Harnessing transposons for cancer gene discovery

Cancer gene discovery continues to drive current cancer research with the promise of identifying new diagnostic markers and therapeutic targets by elucidating novel genetic interactions that promote or sustain tumor formation. Sleeping Beauty（SB） transposoniated insertional mutagenesis has emerged as an exciting approach to identify novel cancer-causing genes in the mouse. The SB transposon faithfully ＂hops＂ throughout the genome by a cut-and-paste mechanism mediated by the ubiquitous expression of the SB transposase. Initial tumor data generated using an SB transposon harboring the MSCV promoter demonstrated a bias towards hematopoietic tumors. More recently, experiments using a modified SB transposon containing the CAG promoter have generated cohorts of mice with solid tumors, primarily carcinomas, which in some cases metastasize. Many animals also develop multiple, inde- pendent primary tumors. These data demonstrate the utility of the SB transposition system for cancer gene discovery across organ systems.

Ethnic differences in gastric cancer genetic susceptibility:Allele flips of interleukin gene

Polymorphisms in promoter regions of inflammatory cytokines have been widely studied,and potentially functional polymorphisms have been discovered.Conflicting results from meta-analyses of interleukin(IL)-1B and IL-10 polymorphisms show differences in gastric cancer susceptibilities between Caucasian and Asian populations.In particular,we note the suggestion of an allele flip in IL-1B and IL-10 gene polymorphisms.In Asian populations,the IL-1B-1464G/-511C/-31T haplotype indicates risk for gastric cancer,while the opposite haplotype,IL-1B-1464C/-511T/-31C is the risk-related allele in Caucasians.Furthermore,while IL-10-1082G/-819C/-592C is associated with gastric cancer in Asians,IL-10-1082A/-819T/-592T is linked to gastric cancer risk in Caucasians.These seemingly contradictory results may be attributed to distinct carcinogenic mechanisms underlying the different gastric cancer subtypes.The allele flip observed in IL-10 and gastric cancer appears to reflect allelic heterogeneity,similar to that observed in IL-1B.In this review,we focus on the allele flip phenomenon observed between different ethnic groups in an effort to resolve certain controversial results from recent studies on interleukin polymorphism.In addition,we re-emphasize the importance of stratifying gastric cancer subtypes based on anatomical site and Lauren classification to prevent false associations arising through dilution of true ones.

Anticancer Gene-engineered MSC-mediated Cancer Cell Death: An Imaging Demonstration

This study was performed to demonstrate the transportation of an engineered MSC-produced intracellular anticancer gene product between mesenchymal stem cell (MSC) and cancer cells.? MSC-mediated anticancer strategy has held great promise owing to MSCs’ capacity of tumor-directed migration and the availability of specific anticancer genes.? All anticancer genes that have been used in previous MSC-mediated anticancer studies were limited in functioning via extracellular mechanisms, mainly because of the restriction by cell membrane to macromolecules including proteins.? In order to apply the majority of potent anticancer genes to the MSC-mediated anticancer system, a specifically designed expression vector which bears an intracellular anticancer gene, PTEN, is utilized to demonstrate the feasibility of the system in cancer therapies.? A transacting activator of transcription (TAT) was introduced into an expression vector followed by a segment for PTEN-RFP fusion protein.? A direct demonstration of PTEN-RFP transportation between MSC and cancer cells was obtained from direct co-cultures.? A marked cancer cell death was observed in indirect co-cultures with conditioned media from PTEN-transfected MSCs.? The demonstration of PTEN-engineered MSC-produced PTEN transportation indicates the feasibility of applying intracellular anticancer gene expression system in MSC-mediated strategies for cancer therapy.

Human cancer genetics

The short report will be focused on the genetic basis and possible mechanisms of tumorigenesis, common types of cancer, the importance of genetic diagnosis of cancer, and the methodology of cancer genetic diagnosis. They will also review presymptomatic testing of hereditary cancers, and the application of expression profiling to identify patients likely to benefit from particular therapeutic approaches.

