Research IndicatorsGraph generated 01 September 2019 using data from PubMed using criteria.
Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic. Tag cloud generated 01 September, 2019 using data from PubMed, MeSH and CancerIndex
Specific Cancers (2)
Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.
Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).
OMIM, Johns Hopkin University
Referenced article focusing on the relationship between phenotype and genotype.
International Cancer Genome Consortium.
Summary of gene and mutations by cancer type from ICGC
Cancer Genome Anatomy Project, NCI
COSMIC, Sanger Institute
Somatic mutation information and related details
GEO Profiles, NCBI
Search the gene expression profiles from curated DataSets in the Gene Expression Omnibus (GEO) repository.
Latest Publications: NCKIPSD (cancer-related)
BACKGROUND: In melanoma, like in other cancers, both genetic alterations and epigenetic underlie the metastatic process. These effects are usually measured by changes in both methylome and transcriptome profiles, whose cross-correlation remains uncertain. We aimed to assess at systems scale the significance of epigenetic treatment in melanoma cells with different metastatic potential.
METHODS AND FINDINGS: Treatment by DAC demethylation with 5-Aza-2'-deoxycytidine of two melanoma cell lines endowed with different metastatic potential, SKMEL-2 and HS294T, was performed and high-throughput coupled RNA-Seq and RRBS-Seq experiments delivered differential profiles (DiP) of both transcriptomes and methylomes. Methylation levels measured at both TSS and gene body were studied to inspect correlated patterns with wide-spectrum transcript abundance levels quantified in both protein coding and non-coding RNA (ncRNA) regions. The DiP were then mapped onto standard bio-annotation sources (pathways, biological processes) and network configurations were obtained. The prioritized associations for target identification purposes were expected to elucidate the reprogramming dynamics induced by the epigenetic therapy. The interactomic connectivity maps of each cell line were formed to support the analysis of epigenetically re-activated genes. i.e. those supposedly silenced by melanoma. In particular, modular protein interaction networks (PIN) were used, evidencing a limited number of shared annotations, with an example being MAPK13 (cascade of cellular responses evoked by extracellular stimuli). This gene is also a target associated to the PANDAR ncRNA, therapeutically relevant because of its aberrant expression observed in various cancers. Overall, the non-metastatic SKMEL-2 map reveals post-treatment re-activation of a richer pathway landscape, involving cadherins and integrins as signatures of cell adhesion and proliferation. Relatively more lncRNAs were also annotated, indicating more complex regulation patterns in view of target identification. Finally, the antigen maps matched to DiP display other differential signatures with respect to the metastatic potential of the cell lines. In particular, as demethylated melanomas show connected targets that grow with the increased metastatic potential, also the potential target actionability seems to depend to some degree on the metastatic state. However, caution is required when assessing the direct influence of re-activated genes over the identified targets. In light of the stronger treatment effects observed in non-metastatic conditions, some limitations likely refer to in silico data integration tools and resources available for the analysis of tumor antigens.
CONCLUSION: Demethylation treatment strongly affects early melanoma progression by re-activating many genes. This evidence suggests that the efficacy of this type of therapeutic intervention is potentially high at the pre-metastatic stages. The biomarkers that can be assessed through antigens seem informative depending on the metastatic conditions, and networks help to elucidate the assessment of possible targets actionability.
Zheng Y, Zhang DY, Zhang H, et al.Photodamaging of Mitochondrial DNA to Overcome Cisplatin Resistance by a Ru
Chemistry. 2018; 24(71):18971-18980 [PubMed
] Related Publications
Emerging studies have shown that mitochondrial DNA (mtDNA) is an attractive target for anticancer therapeutics. Herein, a heterobimetallic complex [Ru(dip)
Mesuraca M, Amodio N, Chiarella E, et al.Turning Stem Cells Bad: Generation of Clinically Relevant Models of Human Acute Myeloid Leukemia through Gene Delivery- or Genome Editing-Based Approaches.
Molecules. 2018; 23(8) [PubMed
] Free Access to Full Article Related Publications
Acute myeloid leukemia (AML), the most common acute leukemia in the adult, is believed to arise as a consequence of multiple molecular events that confer on primitive hematopoietic progenitors unlimited self-renewal potential and cause defective differentiation. A number of genetic aberrations, among which a variety of gene fusions, have been implicated in the development of a transformed phenotype through the generation of dysfunctional molecules that disrupt key regulatory mechanisms controlling survival, proliferation, and differentiation in normal stem and progenitor cells. Such genetic aberrations can be recreated experimentally to a large extent, to render normal hematopoietic stem cells "bad", analogous to the leukemic stem cells. Here, we wish to provide a brief outline of the complementary experimental approaches, largely based on gene delivery and more recently on gene editing, employed over the last two decades to gain insights into the molecular mechanisms underlying AML development and progression and on the prospects that their applications offer for the discovery and validation of innovative therapies.
Karunasinghe N, Ambs S, Wang A, et al.Influence of lifestyle and genetic variants in the aldo-keto reductase 1C3 rs12529 polymorphism in high-risk prostate cancer detection variability assessed between US and New Zealand cohorts.
