1.
Front Oncol. 2020 Mar 13;10:338. doi: 10.3389/fonc.2020.00338. eCollection 2020.
Discovery of Pancreatic Ductal Adenocarcinoma-Related Aberrant Glycosylations: A Multilateral Approach of Lectin Microarray-Based Tissue Glycomic Profiling With Public Transcriptomic Datasets.
Wagatsuma T1,2,3, Nagai-Okatani C3, Matsuda A4, Masugi Y5, Imaoka M5, Yamazaki K5, Sakamoto M5, Kuno A3.
Abstract
Aberrant protein glycosylation is one of the most notable features in cancerous tissues, and thereby glycoproteins with disease-relevant glycosylation alterations are fascinating targets for the development of biomarkers and therapeutic agents. For this purpose, a reliable strategy is needed for the analysis of glycosylation alterations occurring on specific glycoproteins during the progression of cancer. Here, we propose a bilateral approach combining lectin microarray-based tissue glycomic profiling and database-derived transcriptomic datasets. First, lectin microarray was used to perform differential glycomic profiling of crude extracts derived from non-tumor and tumor regions of frozen tissue sections from pancreatic ductal adenocarcinoma (PDAC). This analysis revealed two notable tissue glycome alterations in PDAC samples: increases in sialylated glycans and bisecting N-acetylglucosamine and a decrease in ABO blood group antigens. To examine aberrations in the glycosylation machinery related to these glycomic alterations, we next employed public datasets of gene expression profiles in cancerous and normal pancreases provided by The Cancer Genome Atlas and the Genotype-Tissue Expression projects, respectively. In this analysis, glycosyltransferases responsible for the glycosylation alterations showed aberrant gene expression in the cancerous tissues, consistent with the tissue glycomic profiles. The correlated alterations in glycosyltransferase expression and tissue glycomics were then evaluated by differential glycan profiling of a membrane N-glycoprotein, basigin, expressed in tumor and non-tumor pancreatic cells. The focused differential glycomic profiling for endogenous basigin derived from non-tumor and cancerous regions of PDAC tissue sections demonstrated that PDAC-relevant glycan alterations of basigin closely reflected the notable features in the disease-specific alterations in the tissue glycomes. In conclusion, the present multi-omics strategy using public transcriptomic datasets and experimental glycomic profiling using a tiny amount of clinical specimens successfully demonstrated that basigin is a representative N-glycoprotein that reflects PDAC-related aberrant glycosylations. This study indicates the usefulness of large public data sets such as the gene expression profiles of glycosylation-related genes for evaluation of the highly sensitive tissue glycomic profiling results. This strategy is expected to be useful for the discovery of novel glyco-biomarkers and glyco-therapeutic targets.
Copyright © 2020 Wagatsuma, Nagai-Okatani, Matsuda, Masugi, Imaoka, Yamazaki, Sakamoto and Kuno.
KEYWORDS:
ABO blood group antigen; Genotype-Tissue Expression (GTEx); The Cancer Genome Atlas (TCGA); basigin/CD147; glycosylation; glycosyltransferase; lectin microarray; multi-omics
2.
Front Oncol. 2020 Mar 13;10:335. doi: 10.3389/fonc.2020.00335. eCollection 2020.
The Endosteal Niche in Breast Cancer Bone Metastasis.
