor tissues. In addition, survival analysis was conducted to investigate the association between identified genes and the prognosis of patients with PRCC, indicating the potential involvement of 13 mRNAs, 15 lncRNAs and six miRNAs. In conclusion, the present study may improve understanding of the regulatory mechanisms of ceRNA networks in PRCC and provide novel insight for future studies of prognostic biomarkers and potential therapeutic targets.

Minlikeeva AN, Cannioto R, Jensen A, et al.
Joint exposure to smoking, excessive weight, and physical inactivity and survival of ovarian cancer patients, evidence from the Ovarian Cancer Association Consortium.
Cancer Causes Control. 2019; 30(5):537-547 [PubMed] Free Access to Full Article Related Publications
PURPOSE: Previous epidemiologic studies have shown that smoking, obesity, and physical inactivity are associated with poor survival following a diagnosis of ovarian cancer. Yet, the combined relationship of these unfavorable lifestyle factors on ovarian cancer survival has not been sufficiently investigated.
METHODS: Using data pooled from 13 studies, we examined the associations between combined exposures to smoking, overweight/obesity weight, and physical inactivity and overall survival (OS) as well as progression-free survival (PFS) among women diagnosed with invasive epithelial ovarian carcinoma (n = 7,022). Using age- and stage-adjusted Cox proportional hazards regression models, we estimated hazard ratios (HRs) and 95% confidence intervals (CIs) associated with joint exposure to these factors.
RESULTS: Combined exposure to current smoking, overweight/obesity, and physical inactivity prior to diagnosis was associated with a significantly increased risk of mortality compared to women who never smoked, had normal body mass index (BMI), and were physically active (HR = 1.37; 95% CI 1.10-1.70). The association for a joint exposure to these factors exceeded that of each exposure individually. In fact, exposure to both current smoking and overweight/obesity, and current smoking and physical inactivity was also associated with increased risk of death (HR = 1.28; 95% CI 1.08-1.52, and HR = 1.26; 95% CI 1.04-1.54, respectively). The associations were of a similar magnitude when former smoking was assessed in combination with the other exposures and when excessive weight was limited to obesity only. No significant associations were observed between joint exposure to any of these factors and PFS.
CONCLUSIONS: Joint exposure to smoking, excessive weight, and physical inactivity may negatively impact survival of ovarian cancer patients. These results suggest the importance of examining the combined effect of lifestyle factors on ovarian cancer patients' survival.

Sone K, Oguri T, Uemura T, et al.
Genetic variation in the ATP binding cassette transporter ABCC10 is associated with neutropenia for docetaxel in Japanese lung cancer patients cohort.
BMC Cancer. 2019; 19(1):246 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Docetaxel is a widely used cytotoxic agent for treatments of various cancers. The ATP binding cassette (ABC) transporter / multidrug resistance protein (MRP) ABCC10/MRP7, involved in transporting taxanes, has been associated with resistance to these agents. Since genetic variation in drug transporters may affect clinical outcomes, we examined whether polymorphism of ABCC10 could affect clinical responses to docetaxel.
METHODS: Using 18 NSCLC cell lines and CRISPR-based genome-edited HeLa cells, we analyzed whether genetic variants of ABCC10 (rs2125739, rs9349256) affected cytotoxicity to docetaxel. Subsequently, we analyzed genetic variants [ABCC10 (rs2125739), ABCB1 (C1236T, C3435T, G2677 T/A), ABCC2 (rs12762549), and SLCO1B3 (rs11045585)] in 69 blood samples of NSCLC patients treated with docetaxel monotherapy. Clinical outcomes were evaluated between genotype groups.
RESULTS: In the cell lines, only one genetic variant (rs2125739) was significantly associated with docetaxel cytotoxicity, and this was confirmed in the genome-edited cell line. In the 69 NSCLC patients, there were no significant differences related to rs2125739 genotype in terms of RR, PFS, or OS. However, this SNP was associated with grade 3/4 neutropenia (T/C group 60% vs. T/T group 87%; P = 0.028). Furthermore, no patient with a T/C genotype experienced febrile neutropenia.
CONCLUSIONS: Our results indicate that genetic variation in the ABCC10 gene is associated with neutropenia for docetaxel treatment.