The Investigation into Intrinsic Elements Influencing the Onset of Lung Cancer

Lung cancer is a highly heterogeneous malignancy with a complex pathogenesis, involving a series of endogenous alterations such as genetic mutations, epigenetic modifications, and oxidative stress. Recent advancements in lung cancer research, especially at the genomic and molecular biology levels, have continuously provided new potential targets and perspectives for the diagnosis and treatment of lung cancer. Therefore, this article summarizes the recent progress in the study of endogenous factors related to the pathogenesis of lung cancer, aiming to enhance the understanding of intrinsic factors in lung cancer and to organize ideas for subsequent related research.

The Frequency of the v-AKT Murine Thymoma Viral Oncogene Homologue 1 Gene Amplification among Sudanese Women with Ovarian Cancer: A Cross-Sectional Study

Background: Protein kinase B (AKT/PKB) family is frequently amplified in ovarian cancer (OC). To the greatest of our knowledge, there is a lack of published reports about the amplification of the genes belonging to the AKT family among Sudanese women with OC. The present study was conducted to detect the AKT1 gene amplification and its association with tumour types, grades, and ages among Sudanese women with OC, bearing in mind the ethnic variation. Methods: This institution-based study included 79 cases of women diagnosed with ovarian cancer (OC) at Omdurman Maternity Hospital in the period 2013-2018. Formalin-fixed, paraffin-embedded (FFPE) tissue sections were used to extract RNA. AKT1 gene amplification was assessed using quantitative real-time PCR. Results: The mean age (±SD) of included women was 49.29 (±13.612). The amplification of AKT1 gene was observed in 18/79 (22.8%) of OC women, with a high frequency in women with undifferentiated 1/2 (50%), clear cell 2/6 (33.3%), mucinous 3/11 (27.3%), endometrioid 3/17 (17.6%), and serous carcinomas 5/30 OC (16.7%). High frequency was seen in women with low (26.3%;n = 10/28) rather than in higher (19.5%;n = 8/33) grade carcinoma, and in older (25.8%;n = 8/23) rather than younger (18.2%;n = 2/9) women. No significant association between AKT1 gene amplification and tumour types, grades, and ages of women was observed (Fisher’s Exact test: p = 0.405, 0.593 and 0.851, respectively). Conclusion: AKT1 gene amplification arises in around one-fifth of Sudanese women with ovarian cancer (OC). It is seen more in undifferentiated, clear cell, and mucinous tumours types, and more frequently in low tumour grade and older women, but not to a statistically significant level. These outcomes sustenance previous studies suggesting that activated AKT genes have a vital role in OC progression and may offer a plan for targeted therapy and prognostic evaluation.

Mining and Integrating Reliable Decision Rules for Imbalanced Cancer Gene Expression Data Sets

There have been many skewed cancer gene expression datasets in the post-genomic era. Extraction of differential expression genes or construction of decision rules using these skewed datasets by traditional algorithms will seriously underestimate the performance of the minority class, leading to inaccurate diagnosis in clinical trails. This paper presents a skewed gene selection algorithm that introduces a weighted metric into the gene selection procedure. The extracted genes are paired as decision rules to distinguish both classes, with these decision rules then integrated into an ensemble learning framework by majority voting to recognize test examples; thus avoiding tedious data normalization and classifier construction. The mining and integrating of a few reliable decision rules gave higher or at least comparable classification performance than many traditional class imbalance learning algorithms on four benchmark imbalanced cancer gene expression datasets.

Genetic predisposition to colorectal cancer:Where we stand and future perspectives

The development of colorectal cancer(CRC)can be influenced by genetic factors in both familial cases and sporadic cases.Familial CRC has been associated with genetic changes in high-,moderate-and low-penetrance susceptibility genes.However,despite the availability of current gene-identification techniques,the genetic causes of a considerable proportion of hereditary cases remain unknown.Genome-wide association studies of CRC have identified a number of common lowpenetrance alleles associated with a slightly increased or decreased risk of CRC.The accumulation of low-risk variants may partly explain the familial risk of CRC,and some of these variants may modify the risk of cancer in patients with mutations in high-penetrance genes.Understanding the predisposition to develop CRC will require investigators to address the following challenges:the identification of genes that cause uncharacterized hereditary cases of CRC such as familial CRC type X and serrated polyposis;the classification of variants of unknown significance in known CRC-predisposing genes;and the identification of additional cancer risk modifiers that can be used to perform risk assessments for individual mutation carriers.We performed a comprehensive review of the genetically characterized and uncharacterized hereditary CRC syndromes and of lowand moderate-penetrance loci and variants identified through genome-wide association studies and candidate-gene approaches.Current challenges and future perspectives in the field of CRC predisposition are also discussed.