PLoS One. 2018; 13(6):e0199122 [PubMed
] Free Access to Full Article Related Publications
INTRODUCTION: The prostate-specific antigen (PSA) based prostate cancer (PC) screening is currently being debated. The current assessment is to understand the variability of detecting high-risk PC in a NZ cohort in comparison to a US cohort with better PSA screening facilities. Aldo-keto reductase 1C3 (AKR1C3) is known for multiple functions with a potential to regulate subsequent PSA levels. Therefore, we wish to understand the influence of tobacco smoking and the AKR1C3 rs12529 gene polymorphism in this variability.
METHOD: NZ cohort (n = 376) consisted of 94% Caucasians while the US cohort consisted of African Americans (AA), n = 202, and European Americans (EA), n = 232. PSA level, PC grade and stage at diagnosis were collected from hospital databases for assigning high-risk PC status. Tobacco smoking status and the AKR1C3 rs12529 SNP genotype were considered as confounding variables. Variation of the cumulative % high-risk PC (outcome variable) with increasing PSA intervals (exposure factor) was compared between the cohorts using the Kolmogorov-Smirnov test. Comparisons were carried out with and without stratifications made using confounding variables.
RESULTS: NZ cohort has been diagnosed at a significantly higher mean age (66.67± (8.08) y) compared to both AA (62.65±8.17y) and EA (64.83+8.56y); median PSA (NZ 8.90ng/ml compared to AA 6.86ng/ml and EA 5.80ng/ml); and Gleason sum (NZ (7) compared EA (6)) (p<0.05). The cumulative % high-risk PC detection shows NZ cohort with a significantly lower diagnosis rates at PSA levels between >6 - <10ng/ml compared to both US groups (p<0.05). These were further compounded significantly by smoking status and genetics.
CONCLUSIONS: High-risk PCs recorded at higher PSA levels in NZ could be due to factors including lower levels of PSA screening and subsequent specialist referrals for biopsies. These consequences could be pronounced among NZ ever smokers carrying the AKR1C3 rs12529 G alleles making them a group that requires increased PSA screening attention.
Sun W, Chen X, Xie C, et al.Co-Delivery of Doxorubicin and Anti-BCL-2 siRNA by pH-Responsive Polymeric Vector to Overcome Drug Resistance in In Vitro and In Vivo HepG2 Hepatoma Model.
Biomacromolecules. 2018; 19(6):2248-2256 [PubMed
] Related Publications
Drug resistance, developed through multiple mechanisms, is a major hindrance to successful chemotherapy of tumor. Combination therapy of chemotherapeutic drugs and siRNA represents an emerging strategy which may improve anticancer effect by synergistic actions. In this study, triblock copolymer of poly(ethylene glycol)- block-poly(l-lysine)- block-poly aspartyl ( N-( N', N'-diisopropylaminoethyl)) (PEG-PLL-PAsp(DIP)) was synthesized for the first time to enable the codelivery of BCL-2 siRNA and DOX. The system is supposed to not only bypass drug efflux but also down-regulate the antiapoptotic gene and consequently confronting against chemoresistance as well. Moreover, the pH responsive ability of the codelivery system can prevent drug leakage during circulation and guarantee swift drug release at tumors. The codelivered siRNA serves to suppress the expression of antiapoptotic BCL-2 and hence sensitize the cancer cells to anticancer drugs and produce improved therapeutic effect. Consequently, the codelivery of BCL-2 siRNA and anticancer drug DOX serves as a promising strategy against drug resistance in chemotherapy.
BACKGROUND: Many bioinformatics studies aim to identify markers, or features, that can be used to discriminate between distinct groups. In problems where strong individual markers are not available, or where interactions between gene products are of primary interest, it may be necessary to consider combinations of features as a marker family. To this end, recent work proposes a hierarchical Bayesian framework for feature selection that places a prior on the set of features we wish to select and on the label-conditioned feature distribution. While an analytical posterior under Gaussian models with block covariance structures is available, the optimal feature selection algorithm for this model remains intractable since it requires evaluating the posterior over the space of all possible covariance block structures and feature-block assignments. To address this computational barrier, in prior work we proposed a simple suboptimal algorithm, 2MNC-Robust, with robust performance across the space of block structures. Here, we present three new heuristic feature selection algorithms.
RESULTS: The proposed algorithms outperform 2MNC-Robust and many other popular feature selection algorithms on synthetic data. In addition, enrichment analysis on real breast cancer, colon cancer, and Leukemia data indicates they also output many of the genes and pathways linked to the cancers under study.
CONCLUSIONS: Bayesian feature selection is a promising framework for small-sample high-dimensional data, in particular biomarker discovery applications. When applied to cancer data these algorithms outputted many genes already shown to be involved in cancer as well as potentially new biomarkers. Furthermore, one of the proposed algorithms, SPM, outputs blocks of heavily correlated genes, particularly useful for studying gene interactions and gene networks.
Esteban I, Vilaró M, Adrover E, et al.Psychological impact of multigene cancer panel testing in patients with a clinical suspicion of hereditary cancer across Spain.