Foote JR, Secord AA, Liang MI, et al.
Targeted composite value-based endpoints in platinum-sensitive recurrent ovarian cancer.
Gynecol Oncol. 2019; 152(3):445-451 [PubMed] Related Publications
OBJECTIVES: FDA-approved treatments for platinum-sensitive recurrent ovarian cancer (PSROC) include bevacizumab and PARP inhibitors (PARPi); clinical decisions regarding therapy must be made prior to initiating chemotherapy. Using the American Society of Clinical Oncology (ASCO) and European Society of Medical Oncology (ESMO) value frameworks, we assessed relative values of concurrent/maintenance biologic therapies in PSROC.
METHODS: Value scores were calculated for key maintenance therapies based on randomized controlled trials: bevacizumab (OCEANS, GOG 213); olaparib (Study 19, SOLO2); niraparib (NOVA); rucaparib (ARIEL3). Personalized value scorecards were constructed for patients with germline/somatic-BRCA mutations, homologous recombination deficiency (HRD), and wild-type BRCA (wBRCA). ASCO value scores assess clinical benefit, toxicity, long-term survival, symptom palliation, treatment-free interval, and quality of life (QOL). ESMO value scores assess clinical benefit, toxicity, and QOL.
RESULTS: ASCO scores were highest for maintenance PARPi in germline/somatic-BRCA mutation cohorts: olaparib (SOLO2) = 47, (Study 19) = 62; niraparib = 50; rucaparib = 54. HRD cohorts had slightly lower scores: niraparib = 46; rucaparib = 37. wBRCA cohorts had the lowest scores: niraparib = 26; rucaparib = 26; and olaparib (Study 19) = 32, as did patients receiving bevacizumab (OCEANS) = 35, (GOG 213) = 26. ESMO scores demonstrated high-value for maintenance PARPi in germline/somatic-BRCA mutation cohorts and low-value for bevacizumab and PARPi in wBRCA cohorts.
CONCLUSIONS: The value of maintenance PARPi therapy depends heavily on BRCA status, with the highest value scores in germline/somatic-BRCA mutation cohorts. Personalized value scorecards provide a visual aid to assess the harm-benefit balance of maintenance PARPi for PSROC.

Bjerre MT, Strand SH, Nørgaard M, et al.
Aberrant
Int J Mol Sci. 2019; 20(5) [PubMed] Free Access to Full Article Related Publications
Prostate cancer (PCa) is a clinically heterogeneous disease and currently, accurate diagnostic and prognostic molecular biomarkers are lacking. This study aimed to identify novel DNA hypermethylation markers for PCa with future potential for blood-based testing. Accordingly, to search for genes specifically hypermethylated in PCa tissue samples and not in blood cells or other cancer tissue types, we performed a systematic analysis of genome-wide DNA methylation data (Infinium 450K array) available in the Marmal-aid database for 4072 malignant/normal tissue samples of various types. We identified eight top candidate markers (cg12799885,

Billatos E, Duan F, Moses E, et al.
Detection of early lung cancer among military personnel (DECAMP) consortium: study protocols.
BMC Pulm Med. 2019; 19(1):59 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Lung cancer is the leading cause of cancer-related death due in large part to our inability to diagnose it at an early and potentially curable stage. Screening for lung cancer via low dose computed tomographic (LDCT) imaging has been demonstrated to improve mortality but also results in a high rate of false positive tests. The identification and application of non-invasive molecular biomarkers that improve the performance of CT imaging for the detection of lung cancer in high risk individuals would aid in clinical decision-making, eliminate the need for unnecessary LDCT follow-up, and further refine the screening criteria for an already large high-risk population.
METHODS: The Detection of Early Lung Cancer Among Military Personnel (DECAMP) consortium is conducting two multicenter prospective studies with the goals of developing an integrated panel of both airway and blood-based molecular biomarkers that discriminate benign and malignant indeterminate nodules detected on CT scan as well as predict the future development of lung cancer in high-risk individuals. To achieve these goals, DECAMP is compiling an extensive array of biospecimens including nasal brushings, serum, plasma and intrathoracic airway samples (bronchial brushings and bronchial biopsies) from normal-appearing airway epithelium.
DISCUSSION: This bank of samples is the foundation for multiple DECAMP efforts focused on the identification of those at greatest risk of developing lung cancer as well as the discrimination of benign and malignant pulmonary nodules. The clinical, imaging and biospecimen repositories will serve as a resource for the biomedical community and their investigation of the molecular basis of chronic respiratory disease.
TRIAL REGISTRATION: Retrospectively registered as NCT01785342 - DECAMP-1: Diagnosis and Surveillance of Indeterminate Pulmonary Nodules (DECAMP-1). Date of Registration: February 7, 2013. Retrospectively registered as NCT02504697 - DECAMP-2: Screening of Patients With Early Stage Lung Cancer or at High Risk for Developing Lung Cancer (DECAMP-2). Date of Registration: July 22, 2015.