Abstract
The establishment of bone metastasis remains one of the most frequent complications of patients suffering from advanced breast cancer. Patients with bone metastases experience high morbidity and mortality caused by excessive, tumor-induced and osteoclast-mediated bone resorption. Anti-resorptive treatments, such as bisphosphonates, are available to ease skeletal related events including pain, increased fracture risk, and hypercalcemia. However, the disease remains incurable and 5-year survival rates for these patients are below 25%. Within the bone, disseminated breast cancer cells localize in "metastatic niches," special microenvironments that are thought to regulate cancer cell colonization and dormancy as well as tumor progression and subsequent development into overt metastases. Precise location and composition of this "metastatic niche" remain poorly defined. However, it is thought to include an "endosteal niche" that is composed of key bone cells that are derived from both, hematopoietic stem cells (osteoclasts), and mesenchymal stromal cells (osteoblasts, fibroblasts, adipocytes). Our knowledge of how osteoclasts drive the late stage of the disease is well-established. In contrast, much less is known about the interaction between osteogenic cells and disseminated tumor cells prior to the initiation of the osteolytic phase. Recent studies suggest that mesenchymal-derived cells, including osteoblasts and fibroblasts, play a key role during the early stages of breast cancer bone metastasis such as tumor cell homing, bone marrow colonization, and tumor cell dormancy. Hence, elucidating the interactions between breast cancer cells and mesenchymal-derived cells that drive metastasis progression could provide novel therapeutic approaches and targets to treat breast cancer bone metastasis. In this review we discuss evidences reporting the interaction between tumor cells and endosteal niche cells during the early stages of breast cancer bone metastasis, with a particular focus on mesenchymal-derived osteoblasts and fibroblasts.
Copyright © 2020 Haider, Smit and Taipaleenmäki.
KEYWORDS:
bone metastases; breast cancer; endosteal niche; fibroblast; microenvironment; osteoblast
3.
Front Oncol. 2020 Mar 13;10:332. doi: 10.3389/fonc.2020.00332. eCollection 2020.
Differentiation of Breast Lesions and Distinguishing Their Histological Subtypes Using Diffusion-Weighted Imaging and ADC Values.
Maric J1, Boban J2,3, Ivkovic-Kapicl T2,3, Djilas D2,3, Vucaj-Cirilovic V2,3, Bogdanovic-Stojanovic D2,3,4.
Abstract
Diffusion-weighted imaging (DWI) has not been well explored in differentiation of malignant from benign breast lesions. The aims of this study were to examine the role of apparent diffusion coefficient (ADC) values in differentiation of malignant from benign tumors and distinguishing histological subtypes of malignant lesions, and to determine correlations between ADC values and breast tumors structure. This cohort-study included 174 female patients who underwent contrast-enhanced breast MR examination on a 3T scanner and were divided into two groups: patient group (114 patients with proven tumors) and control group (60 healthy patients). One-hundred-thirty-nine lesions (67 malignant and 72 benign) were detected and pathohistologically analyzed. Differences between variables were tested using chi-square test; correlations were determined using Pearson's correlation test. For determination of cut off values for diagnostic potential, Receiver Operating Characteristic curves were constructed. Statistical significance was set at p < 0.05. Mean ADC values were significantly lower in malignant compared to benign lesions (0.68 × 10-3mm2/s vs. 1.12 × 10-3mm2/s, p < 0.001). The cut off value of ADC for benign lesions was 0.792 × 10-3mm2/s (sensitivity 98.6%, specificity 65.7%), and for malignant 0.993 × 10-3mm2/s (98.5, 80.6%). There were no significant correlations between malignant lesion subtypes and ADC values. DWI is a clinically useful tool for differentiation of malignant from benign lesions based on mean ADC values. The cut off value for benign lesions was higher than reported recently, due to high amount of fibrosis in included benign lesions. Finally, ADC values might have implications in determination of the biological nature of the malignant lesions.
Copyright © 2020 Maric, Boban, Ivkovic-Kapicl, Djilas, Vucaj-Cirilovic and Bogdanovic-Stojanovic.
KEYWORDS:
ADC values; Diffusion-weighted (DW) imaging; breast cancer; differentiation; magnetic resonance imaging
4.
Front Oncol. 2020 Mar 13;10:328. doi: 10.3389/fonc.2020.00328. eCollection 2020.
Micro-RNA Expression Patterns Predict Metastatic Spread in Solid Pseudopapillary Neoplasms of the Pancreas.