Literature-based knowledgebase of pancreatic cancer gene to prioritize the key genes and pathways

Pancreatic cancer （PC） occurs when malignant cells develop in the part of the pancreas, a glandular organ behind the stomach. For 2015, there are about 40,560 people dead of pancreatic cancer （20,710 men and 19,850 women） in the US （Siegel et al., 2015）. Though PC accounts for about 3% of all cancers in the US, it can cause about 7% of cancer deaths. This is mainly because that the early stages of this cancer do not usually produce symptoms, and thus the cancer is almost always fatal when it is diagnosed.

Detection of Breast Cancer 1 (BRCA1) Gene Using an Electrochemical DNA Biosensor Based on Immobilized ZnO Nanowires

Herein we report an electrochemical DNA biosensor for the rapid detection of sequence (5’ AAT GGA TTT ATC TGC TCT TCG 3’) specific for the breast cancer 1 (BRCA1) gene. The proposed electrochemical genosensor is based on short oligonucleotide DNA probe immobilized onto zinc oxide nanowires (ZnONWs) chemically synthesized onto gold electrode via hydrothermal technique. The morphology studies of the ZnONWs, performed by field emission scanning electron microscopy (FESEM), showed that the ZnO nanowires are uniform, highly dense and oriented perpendicularly to the substrate. Recognition event between the DNA probe and the target was investigated by differential pulse voltammetry (DPV) in 0.1 M acetate buffer solution (ABS), pH 7.00;as a result of the hybridization, an oxidation signal was observed at +0.8 V. The influences of pH, target concentration, and non-complimentary DNA on biosensor performance were examined. The proposed DNA biosensor has the ability to detect the target sequence in the range of concentration between 10.0 and 100.0 μM with a detection limit of 3.32 μM. The experimental results demonstrated that the prepared ZnONWs/Au electrodes are suitable platform for the immobilization of DNA.

A developed ant colony algorithm for cancer molecular subtype classification to reveal the predictive biomarker in the renal cell carcinoma

Background:Recently,researchers have been attracted in identifying the crucial genes related to cancer,which plays important role in cancer diagnosis and treatment.However,in performing the cancer molecular subtype classification task from cancer gene expression data,it is challenging to obtain those significant genes due to the high dimensionality and high noise of data.Moreover,the existing methods always suffer from some issues such as premature convergence.Methods:To address those problems,we propose a new ant colony optimization(ACO)algorithm called DACO to classify the cancer gene expression datasets,identifying the essential genes of different diseases.In DACO,first,we propose the initial pheromone concentration based on the weight ranking vector to accelerate the convergence speed;then,a dynamic pheromone volatility factor is designed to prevent the algorithm from getting stuck in the local optimal solution;finally,the pheromone update rule in the Ant Colony System is employed to update the pheromone globally and locally.To demonstrate the performance of the proposed algorithm in classification,different existing approaches are compared with the proposed algorithm on eight high-dimensional cancer gene expression datasets.Results:The experiment results show that the proposed algorithm performs better than other effective methods in terms of classification accuracy and the number of feature sets.It can be used to address the classification problem effectively.Moreover,a renal cell carcinoma dataset is employed to reveal the biological significance of the proposed algorithm from a number of biological analyses.Conclusion:The results demonstrate that CAPS may play a crucial role in the occurrence and development of renal clear cell carcinoma.

Genomic and genetic alterations influence the progression of gastric cancer

Gastric cancer is one of the leading causes of cancerrelated deaths worldwide, although the incidence has gradually decreased in many Western countries. Two main gastric cancer histotypes, intestinal and diffuse, are recognised. Although most of the described genetic alterations have been observed in both types, different genetic pathways have been hypothesized. Genetic and epigenetic events, including 1q loss of heterozygosity (LOH), microsatellite instability and hypermethylation, have mostly been reported in intestinal-type gastric carcinoma and its precursor lesions, whereas 17p LOH, mutation or loss of E-cadherin are more often implicated in the development of diffuse-type gastric cancer.In this review, we summarize the sometimes contradictory findings regarding those markers which influence the progression of gastric adenocarcinoma.