Psychooncology. 2018; 27(6):1530-1537 [PubMed
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OBJECTIVE: Patients' psychological reactions to multigene cancer panel testing might differ compared with the single-gene testing reactions because of the complexity and uncertainty associated with the different possible results. Understanding patients' preferences and psychological impact of multigene panel testing is important to adapt the genetic counselling model.
METHODS: One hundred eighty-seven unrelated patients with clinical suspicion of hereditary cancer undergoing a 25-gene panel test completed questionnaires after pretest genetic counselling and at 1 week, 3 months, and 12 months after results to elicit their preferences regarding results disclosure and to measure their cancer worry and testing-specific distress and uncertainty.
RESULTS: A pathogenic variant was identified in 38 patients (34 high penetrance and 4 moderate penetrance variants), and 54 patients had at least one variant of uncertain significance. Overall, cancer panel testing was not associated with an increase in cancer worry after results disclosure (P value = .87). Twelve months after results, carriers of a moderate penetrance variant had higher distress and uncertainty scores compared with carriers of high penetrance variants. Cancer worry prior to genetic testing predicted genetic testing specific distress after results, especially at long term (P value <.001). Most of the patients reported the wish to know all genetic results.
CONCLUSIONS: Our results suggest that patients can psychologically cope with cancer panel testing, but distress and uncertainty observed in carriers of moderate penetrance cancer variants in this cohort warrant further research.
BACKGROUND: Sirolimus has been shown to be effective in patients with lymphangioleiomyomatosis (LAM). We wish to summarize our experience using sirolimus and its effectiveness in LAM patients.
METHODS: We analyzed data from 98 patients who were diagnosed with definite or probable sporadic LAM based on the European Respiratory Society diagnosis criteria for LAM in 2010 at Peking Union Medical College Hospital and who had received sirolimus during January 2007 to June 2015. The data before and after the initiation of sirolimus therapy included pulmonary function tests, arterial blood gas analysis, 6-min walking distance (6MWD), size of chylous effusion and renal angiomyolipomas (AML), St. George's Respiratory Questionnaires (SGRQ) and vascular endothelial growth factor-D (VEGF-D) levels. Serum levels of sirolimus and adverse events were collected.
RESULTS: Median follow-up was 2.5 years. Most patients had forced expiratory volume in 1 s (FEV
CONCLUSION: Long-term use of sirolimus is safe in patients with LAM. LAM patients with FEV
Sciamanna I, Sinibaldi-Vallebona P, Serafino A, Spadafora CLINE-1-encoded reverse Transcriptase as a target in cancer therapy.
Front Biosci (Landmark Ed). 2018; 23:1360-1369 [PubMed
] Related Publications
LINE-1 elements account for about 17% of the human genome and harbour two open reading frames: ORF1, encoding a 40 kDa RNA-binding protein, and ORF2, coding for a 150 kDa protein with reverse transcriptase (RT) activity. LINE-1s are highly expressed in embryos and tumor cells while being virtually silent in differentiated tissues and, consistently, both ORF-1p and ORF-2p have been detected in human cancers. RT-encoding ORF2 is expressed early in pre-neoplastic lesions suggesting that RT expression may be a potential cause, rather than a consequence, of cancer onset. Experimental data emerging from
Gene expression profiles of cutaneous melanoma were analyzed to identify critical genes associated with metastasis. Two gene expression datasets were downloaded from Gene Expression Omnibus (GEO) and another dataset was obtained from The Cancer Genome Atlas (TCGA). Differentially expression genes (DEGs) between metastatic and non‑metastatic melanoma were identified by meta‑analysis. A protein‑protein interaction (PPI) network was constructed for the DEGs using information from BioGRID, HPRD and DIP. Betweenness centrality (BC) was calculated for each node in the network and the top feature genes ranked by BC were selected to construct the support vector machine (SVM) classifier using the training set. The SVM classifier was then validated in another independent dataset. Pathway enrichment analysis was performed for the feature genes using Fisher's exact test. A total of 798 DEGs were identified and a PPI network including 337 nodes and 466 edges was then constructed. Top 110 feature genes ranked by BC were included in the SVM classifier. The prediction accuracies for the three datasets were 96.8, 100 and 94.4%, respectively. A total of 11 KEGG pathways and 13 GO biological pathways were significantly over‑represented in the 110 feature genes, including endometrial cancer, regulation of actin cytoskeleton, focal adhesion, ubiquitin mediated proteolysis, regulation of apoptosis and regulation of cell proliferation. A SVM classifier of high prediction accuracy was acquired. Several critical genes implicated in melanoms metastasis were also revealed. These results may advance understanding of the molecular mechanisms underlying metastasis, and also provide potential therapeutic targets.