Borzooee F, Larijani M
Pichia pastoris as a host for production and isolation of mutagenic AID/APOBEC enzymes involved in cancer and immunity.
N Biotechnol. 2019; 51:67-79 [PubMed] Related Publications
AID/APOBEC3 enzymes are cytidine deaminases that mutate antibody and retroviral genes and also mediate extensive tumor genome mutagenesis. The study of purified AID/APOBEC3 proteins is challenged by difficulties with their expression and purification arising from genotoxicity in expression hosts, extensive non-specific protein-protein/DNA/RNA interactions and haphazard oligomerization. To date, expression hosts for purification of AID/APOBEC3 enzymes include bacteria, insect and mammalian cells. Here the establishment and optimization of a yeast expression/secretion system for AID/APOBEC3s are reported, followed by comparison with the same enzymes expressed in bacterial and mammalian hosts. AID and APOBEC3G were expressed successfully in Pichia pastoris, each either with an N-terminal GST tag, C-terminal V5-His tag or as untagged native form. It was verified that the yeast-expressed enzymes exhibit identical biochemical properties to those reported using bacterial and mammalian expression, indicating high fidelity of protein folding. It was demonstrated that the system can be adapted for secretion of the enzymes into the media which was used directly in various enzyme assays. The system is also amenable to elimination of bulky fusion tags, providing native untagged enzymes. Thus, P. pastoris is an advantageous expression factory for AID/APOBEC3 enzymes, considering the cost, time, efficiency and quality of the obtained enzymes. The first report is also provided here of a functionally active, untagged, secreted AID, which may become a useful research reagent. A comprehensive comparison is made of the effect of fusion tags and expression hosts on the biochemical actions of AID and APOBEC3G.

Lu Y, Li Y, Wang Z, et al.
Downregulation of RGMA by HIF-1A/miR-210-3p axis promotes cell proliferation in oral squamous cell carcinoma.
Biomed Pharmacother. 2019; 112:108608 [PubMed] Related Publications
Repulsive guidance molecules comprise a group of proteins that play an important role in carcinogenesis through interactions with their receptors, but their function in oral squamous cell carcinoma (OSCC) is unclear. Here, we investigated the potential role of the RGM family members in oral cancer pathogenesis. Our study showed that only RGMA was significantly downregulated in the OSCC tissues analyzed by TCGA and validated this finding in OSCC cells. The decreased expression of RGMA was strongly associated with the T stage and with poor prognosis. The ectopic expression of RGMA significantly inhibited the proliferation of OSCC cells both in vitro and in vivo. Moreover, we confirmed that RGMA was a target of miR-210-3p in OSCC and miR-210-3p overexpression contributed to the acceleration of OSCC growth. Further experiments revealed that HIF1A specifically interacted with the promoter of miR-210-3p and enhanced its expression. In summary, our research indicates that RGMA is regulated by the HIF1A/miR-210-3p axis and inhibits OSCC cell proliferation; thus, in the future, the development of therapies that target the HIF1A/miR-210-3p/RGMA axis may aid in the treatment of aggressive cancers.

Xiao Q, Luo J, Liang C, et al.
CeModule: an integrative framework for discovering regulatory patterns from genomic data in cancer.
BMC Bioinformatics. 2019; 20(1):67 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Non-coding RNAs (ncRNAs) are emerging as key regulators and play critical roles in a wide range of tumorigenesis. Recent studies have suggested that long non-coding RNAs (lncRNAs) could interact with microRNAs (miRNAs) and indirectly regulate miRNA targets through competing interactions. Therefore, uncovering the competing endogenous RNA (ceRNA) regulatory mechanism of lncRNAs, miRNAs and mRNAs in post-transcriptional level will aid in deciphering the underlying pathogenesis of human polygenic diseases and may unveil new diagnostic and therapeutic opportunities. However, the functional roles of vast majority of cancer specific ncRNAs and their combinational regulation patterns are still insufficiently understood.
RESULTS: Here we develop an integrative framework called CeModule to discover lncRNA, miRNA and mRNA-associated regulatory modules. We fully utilize the matched expression profiles of lncRNAs, miRNAs and mRNAs and establish a model based on joint orthogonality non-negative matrix factorization for identifying modules. Meanwhile, we impose the experimentally verified miRNA-lncRNA interactions, the validated miRNA-mRNA interactions and the weighted gene-gene network into this framework to improve the module accuracy through the network-based penalties. The sparse regularizations are also used to help this model obtain modular sparse solutions. Finally, an iterative multiplicative updating algorithm is adopted to solve the optimization problem.
CONCLUSIONS: We applied CeModule to two cancer datasets including ovarian cancer (OV) and uterine corpus endometrial carcinoma (UCEC) obtained from TCGA. The modular analysis indicated that the identified modules involving lncRNAs, miRNAs and mRNAs are significantly associated and functionally enriched in cancer-related biological processes and pathways, which may provide new insights into the complex regulatory mechanism of human diseases at the system level.