Gene-diet interactions in gastric cancer risk: A systematic review

AIM:To conduct a systematic review of the published epidemiological studies investigating the association of the interactions between gene variants and dietary intake with gastric cancer risk.METHODS:A literature search was conducted in PubMed,EMBASE,and MEDLINE for articles published between January 2000 and July 2013,and 38 studies were identified.Previous studies included various dietary factors(e.g.,fruits and vegetables,soybean products,salt,meat,and alcohol)and genetic variants that are involved in various metabolic pathways.RESULTS:Studies suggest that individuals who carry high-risk genetic variants and demonstrate particular dietary habits may have an increased risk of gastric cancer compared with those who do not carry high-risk genetic variants.Distinctive dietary patterns and variations in the frequency of genetic variants may explain the higher incidence of gastric cancer in a particular region.However,most previous studies have limitations,such as a small sample size and a retrospective casecontrol design.In addition,past studies have been unable to elucidate the specific mechanism in gene-diet interaction associated with gastric carcinogenesis.CONCLUSION:Additional large prospective epidemiological and experimental studies are required to identify the gene-diet metabolic pathways related to gastric cancer susceptibility.

Targeting Gene-Virotherapy of Cancer and its prosperity

为癌症的基因和病毒的治疗显示出一些治疗学的效果，但是有真实突破的缺乏。为了达到肿瘤的完全的消除的目标，在动物的异种皮移植当模特儿，我们开发了叫的新策略指向癌症的 Gene-Virotherapy，它试图联合基因治疗和 virotherapy 的优点。这新策略独自比基因或病毒的治疗生产了更强壮的反肿瘤效果。肿瘤特定的 replicative 侵入人体气管粘膜的病菌向量，指定了为 ZD55，被侵入人体气管粘膜的病菌的 55kDa E1B 区域的删除构造。结果病毒的构造不仅由明确地指向 p53 保留类似的功能到 ONYX-015 否定肿瘤，而且允许各种各样的治疗学的基因到的插入由于最新介绍的克隆的地点形成适当 ZD55 衍生物，与原来的 ONYX-015 病毒不可行的一项任务。我们证明反肿瘤一如此的衍生物完成， ZD55-IL-24，比 ZD55 virotherapy 或 Ad-IL-24 基因治疗的是乘更多的有势力的至少 100。不过，由 ZD55-IL-24 的使用的肿瘤质量的完全的消除是仅仅在一些然而并非所有老鼠观察了，显示那一治疗学的基因不对“痊愈”足够这些老鼠。有互补或合作的效果的基因是什么时候，独立克隆进 ZD55 向量并且在联合使用了(指定了为双基因治疗策略) ，好一些的结果被获得；并且如果二合适的基因被选择，在所有老鼠完成所有异种皮移植肿瘤群众的完全的消除是可能的。更全面的研究将多半为临床的试用基于这新策略导致一个协议。最后，为癌症治疗的两倍控制指向的病毒双的基因治疗的概念，和在癌症干细胞的最近的进步的含意也被讨论。