The Cancer Genome Atlas (TCGA) has profiled over 10,000 tumors across 33 different cancer-types for many genomic features, including gene expression levels. Gene expression measurements capture substantial information about the state of each tumor. Certain classes of deep neural network models are capable of learning a meaningful latent space. Such a latent space could be used to explore and generate hypothetical gene expression profiles under various types of molecular and genetic perturbation. For example, one might wish to use such a model to predict a tumor's response to specific therapies or to characterize complex gene expression activations existing in differential proportions in different tumors. Variational autoencoders (VAEs) are a deep neural network approach capable of generating meaningful latent spaces for image and text data. In this work, we sought to determine the extent to which a VAE can be trained to model cancer gene expression, and whether or not such a VAE would capture biologically-relevant features. In the following report, we introduce a VAE trained on TCGA pan-cancer RNA-seq data, identify specific patterns in the VAE encoded features, and discuss potential merits of the approach. We name our method "Tybalt" after an instigative, cat-like character who sets a cascading chain of events in motion in Shakespeare's "Romeo and Juliet". From a systems biology perspective, Tybalt could one day aid in cancer stratification or predict specific activated expression patterns that would result from genetic changes or treatment effects.
Stevens JR, Herrick JS, Wolff RK, Slattery MLIdentifying factors associated with the direction and significance of microRNA tumor-normal expression differences in colorectal cancer.
BMC Cancer. 2017; 17(1):707 [PubMed
] Free Access to Full Article Related Publications
BACKGROUND: microRNAs are small non-protein-coding RNA molecules that regulate gene expression, and have a potential epigenetic role in disease progression and survival of colorectal cancer. In terms of tumor-normal expression differences, many microRNAs exhibit evidence of being up-regulated in some subjects but down-regulated in others, or are dysregulated only for a subset of the population. We present and implement an approach to identify factors (lifestyle, tumor molecular phenotype, and survival-related) that are associated with the direction and/or significance of these microRNAs' tumor-normal expression differences in colorectal cancer.
METHODS: Using expression data for 1394 microRNAs and 1836 colorectal cancer subjects (each with both tumor and normal samples), we perform a dip test to identify microRNAs with multimodal distributions of tumor-normal expression differences. For proximal, distal, and rectal tumor sites separately, these microRNAs are tested for tumor-normal differential expression using a signed rank test, both overall and within levels of each lifestyle, tumor molecular phenotype, and survival-related factor. Appropriate adjustments are made to control the overall FDR.
RESULTS: We identify hundreds of microRNAs whose direction and/or significance of tumor-normal differential expression is associated with one or more lifestyle, tumor molecular phenotype, or survival-related factors.
CONCLUSIONS: The results of this study demonstrate the benefit to colorectal cancer researchers to consider multiple subject-level factors when studying dysregulation of microRNAs, whose tumor-related changes in expression can be associated with multiple factors. Our results will serve as a publicly-available resource to provide clarifying information about various factors associated with the direction and significance of tumor-normal differential expression of microRNAs in colorectal cancer.
Li S, Chen X, Liu X, et al.Complex integrated analysis of lncRNAs-miRNAs-mRNAs in oral squamous cell carcinoma.
Oral Oncol. 2017; 73:1-9 [PubMed
] Related Publications
OBJECTIVES: This study aims to reveal regulatory network of lncRNAs-miRNAs-mRNAs in oral squamous cell carcinoma (OSCC) through gene expression data.
MATERIAL AND METHODS: Differentially expressed lncRNAs, miRNAs and mRNAs (cut-off: False discovery rate (FDR)<0.05 and |fold change|>1.5) were unveiled by package edgeR of R. Cox regression analysis was performed to screen prognostic factors in OSCC related with overall survival (OS) and relapse-free survival (RFS). Protein-protein interaction (PPI) network was constructed for differentially expressed mRNAs using BioGRID, HPRD and DIP. Key hub genes were identified from top 100 differentially expressed mRNAs ranked by betweenness centrality using recursive feature elimination. LncRNA-miRNA and miRNA-mRNA regulatory network were constructed and combined into ceRNAs regulatory network. Gene ontology biological terms and Kyoto Encyclopedia of Genes and Genomes pathways were identified using Fisher's exact test.
RESULTS: A total of 929 differentially expressed mRNAs, 23 differentially expressed lncRNAs and 29 differentially expressed miRNAs were identified. 59 mRNAs, 6 miRNAs (hsa-mir-133a-1, hsa-mir-1-2, hsa-mir-486, hsa-mir-135b, hsa-mir-196b, hsa-mir-193b) and 6 lncRNAs (C10orf91, C2orf48, SFTA1P, FLJ41941,PART1,TTTY14) were related with OS; and 52 mRNAs, 4 miRNAs (hsa-mir-133a-1, hsa-mir-135b, hsa-mir-196b, hsa-mir-193b) and 2 lncRNAs (PART1, TTTY14) were associated with RFS. A support vector machine (SVM) classifier containing 37 key hub genes was obtained. A ceRNA regulatory network containing 417 nodes and 696 edges was constructed. ECM-receptor interaction, cytokine-cytokine receptor interaction, focal adhesion, arachidonic acid metabolism, and p53 signaling pathway were significantly enriched in the network.
CONCLUSION: These findings uncover the pathogenesis of OSCC and might provide potential therapeutic targets.