Ding W, Chen G, Shi T
Integrative analysis identifies potential DNA methylation biomarkers for pan-cancer diagnosis and prognosis.
Epigenetics. 2019; 14(1):67-80 [PubMed] Article available free on PMC after 29/01/2020 Related Publications
DNA methylation status is closely associated with diverse diseases, and is generally more stable than gene expression, thus abnormal DNA methylation could be important biomarkers for tumor diagnosis, treatment and prognosis. However, the signatures regarding DNA methylation changes for pan-cancer diagnosis and prognosis are less explored. Here we systematically analyzed the genome-wide DNA methylation patterns in diverse TCGA cancers with machine learning. We identified seven CpG sites that could effectively discriminate tumor samples from adjacent normal tissue samples for 12 main cancers of TCGA (1216 samples, AUC > 0.99). Those seven potential diagnostic biomarkers were further validated in the other 9 different TCGA cancers and 4 independent datasets (AUC > 0.92). Three out of the seven CpG sites were correlated with cell division, DNA replication and cell cycle. We also identified 12 CpG sites that can effectively distinguish 26 different cancers (7605 samples), and the result was repeatable in independent datasets as well as two disparate tumors with metastases (micro-average AUC > 0.89). Furthermore, a series of potential signatures that could significantly predict the prognosis of tumor patients for 7 different cancer were identified via survival analysis (p-value < 1e-4). Collectively, DNA methylation patterns vary greatly between tumor and adjacent normal tissues, as well as among different types of cancers. Our identified signatures may aid the decision of clinical diagnosis and prognosis for pan-cancer and the potential cancer-specific biomarkers could be used to predict the primary site of metastatic breast and prostate cancers.

Suzuki H, Yano M, Miyazawa M, et al.
Association of the hypoxia-inducible factor-1α (HIF-1α) gene polymorphisms with prognosis in ovarian clear cell carcinoma.
J Ovarian Res. 2019; 12(1):7 [PubMed] Article available free on PMC after 29/01/2020 Related Publications
BACKGROUND: Ovarian clear cell carcinoma (OCCC) is the second most common ovarian cancer after serous carcinoma in Japan. OCCC has a more unfavorable clinical outcome due to a poor response to platinum-based chemotherapy, compared with serous carcinoma. Hypoxia inducible factor-1α (HIF-1α) is a key regulator of cellular response to hypoxia and plays an important role in tumor growth, and HIF-1α gene single-nucleotide polymorphisms (SNPs) adversely affect the outcome in some cancers. Herein, we investigated the association of the HIF-1α gene SPNs with clinical outcome in OCCCs. Eighty-nine patients with OCCC were recruited in whom pathological diagnosis was confirmed with surgically resected specimen.
RESULTS: The SNPs of C1772T and G1790A in the HIF-1α gene occurred in 23.6 and 3.3% of the patients, respectively. In the univariate analysis, overall survival was associated with stage and surgical residual tumor but not with the SNPs C1772T, G1790A, C1772T and/or G1790A. In the multivariate survival analysis, a significant association was observed between outcome and FIGO stage and/or surgical residual tumor; however, no association was obtained between HIF-1α gene SNPs and these factors.
CONCLUSION: In conclusion, unlike the other cancers in which HIF-1α gene SNPs were demonstrated to be associated with the outcome, OCCC prognosis may not be affected by HIF-1α gene SNPs. Further studies need to be performed to clarify the association of HIF-1α expression with the unfavorable prognosis in OCCCs, in terms of transcriptional/translational activity, nuclear translocation of the protein, and protein degradation.