Gene expression profile of peripheral blood in colorectal cancer

AIM:Optimal molecular markers for detecting colorectal cancer(CRC)in a blood-based assay were evaluated.METHODS:A matched(by variables of age and sex)case-control design(111 CRC and 227 non-cancer samples)was applied.Total RNAs isolated from the338 blood samples were reverse-transcribed,and the relative transcript levels of candidate genes were analyzed.The training set was made of 162 random samples of the total 338 samples.A logistic regression analysis was performed,and odds ratios for each gene were determined between CRC and non-cancer.The samples(n=176)in the testing set were used to validate the logistic model,and an inferred performance(generality)was verified.By pooling 12 public microarray datasets(GSE 4107,4183,8671,9348,10961,13067,13294,13471,14333,15960,17538,and 18105),which included 519 cases of adenocarcinoma and 88 controls of normal mucosa,we were able to verify the selected genes from logistic models and estimate their external generality.RESULTS:The logistic regression analysis resulted in the selection of five significant genes(P<0.05;MDM2,DUSP6,CPEB4,MMD,and EIF2S3),with odds ratios of 2.978,6.029,3.776,0.538 and 0.138,respectively.The five-gene model performed stably for the discrimination of CRC cases from controls in the training set,with accuracies ranging from 73.9%to 87.0%,a sensitivity of 95%and a specificity of 95%.In addition,a good performance in the test set was obtained using the discrimination model,providing 83.5%ac-curacy,66.0%sensitivity,92.0%specificity,a positive predictive value of 89.2%and a negative predictive value of 73.0%.Multivariate logistic regressions analyzed 12 pooled public microarray data sets as an external validation.Models that provided similar expected and observed event rates in subgroups were termed well calibrated.A model in which MDM2,DUSP6,CPEB4,MMD,and EIF2S3 were selected showed the result in logistic regression analysis(H-L P=0.460,R2=0.853,AUC=0.978,accuracy=0.949,specificity=0.818 and sensitivity=0.971).CONCLUSION:A novel gene expression profile was associated with CRC and can potentially be applied to blood-based detection assays.

A novel strategy for cancer gene therapy:RNAi

RNA 干扰(RNA ) 由两倍搁浅的 RNA 在 posttranscriptionmediated 的水平导致基因 silencing。为小 double-strandedinterference RNA (siRNA ) 的交货有众多的方法到目标房间，包括非病毒、病毒的向量。在这些方法之中，病毒的向量是更有效的车辆。由在目标房间的病毒的向量的短发卡 RNA (shRNA ) 的表示能被 Dicer 酶切成为约 21 bp siRNA，它能指导血缘的 mRNA 的降级。RNAi 技术能用许多策略对癌症被指导，包括抑制，支持 apoptosis，调整房间周期在上表示了 oncogenes， antiangiogenesis 并且提高化疗和放射疗法的功效。因为 RNAi 技术为癌症基因治疗成为了优秀策略，这评论构画出如此的一种新奇技术的最近的开发和应用程序。

Targeting gene-virotherapy of cancer

我们的目的到完全在动物肿瘤的异种皮移植肿瘤的消除当模特儿以便为痊愈得出 protocal 耐心。为癌症的基因治疗和病毒的治疗得到了一些治疗学的效果，但是两个都没有大突破。因此，我们得出了叫的新策略指向是基因治疗和 virotherapy 的优点的联合的癌症的 Gene-Virotherapy。这新策略独自他们比也有更强壮的反肿瘤效果。一个肿瘤特定的 replicative 侵入人体气管粘膜的病菌向量 ZD55 (E1B 55KD 删除了副词) 它类似于在指向 fuction 的 ONYX-015 但是重要在建设不同被生产，各种各样的单个治疗学的基因被插入到 ZD55。现在，象指向癌症的 Gene-Virotherapy 的如此的一个概念被提起，尽管独立 ONYX-015-tk， -cd 或 cd/-tk 等等上有一些工作，全身的联盟者以前学习了。ZD55 基因的反肿瘤效果(例如 IL-24 基因) 独自比 ZD55 (virotherapy ) 好一些并且比 Ad-IL-24 (基因治疗) 的高的百褶层独自一个。ZD55-IL-24 在在 ZD55-IL-24 治疗学习的 preclinal，完全，肿瘤质量的消除在一些老鼠然而并非在所有老鼠被发生，那意味着一基因不是足够的 effictive 在所有老鼠消除所有肿瘤团。因此，有赔偿或合作的效果的二基因独立被插入到 ZD55 并且在联合使用了。这策略被叫指向癌症的双 Gene-Virotherapy (与 % 专利) 。那么好一些的结果被获得，所有异种皮移植肿瘤群众完全在所有老鼠被消除，如果二合适的基因被选择。根据二基因结果的开始，使用二个肿瘤倡导者控制病毒向量将对指向的效果和这些药的 safty 更好，这被考虑。然后双的肿瘤控制了怀有二基因的病毒向量因为癌症治疗被得出。更好的结果被获得了，另一项专利被使用了。这反肿瘤策略能被用来与正常房间的最小的损坏在所有老鼠完全杀死所有肿瘤房间。

PCR-SSCP-DNA sequencing method in detecting PTEN gene mutation and its signifi cance in human gastric cancer