Endometrial cancer is the most common malignancy of the female genital tract. Progesterone (P4) has been used for several decades in endometrial cancer treatment, especially in women who wish to retain fertility. However, it is unpredictable which patients will respond to P4 treatment and which may have a P4-resistant cancer. Therefore, identifying the mechanism of P4 resistance is essential to improve the therapies for endometrial cancer. Mitogen-inducible gene 6 (Mig-6) is a critical mediator of progesterone receptor (PGR) action in the uterus. In order to study the function of Mig-6 in P4 resistance, we generated a mouse model in which we specifically ablated Mig-6 in uterine epithelial cells using Sprr2f-cre mice (Sprr2f
Oral squamous cell carcinoma (OSCC) develops through a multistep carcinogenic process involving field cancerization. The DEK gene is a proto-oncogene with functions in genetic and epigenetic modifications, and has oncogenic functions, including cellular proliferation, differentiation, and senescence. DEK overexpression is associated with malignancies; however, the functional roles of DEK overexpression are unclear. We demonstrated that DEK-expressing cells were significantly increased in human dysplasia/carcinoma in situ and OSCC. Furthermore, we generated ubiquitous and squamous cell-specific doxycycline (DOX)-inducible Dek mice (iDek and iDek-e mice respectively). Both DOX+ iDek and iDek-e mice did not show differences in the oral mucosa compared with DOX- mice. In the environment exposed to carcinogen, DOX-treated (DOX+) iDek mice showed field cancerization and OSCC development. Microarray analysis revealed that DEK overexpression was mediated by the upregulation of DNA replication- and cell cycle-related genes, particularly those related to the G
You E, Huh YH, Kwon A, et al.SPIN90 Depletion and Microtubule Acetylation Mediate Stromal Fibroblast Activation in Breast Cancer Progression.
Cancer Res. 2017; 77(17):4710-4722 [PubMed
] Related Publications
Biomechanical remodeling of stroma by cancer-associated fibroblasts (CAF) in early stages of cancer is critical for cancer progression, and mechanical cues such as extracellular matrix stiffness control cell differentiation and malignant progression. However, the mechanism by which CAF activation occurs in low stiffness stroma in early stages of cancer is unclear. Here, we investigated the molecular mechanism underlying CAF regulation by SPIN90 and microtubule acetylation under conditions of mechanically soft matrices corresponding to normal stromal rigidity. SPIN90 was downregulated in breast cancer stroma but not tumor, and this low stromal expression correlated with decreased survival in breast cancer patients.
Pettit C, Walston S, Wald P, et al.Molecular profiling of locally-advanced rectal adenocarcinoma using microRNA expression (Review).
Int J Oncol. 2017; 51(2):393-404 [PubMed
] Related Publications
Treatment for locally-advanced rectal cancer (LARC) typically consists of neoadjuvant chemoradiation followed by total mesorectal excision. Recently, there has been growing interest in non-operative management for patients who are medically-inoperable or wish to avoid surgical morbidity and permanent colostomy. Approximately 50% of patients who receive pre-operative neoadjuvant chemoradiation develop some degree of pathologic response. Approximately 10-20% of patients are found to have a complete pathologic response, a finding which has frequently been shown to predict better clinical outcomes, including local-regional control, distant metastasis and survival. Many recent studies have evaluated the role of molecular biomarkers in predicting response to neoadjuvant therapy. MicroRNAs (miRNAs) are an emerging class of biomarkers that have the potential to predict which patients are most likely to benefit from pre-operative therapy and from a selective surgical approach. Here, we review the published literature on microRNAs as prognostic and predictive biomarkers in rectal cancer after pre-operative therapy. In the future, the development of prospectively validated miRNA signatures will allow clinical implementation of miRNAs as prognostic and predictive signatures in LARC.
Ulcerative colitis (UC) is defined as an idiopathic inflammatory disorder primarily involving the mucosa and submucosa of the colon. UC-associated colon cancers (also known as colitic cancers) develop through the inflammation-dysplasia sequence, which is a major problem affecting the prognosis of patients with UC. It is therefore very important to detect malignancy from UC at an early stage. As precancerous lesions arising in UC, there are pathological adenomatous changes, basal cell changes, in situ anaplasia, clear cell changes, and pan-cellular change. It is considered that the mutation of the p53 gene plays a crucial role, and the protein expression of p53 in dysplastic crypts may serve as a good biomarker in the early stages of UC-associated colon carcinogenesis. Immunohistochemistry for p53 is a very valuable diagnostic tool in UC-associated colon cancers. However, protein expression of p53 is not always universal, and additional methods may be required to assess p53 status in UC-associated colon cancers.
Shiseki M, Yoshida C, Takezako N, et al.Dasatinib rapidly induces deep molecular response in chronic-phase chronic myeloid leukemia patients who achieved major molecular response with detectable levels of BCR-ABL1 transcripts by imatinib therapy.
Int J Clin Oncol. 2017; 22(5):972-979 [PubMed
] Free Access to Full Article Related Publications
BACKGROUND: With the introduction of imatinib, a first-generation tyrosine kinase inhibitor (TKI) to inhibit BCR-ABL1 kinase, the outcome of chronic-phase chronic myeloid leukemia (CP-CML) has improved dramatically. However, only a small proportion of CP-CML patients subsequently achieve a deep molecular response (DMR) with imatinib. Dasatinib, a second-generation TKI, is more potent than imatinib in the inhibition of BCR-ABL1 tyrosine kinase in vitro and more effective in CP-CML patients who do not achieve an optimal response with imatinib treatment.