Song Y, He S, Zhuang J, et al.
MicroRNA‑601 serves as a potential tumor suppressor in hepatocellular carcinoma by directly targeting PIK3R3.
Mol Med Rep. 2019; 19(3):2431-2439 [PubMed] Related Publications
Recently, microRNAs (miRNAs) have been acknowledged as important regulators of hepatocarcinogenesis and tumor progression. Therefore, identifying the underlying molecular mechanisms of miRNAs in the occurrence and development of hepatocellular carcinoma (HCC) may be important for understanding the pathogenesis of HCC and aid the identification of potential therapeutic strategies. In the present study, miRNA (miR)‑601 was significantly downregulated in HCC tissues and cell lines; low miR‑601 expression was strongly associated with tumor, node and metastasis staging and lymph node metastasis of patients with HCC. In addition, the overexpression of miR‑601 expression significantly inhibited the proliferation and invasion of HCC cells. Regarding the underlying mechanism, phosphoinositide‑3‑kinase regulatory subunit 3 (PIK3R3) was predicted to be a direct target of miR‑601 in HCC cells. Furthermore, restoration of PIK3R3 expression in these cells counteracted the inhibitory effects of miR‑601 on cell proliferation and invasion in HCC. Notably, miR‑601 overexpression inhibited the protein kinase B (AKT)/mammalian target of rapamycin (mTOR) signaling pathway in HCC via the regulation of PIK3R3. Collectively, these results demonstrated that miR‑601 may inhibit the progression of HCC by directly targeting PIK3R3 and regulating the AKT/mTOR signaling pathway. Therefore, miR‑601 may be an effective therapeutic target for the treatment of patients with HCC.

Panagopoulou M, Karaglani M, Balgkouranidou I, et al.
Circulating cell-free DNA in breast cancer: size profiling, levels, and methylation patterns lead to prognostic and predictive classifiers.
Oncogene. 2019; 38(18):3387-3401 [PubMed] Related Publications
Blood circulating cell-free DNA (ccfDNA) is a suggested biosource of valuable clinical information for cancer, meeting the need for a minimally-invasive advancement in the route of precision medicine. In this paper, we evaluated the prognostic and predictive potential of ccfDNA parameters in early and advanced breast cancer. Groups consisted of 150 and 16 breast cancer patients under adjuvant and neoadjuvant therapy respectively, 34 patients with metastatic disease and 35 healthy volunteers. Direct quantification of ccfDNA in plasma revealed elevated concentrations correlated to the incidence of death, shorter PFS, and non-response to pharmacotherapy in the metastatic but not in the other groups. The methylation status of a panel of cancer-related genes chosen based on previous expression and epigenetic data (KLK10, SOX17, WNT5A, MSH2, GATA3) was assessed by quantitative methylation-specific PCR. All but the GATA3 gene was more frequently methylated in all the patient groups than in healthy individuals (all p < 0.05). The methylation of WNT5A was statistically significantly correlated to greater tumor size and poor prognosis characteristics and in advanced stage disease with shorter OS. In the metastatic group, also SOX17 methylation was significantly correlated to the incidence of death, shorter PFS, and OS. KLK10 methylation was significantly correlated to unfavorable clinicopathological characteristics and relapse, whereas in the adjuvant group to shorter DFI. Methylation of at least 3 or 4 genes was significantly correlated to shorter OS and no pharmacotherapy response, respectively. Classification analysis by a fully automated, machine learning software produced a single-parametric linear model using ccfDNA plasma concentration values, with great discriminating power to predict response to chemotherapy (AUC 0.803, 95% CI [0.606, 1.000]) in the metastatic group. Two more multi-parametric signatures were produced for the metastatic group, predicting survival and disease outcome. Finally, a multiple logistic regression model was constructed, discriminating between patient groups and healthy individuals. Overall, ccfDNA emerged as a highly potent predictive classifier in metastatic breast cancer. Upon prospective clinical evaluation, all the signatures produced could aid accurate prognosis.