AIM: To discuss the possible effect of PTEN gene mutations on occurrence and development of gastric cancer. METHODS: Fifty-three gastric cancer specimens were selected to probe PTEN gene mutations in genome of gastric cancer and paracancerous tissues using PCR-SSCP-DNA sequencing method based on microdissection and to observe the protein expression by immunohistochemistry technique. RESULTS: PCR-SSCP-DNA sequencing indicated that 4 kinds of mutation sites were found in 5 of 53 gastric cancer specimens. One kind of mutation was found in exons. AA-TCC mutation was located at 40bp upstream of 3’ lateral exon 7 (115946 AA-TCC). Such mutations led to terminator formation in the 297th codon of the PTEN gene. The other 3 kinds of mutation were found in introns,including a G-C point mutation at 91 bp upstream of 5’ lateral exon 5(90896 G-C),a T-G point mutation at 24 bp upstream of 5’ lateral exon 5 (90963 T-G),and a single base A mutation at 7 bp upstream of 5’ lateral exon 5 (90980 A del). The PTEN protein expression in gastric cancer and paracancerous tissues detected using immunohistochemistry technique indicated that the total positive rate of PTEN protein expression was 66% in gastric cancer tissue,which was significantly lower than that (100%) in paracancerous tissues (P < 0.005). CONCLUSION: PTEN gene mutation and expression may play an important role in the occurrence and development of gastric cancer.

Adenoviral gene therapy in gastric cancer: A review

Gastric cancer is one of the most common malignancies worldwide. With current therapeutic approaches the prognosis of gastric cancer is very poor, as gastric cancer accounts for the second most common cause of death in cancer related deaths. Gastric cancer like almost all other cancers has a molecular genetic basis which relies on disruption in normal cellular regulatory mechanisms regarding cell growth, apoptosis and cell division. Thus novel therapeutic approaches such as gene therapy promise to become the alternative choice of treatment in gastric cancer. In gene therapy, suicide genes, tumor suppressor genes and anti-angiogenesis genes among many others are introduced to cancer cells via vectors. Some of the vectors widely used in gene therapy are Adenoviral vectors. This review provides an update of the new developments in adenoviral cancer gene therapy including strategies for inducing apoptosis, inhibiting metastasis and targeting the cancer cells.

UGT1A1 gene polymorphism: Impact on toxicity and efficacy of irinotecan-based regimens in metastatic colorectal cancer

AIM: To investigate the correlation between uridine diphosphate glucuronosyl transferase 1A1 (UGT1A1) gene polymorphisms and irinotecan-associated side effects and parameters of drug efficacy in patients with metastatic colorectal cancer (mCRC) receiving a low-dose weekly irinotecan chemotherapeutic regimen. METHODS: Genotypes were retrospectively evaluated by gene scan analysis on the ABI 310 sequencer of the TATAA box in the promoter region of the UGT1A1 gene in blood samples from 105 patients who had received 1st line irinotecan-based chemotherapy for mCRC. RESULTS: The distribution of the genotypes was as follows: wild type genotype (WT) (6/6 ) 39.0%, heterozygous genotype (6/7) 49.5%, and homozygous genotype (7/7) 9.5%. The overall response rate (OR) was similar between patients carrying the (6/7, 7/7) or the WT genotype (6/6) (44.3% vs 43.2%, P = 0.75). Neither time to progression [(TTP) 8.1 vs 8.2 mo, P = 0.97] nor overall survival [(OS) 21.2 vs 18.9 mo, P = 0.73] differed significantly in patients who carried the(6/6) when compared to the (6/7, 7/7) genotype. No significant differences in toxicity were observed: Grade 3 and 4 delayed diarrhoea [(6/7, 7/7) vs (6/6); 13.0% vs 6.2%, P =0.08], treatment delays [(6/7, 7/7) vs (6/6); 25.1% vs 19.3%, P = 0.24] or dose reductions [(6/7, 7/7) vs (6/6); 21.5% vs 27.2%, P = 0.07].CONCLUSION: This analysis demonstrates the non-significant influence of the UGT1A1 gene polymorphism on efficacy and rate of irinotecan-associated toxicity in mCRC patients receiving low-dose irinotecan based chemotherapy.