METHODS: In the present study, we attempted to investigate whether switching the treatment from imatinib to dasatinib can induce DMR in 16 CP-CML patients treated with imatinib for at least two years who achieved a major molecular response (MMR) with detectable levels of BCR-ABL1 transcripts.
RESULTS: The rates of achievement of DMR at 1, 3, 6 and 12 months after switching to dasatinib treatment in the 16 patients were 44% (7/16), 56% (9/16), 63% (10/16) and 75% (12/16), respectively. The cumulative rate of achieving DMR at 12 months from initiation of dasatinib therapy was 93.8% (15/16). The proportion of natural killer cells and cytotoxic T cells in peripheral lymphocytes increased after switching to dasatinib. In contrast, the proportion of regulatory T cells decreased during treatment. The safety profile of dasatinib was consistent with previous studies.
CONCLUSION: Switching to dasatinib would be a therapeutic option for CP-CML patients who achieved MMR but not DMR by imatinib, especially for patients who wish to discontinue TKI therapy.
Exploration of a new differentiation therapy that extends the range of differentiation for treating acute myeloid leukemia (AML) is attractive to researchers and clinicians. Here we report that diptoindonesin G (Dip G), a natural resveratrol aneuploid, exerts antiproliferative activity by inducing G2/M phase arrest and cell differentiation in AML cell lines and primary AML cells. Gene-profiling experiments showed that treating human leukemia HL-60 cells with Dip G was associated with a remarkable upregulation of STAT1 target gene expression, including IFIT3 and CXCL10. Mechanistically, Dip G activated ERK, which caused phosphorylation of STAT1 at Ser727 and selectively enhanced the interaction of p-STAT1 (Ser727) and p-ERK, further promoting their nuclear translocation. The nuclear translocation of p-STAT1 and p-ERK enhanced the transactivation of STAT1-targeted genes in AML cells. Furthermore, in vivo treatment of HL-60 xenografts demonstrated that Dip G significantly inhibited tumor growth and reduced tumor weight by inducing cell differentiation. Taken together, these results shed light on an essential role for ERK-mediated nuclear translocation of p-STAT1 (Ser727) and its full transcriptional activity in Dip G-induced differentiation of AML cells. Furthermore, these results demonstrate that Dip G could be used as a differentiation-inducing agent for AML therapy, particularly for non-acute promyelocytic leukemia therapy.
Long interspersed nuclear element 1 (LINE-1 or L1) belongs to the non-long terminal repeat (non-LTR) retrotransposon family, which has been implicated in carcinogenesis and disease progression. Circulating tumor cells (CTCs) are also known to be involved in cancer progression. The present study aimed to compare the L1 expression between circulating tumor cells and non-cancerous samples. Blood samples were collected from 10 healthy individuals and 22 patients with different types of cancer. The whole blood cells were isolated using enrichment protocols and the DNA and RNA were extracted. RT-qPCR was performed for L1-ORF1 (open reading frame 1) and L1-ORF2, using 18S rRNA as the reference gene. The data were analyzed with the Livak method and statistical analyses were carried out with the Mann-Whitney and Kruskal-Wallis tests. In parallel with the above molecular biology experiments, FISH experiments were performed on the interphase nuclei of the cells for the detection of ORF2 RNA. DNA analysis revealed the presence of both ORF1 and ORF2 in all samples. RNA expression experiments demonstrated that ORF1 was not expressed in all samples, while ORF2 was expressed at varying levels in the non-cancer samples and the samples representing the different cancer types. A significant difference in ORF2 expression was observed between the CTCs and non-cancer samples (p = 0,00043), and significant differences were also observed between normal and lung (p = 0,034), pancreatic (p = 0,022), prostate (p = 0,014), and unknown primary of origin (p = 0,0039) cancer samples. Cytogenetic analysis revealed higher levels of ORF2 in the nuclei of CTCs than in normal samples. This study highlights the significant difference in L1-ORF2 expression between CTCs and normal samples. The increased expression levels observed for CTCs may be correlated with the characteristic features of these cells.
High-throughput genetic and epigenetic data are often screened for associations with an observed phenotype. For example, one may wish to test hundreds of thousands of genetic variants, or DNA methylation sites, for an association with disease status. These genomic variables can naturally be grouped by the gene they encode, among other criteria. However, standard practice in such applications is independent screening with a universal correction for multiplicity. We propose a Bayesian approach in which the prior probability of an association for a given genomic variable depends on its gene, and the gene-specific probabilities are modeled nonparametrically. This hierarchical model allows for appropriate gene and genome-wide multiplicity adjustments, and can be incorporated into a variety of Bayesian association screening methodologies with negligible increase in computational complexity. We describe an application to screening for differences in DNA methylation between lower grade glioma and glioblastoma multiforme tumor samples from The Cancer Genome Atlas. Software is available via the package BayesianScreening for R: github.com/lockEF/BayesianScreening.