Drusbosky LM, Vidva R, Gera S, et al.
Predicting response to BET inhibitors using computational modeling: A BEAT AML project study.
Leuk Res. 2019; 77:42-50 [PubMed] Article available free on PMC after 01/02/2020 Related Publications
Despite advances in understanding the molecular pathogenesis of acute myeloid leukaemia (AML), overall survival rates remain low. The ability to predict treatment response based on individual cancer genomics using computational modeling will aid in the development of novel therapeutics and personalize care. Here, we used a combination of genomics, computational biology modeling (CBM), ex vivo chemosensitivity assay, and clinical data from 100 randomly selected patients in the Beat AML project to characterize AML sensitivity to a bromodomain (BRD) and extra-terminal (BET) inhibitor. Computational biology modeling was used to generate patient-specific protein network maps of activated and inactivated protein pathways translated from each genomic profile. Digital drug simulations of a BET inhibitor (JQ1) were conducted by quantitatively measuring drug effect using a composite AML disease inhibition score. 93% of predicted disease inhibition scores matched the associated ex vivo IC

Hines SL, Mohammad AN, Jackson J, et al.
Integrative data fusion for comprehensive assessment of a novel CHEK2 variant using combined genomics, imaging, and functional-structural assessments via protein informatics.
Mol Omics. 2019; 15(1):59-66 [PubMed] Related Publications
The CHEK2 gene and its encoded protein Chk2 have a well-known role in cancers, especially those related to breast cancer mediated through the BRCA1 gene. Additionally Chk2 has a crucial role in DNA repair, apoptosis and the cell cycle, which is why classification of variants of uncertain significance (VUS) is an area highly sought for a better elucidation of the "genomic effect" that results. Because it can often take years before enough clinical data is accumulated, and the costly and expensive functional analysis for individual variants presents a significant hurdle, it is important to identify other tools to help aid in clarifying the impact of specific variants on a protein's function and eventually the patient's health outcome. Here we describe a newly identified CHEK2 variant and analyze with an integrated approach combining genomics (whole exome analysis), clinical study, radiographic imaging, and protein informatics to identify and predict the functional impact of the VUS on the protein's behavior and predicted impact on the related pathways. The observed and analyzed defects in the protein were consistent with the expected clinical effect. Here, we support the use of personalized protein modeling and informatics and further our goal of developing a large-scale protein deposition archive for all protein-level VUS.

Furuya M, Nakatani Y
Pathology of Birt-Hogg-Dubé syndrome: A special reference of pulmonary manifestations in a Japanese population with a comprehensive analysis and review.
Pathol Int. 2019; 69(1):1-12 [PubMed] Related Publications
Birt-Hogg-Dubé (BHD) syndrome is a rare genetic disorder characterized by cutaneous fibrofolliculomas, pulmonary cysts and renal cell carcinomas. Affected individuals inherit germline mutations in the folliculin gene (FLCN). Approximately 150 pathogenic FLCN variants have been identified worldwide. Many Japanese probands of BHD syndrome were first identified by pulmonologists and/or radiologists during treatment of pneumothoraces. Lung specimens obtained through video-assisted thoracoscopic surgery (VATS) have characteristic features unique to BHD syndrome; however, pathologists often miss key findings and diagnose patients with "bullae/blebs". The pleural and subpleural cysts of BHD syndrome-associated lung diseases are often modified by tissue remodeling and can be difficult to distinguish from emphysematous bullae/blebs. Intraparenchymal unruptured cysts tend to retain distinctive features that are different from other cystic lung diseases. Here, we review the clinicopathological findings of BHD syndrome in a Japanese population based on data from 200 probands diagnosed by genetic testing and a total of 520 symptomatic family members identified through BHD-NET Japan (http://www.bhd-net.jp/). Detailed morphology of pulmonary cysts obtained from VATS and autopsied lung specimens are described, and pathological clues for differentiating miscellaneous cystic lung disorders are discussed.