Bone marrow monocytes are primarily committed to osteoclast formation. It is, however, unknown whether potential primary alterations are specifically present in bone marrow monocytes from patients with multiple myeloma, smoldering myeloma or monoclonal gammopathy of undetermined significance. We analyzed the immunophenotypic and transcriptional profiles of bone marrow CD14
Janani G, Pillai MM, Selvakumar R, et al.An in vitro 3D model using collagen coated gelatin nanofibers for studying breast cancer metastasis.
Biofabrication. 2017; 9(1):015016 [PubMed
] Related Publications
The study of breast cancer metastasis is limited due to poor knowledge of molecular progression of breast tumor and varied heterogeneity. For a better understanding of tumor metastasis, a reliable 3D in vitro model bridging the gap between 2D cultures and in vivo animal model studies is essential. Our study is focused on two key points: (i) designing a 3D microenvironment for studying metastasis and (ii) simulating the metastasis milieu by inducing epithelial to mesenchymal transition (EMT) and mesenchymal to epithelial transition (MET). An electrospun gelatin nanofiber matrix (EGNF) was fabricated using electrospinning and further dip coated with different concentrations of collagen to obtain surface complexity and mechanical properties, similar to connective tissues. Nanofiber matrices were physically characterized by Fourier transform infrared spectroscopy (FTIR), atomic force microscopy (AFM), and field-emission scanning electron microscopy (FESEM). The FTIR, AFM, and FESEM results indicated the crosslinking and confirmed the presence of pores in the nanofiber matrices. Comparative studies on biocompatibility, cell attachment, and the proliferation of MCF-7 cells on EGNF and collagen coated gelatin nanofibrous matrix (CCGM) revealed higher cellular attachment and proliferation in CCGM. CCGM with human metastatic breast cancer cell line (MCF-7) was taken to study breast cancer metastasis using estrogen (induces EMT) and progesterone (induces MET) hormones for 24 h. Quantitative real-time PCR was used for quantifying the expression of metastasis related genes, and fluorescence microscopy for verifying the invasion of cells to the matrices. The expression of E-cadherin and matrix metalloproteinase 2 (MMP 2) confirmed the occurrence of EMT and MET. Live cell imaging and cellular attachment showed significant increase of cellular invasion in crosslinked 0.15% CCGM that serves as a suitable non-toxic, biocompatible, and affordable scaffold for studying breast cancer metastasis. Our findings suggested that CCGM can be used as a tissue-like 3D model for studying breast cancer metastatic events in vitro.
Mussi CE, Colombo P, Lo Russo C, et al.Sporadic desmoid tumors of the abdominal wall: the results of surgery.
Tumori. 2016; 102(6):582-587 [PubMed
] Related Publications
PURPOSE: Before the wait-and-see policy became the standard approach in abdominal wall desmoid tumors, surgery was performed on a systematic basis. Surgery remains indicated for progressing tumors but its extent is debatable. The abdominal wall is a common site of origin of sporadic desmoids, usually associated with a favorable prognosis. We analyzed the results of surgery at this specific site.
METHODS: Data from 33 patients affected by sporadic desmoid tumors of the abdominal wall (31 primary, 2 recurrent) consecutively treated at our cancer center between January 2000 and September 2013 were retrospectively studied.
RESULTS: Twenty-nine patients underwent surgery upfront and 1 after progression during the initial wait-and-see period. Prosthetic reconstruction of the abdominal wall was required in 28 patients. The average hospital stay was 5 days. Three patients developed surgical complications. Local recurrence-free survival was 90% at 5 and 10 years. Three patients had an uneventful childbirth during the follow-up after surgery.
CONCLUSIONS: Desmoid tumors of the abdominal wall have a favorable prognosis after surgical resection, which remains a safe and effective treatment. Wild-type tumors are common, whereas the incidence of S45F mutation in the beta-catenin gene is lower than in other anatomic sites. Upfront surgery may be considered in selected women who wish to bear a child.
Cheo FF, Leow WQDiagnosing a rare case of desmoplastic small round cell tumour on liver biopsy.
Malays J Pathol. 2016; 38(2):149-52 [PubMed
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A 50-year-old male of Indian descent presented with jaundice and right hypochondrium pain. Following a computed tomography (CT) scan of the abdomen, a segment 7 liver lesion was visualized, accompanied by extensive peritoneal tumour deposits. An ultrasound guided liver biopsy was performed and histology showed loose nests and sheets of tumour cells with a small blue round cell morphology. The tumour cells showed patchy strong immunopositivity for cytokeratins (AE1/3, CK7, CK19) and synaptophysin, while showing diffuse strong perinuclear positivity for desmin. Interphase fluorescence in-situ hybridization (FISH) study using EWSR1 breakapart probe was positive for EWSR1 gene rearrangement. Desmoplastic small round cell tumour is a rare but aggressive intra-abdominal mesenchymal tumour. While the primary sites of involvement are usually the peritoneum and omentum, visceral involvement can occur. We wish to highlight the importance of considering this entity when evaluating a liver biopsy especially in a less than classical clinical context.
BACKGROUND: Prostate cancer (PC) is a major health concern for men worldwide, with an estimated lifetime risk of ~14 %. A recent comprehensive analysis of mutational processes revealed ageing and mismatch repair as the only altered processes in PC. We wish to test if a cohort of men with inherited risk of mismatch repair defect through BRCA1/2 or Lynch Syndrome mutations represents a target population for prostate cancer testing.
METHODS: Fifty-eight men (aged 40-69 years) from families with a history of BRCA1/2 or HNPCC/Lynch mutations were invited to take part. Men with PSA >3.0 ng/ml were recommended to have transrectal ultrasound-guided prostatic biopsies.
RESULTS: Overall 1 of 7 (14 %) and 1 of 20 (5 %) men with BRCA1/2 mutations were positive for a diagnosis of prostate cancer. In men with Lynch syndrome, 1 of 4 (25 %) was diagnosed to have prostate cancer. The index case with Lynch syndrome harbours a heterozygous mutation in the mismatch repair MSH6 gene. Near to complete loss of MSH6 immunoreactivity in the prostate tumour supports silencing of the remaining MSH6 allele during prostate carcinogenesis.
CONCLUSION: The finding of near-to-complete loss of MSH6 expression in affected men with a family history of Lynch Syndrome supports its mechanistic involvement during prostate carcinogenesis. This work therefore contributes to the argument that, in certain male populations, Lynch Syndrome mutations are biologically implicated in men with prostate cancer.
Array Comparative Genomic Hybridization (aCGH) is a rapid screening technique to detect gene deletions and duplications, providing an overview of chromosomal aberrations throughout the entire genome of a tumor, without the need for cell culturing. However, the heterogeneity of aCGH data obfuscates existing methods of data analysis. Analysis of aCGH data from a systems biology perspective or in the context of total aberrations is largely absent in the published literature. We present here a novel alternative to the functional analysis of aCGH data using the phylogenetic paradigm that is well-suited to high dimensional datasets of heterogeneous nature, but has not been widely adapted to aCGH data. Maximum parsimony phylogenetic analysis sorts out genetic data through the simplest presentation of the data on a cladogram, a graphical evolutionary tree, thus providing a powerful and efficient method for aCGH data analysis. For example, the cladogram models the multiphasic changes in the cancer genome and identifies shared early mutations in the disease progression, providing a simple yet powerful means of aCGH data interpretation. As such, applying maximum parsimony phylogenetic analysis to aCGH results allows for the differentiation between drivers and passenger genes aberrations in cancer specimens. In addition to offering a novel methodology to analyze aCGH results, we present here a crucial software suite that we wrote to carry out the analysis. In a broader context, we wish to underscore that phylogenetic analysis of aCGH data is a non-parametric method that circumvents the pitfalls and frustrations of standard analytical techniques that rely on parametric statistics. Organizing the data in a cladogram as explained in this research article provides insights into the disease common aberrations, as well as the disease subtypes and their shared aberrations (the synapomorphies) of each subtype. Hence, we report the method and make the software suite publicly and freely available at http://software.phylomcs.com so that researchers can test alternative and innovative approaches to the analysis of aCGH data.
ERβ is regarded as a "tumor suppressor" in breast cancer due to its anti-proliferative effects. However, unlike ERα, ERβ has not been developed as a therapeutic target in breast cancer due to loss of ERβ in aggressive cancers. In a small-molecule library screen for ERβ stabilizers, we identified Diptoindonesin G (Dip G), which significantly increases ERβ protein stability while decreasing ERα protein levels. Dip G enhances the transcription and anti-proliferative activities of ERβ, while attenuating the transcription and proliferative effects of ERα. Further investigation revealed that instead of targeting ER, Dip G targets the CHIP E3 ubiquitin ligase shared by ERα and ERβ. Thus, Dip G is a dual-functional moiety that reciprocally controls ERα and ERβ protein stability and activities via an indirect mechanism. The ERβ stabilization effects of Dip G may enable the development of ERβ-targeted therapies for human breast cancers.
D'Andrea E, Marzuillo C, Pelone F, et al.Genetic testing and economic evaluations: a systematic review of the literature.
Epidemiol Prev. 2015 Jul-Aug; 39(4 Suppl 1):45-50 [PubMed
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OBJECTIVES: To identify those studies in which economic analysis of predictive genetic and pharmacogenetic testing programs have been carried out. Since the Italian National Prevention Plan 2014-2018 foresees the implementation of genetic testing for inherited breast cancer, special attention was given to the cost-effectiveness of BRCA1/2 testing programs.
METHODS: A systematic review of primary economic evaluations (EEs) of predictive genetic and pharmacogenetic testing programs and an overview of previously published systematic reviews of economic evaluations (ERs) was performed.
RESULTS: Overall 128 EEs and 11 ERs were identified. The methodological quality of both EEs and ERs was good on average. Both predictive genetic and pharmacogenetic testing programs were mainly concerned with oncological diseases. Seventeen percent of genetic testing programs are cost-saving, while a further 44% of cost/QALY ratios fall under the commonly used threshold of €37,000 per QALY. For BRCA1/2 testing, only cascade genetic screening programs, targeted to close relatives of carriers, show clear evidence of cost-effectiveness.
CONCLUSION: Despite some limitations, EEs and ERs are powerful tools that provide indications to policy-makers on which genetic testing programs might be introduced into health care systems and public health practice.