Yang H, Jin L, Sun X
A thirteen‑gene set efficiently predicts the prognosis of glioblastoma.
Mol Med Rep. 2019; 19(3):1613-1621 [PubMed] Article available free on PMC after 01/02/2020 Related Publications
Glioblastoma multiforme (GBM) is the most common type of brain cancer; it usually recurs and patients have a short survival time. The present study aimed to construct a gene expression classifier and to screen key genes associated with GBM prognosis. GSE7696 microarray data set included samples from 10 recurrent GBM tissues, 70 primary GBM tissues and 4 normal brain tissues. Seed genes were identified by the 'survival' package in R and subjected to pathway enrichment analysis. Prognostic genes were selected from the seed genes using the 'rbsurv' package in R, unsupervised hierarchical clustering, survival analysis and enrichment analysis. Multivariate survival analysis was performed for the prognostic genes, and the GBM data set from The Cancer Genome Atlas database was utilized to validate the prognostic genes. Of the 1,785 seed genes analyzed, 13 prognostic feature genes, including collagen type XXVIII α1 chain (COL28A1), PDS5 cohesin‑associated factor A (PDS5A), zinc‑finger DHHC‑type containing 2 (ZDHHC2), zinc‑finger protein 24 (ZNF24), myosin VA (MYO5A) and myeloid/lymphoid or mixed‑lineage leukemia translocated to 4 (MLLT4), were identified. These genes performed well on sample classification and prognostic risk differentiation, and six pathways, including adherens junction, cyclic adenosine 3',5'‑monophosphate signaling and Ras signaling pathways, were enriched for these feature genes. The high‑risk group was slightly older compared with the low‑risk group. The validation data set confirmed the prognostic value of the 13 feature genes for GBM; of these, COL28A1, PDS5A, ZDHHC2, ZNF24, MYO5A and MLLT4 may be crucial. These results may aid the understanding of the pathogenesis of GBM and provide important clues for the development of novel diagnostic markers or therapeutic targets.

Paziewska A, Polkowski M, Rubel T, et al.
Mass Spectrometry-Based Comprehensive Analysis of Pancreatic Cyst Fluids.
Biomed Res Int. 2018; 2018:7169595 [PubMed] Article available free on PMC after 01/02/2020 Related Publications
Pancreatic cyst fluids (PCFs) enriched in tumour-derived proteins are considered a potential source of new biomarkers. This study aimed to determine compositional and quantitative differences between the degradome and proteome of PCFs aspirated from different types of pancreatic cyst lesions (PCLs). 91 patients who underwent endoscopic ultrasound-fine needle aspiration under routine clinical diagnosis of PCLs were enrolled. Four cysts were malignant (CAs), and 87 were nonmalignant and consisted of 18 intraductal papillary mucinous neoplasms (IPMNs), 14 mucinous cystic neoplasms (MCNs), nine serous cystic neoplasms (SCNs), 29 pseudocysts (PCs), and 17 unclassified. Profiles of the <5 kDa fraction, the degradome, and the trypsin-digested proteome were analysed using an LTQ-Orbitrap Elite mass spectrometer coupled with a nanoACQUITY LC system. Qualitative analyses identified 796 and 366 proteins in degradome and proteome, respectively, and 689 (77%) and 285 (78%) of them were present in the Plasma Proteome Database. Gene Ontology analysis showed a significant overrepresentation of peptidases and peptidases inhibitors in both datasets. In the degradome fraction, quantitative values were obtained for 6996 peptides originating from 657 proteins. Of these, 2287 peptides were unique to a single type, and 515 peptides, derived from 126 proteins, were shared across cyst types. 32 peptides originating from 12 proteins had differential (adjusted

Li W, Qiu T, Guo L, et al.
NGS-based oncogenic mutations analysis in advanced colorectal cancer patients improves targeted therapy prediction.
Pathol Res Pract. 2019; 215(3):483-489 [PubMed] Related Publications
BACKGROUND: Characterization of genetic alterations has been revealed to be important to predict the outcomes of targeted therapy in cancer. We here aimed to assess the mutation profiling of 526 colorectal cancer (CRC) patients by next-generation sequencing (NGS) to enable a more personalized anti-EGFR treatment.
METHODS: Tumors were analyzed using NGS to determine hotspot mutations in 22 cancer-related genes.
RESULTS: Mutations were observed in 13 genes in 436 of 526 (82.9%) tumors, and the most common mutations occurred in TP53 and KRAS. PIK3CA mutations usually coexisted with KRAS, NRAS or BRAF mutations. A higher frequency of concomitant PIK3CA mutations was observed in tumors with KRAS outside codon 13 mutations, with NRAS codon 61 mutations and with BRAF kinase-activated mutations. Moreover, KRAS, PIK3CA, AKT1 and FBXW7 mutations were statistically associated with some clinicopathological features, including location, age or metastasis of CRC patients. For RAS wild-type patients treated with cetuximab, longer progression-free survival (PFS) was observed in patients identified as wild type in all 22 genes compared with patients with mutations in one or more genes.
CONCLUSIONS: A wild-type result in all 22 cancer-related genes detected by NGS is associated with a better outcome of cetuximab treatment. Determining mutation patterns by NGS may aid to understand the molecular mechanisms of CRC and improve targeted therapy prediction.

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