Cohen SJ1, Papoulas M2, Graubardt N1, Ovdat E2, Loewenstein S1, Kania-Almog J1, Pasmanik-Chor M3, Brazowski E4, Cagnano E4, Nachmany I2, Lahat G2, Klausner JM2, Lubezky N1,2.
Abstract
Solid pseudopapillary neoplasm (SPN) of pancreas is a rare pancreatic neoplasm with a low metastatic potential. Up to 10% of patients with localized disease at presentation will develop systemic metastases, usually in the peritoneum or the liver. Due to the rarity of SPNs and the overall excellent prognosis, reliable prognostic factors to predict malignant biological behavior remain undetermined. Therefore, we aimed to define clinical, histological, and microRNA patterns that are associated with metastatic disease. We conducted a retrospective single center study on all patients operated for SPN of pancreas between 1995 and 2018. Clinical and pathological data were collected, and expression patterns of 2,578 human microRNAs were analyzed using microRNA array (Affimetrix 4.1) in normal pancreases (NPs), localized tumors (LTs), and metastatic tumors (MTs). The diagnosis of SPN was confirmed in 35 patients who included 28 females and 3 males, with a mean age of 33.8 ± 13.9 years. The only clinical factor associated with metastases was tumor size (mean tumor size 5.20 ± 3.78 in LT vs. 8.13± 1.03 in MT, p < 0.012). Microscopic features of malignancy were not associated with metastases, nor were immunohistochemical stains, including the proliferative index KI67. Higher expressions of miR-184, miR-10a, and miR-887, and lower expressions of miR-375, miR-217, and miR-200c were observed in metastatic tissues on microarray, and validated by real-time polymerase chain reaction. Hierarchal clustering demonstrated that the microRNA expression pattern of MTs was significantly different from that of LTs. The only clinical factor associated with metastases of SPN of pancreas was tumor size. Histological features and immunohistological staining were not predictive of metastases. A panel of six microRNAs was differentially expressed in MTs, and these findings could potentially be used to predict tumor behavior. Validation of these results is needed in larger series.
Copyright © 2020 Cohen, Papoulas, Graubardt, Ovdat, Loewenstein, Kania-Almog, Pasmanik-Chor, Brazowski, Cagnano, Nachmany, Lahat, Klausner and Lubezky.
KEYWORDS:
metastasis; microRNA; pancreatic cancer; prognostic factors; solid pseudopapillary neoplasm (SPN)
5.
Front Oncol. 2020 Mar 13;10:326. doi: 10.3389/fonc.2020.00326. eCollection 2020.
Gastric Cancer Cell-Derived Exosomal microRNA-23a Promotes Angiogenesis by Targeting PTEN.
Abstract
Hypoxia-exposed lung cancer-released exosomal microRNA-23a (miR-23a) has been shown to enhance angiogenesis as well as vascular permeability, contributing to the close correlation between exosomal miR-23a and tumorigenesis. The current study aimed to investigate whether gastric cancer (GC) cell-derived exosomal miR-23a could induce angiogenesis and to elucidate the potential mechanisms associated with the process. Differentially expressed miRNAs in GC were initially screened from the Gene Expression Omnibus database. Target genes were selected following miRNA-mRNA prediction and subsequently verified by dual luciferase reporter assay. RT-qPCR was conducted to detect miR-23a and PTEN expression in GC tissues, cells and exosomes. Human umbilical venous endothelial cells (HUVECs) were co-cultured with GC cell-derived exosomes to assess the angiogenesis mediated by exosomes in vitro. Additionally, PTEN was overexpressed in HUVECs to analyze the mechanism by which miR-23a regulates angiogenesis. miR-23a was highly expressed in GC tissues and cells and GC cell-derived exosomes. Angiogenesis was promoted by the co-culture of HUVECs and GC cells-derived exosomes, as evidenced by the increased expression of VEGF but decreased expression of TSP-1. PTEN was targeted by miR-23a and was lowly expressed in GC tissues. In a co-culture system, miR-23a carried by GC cells-derived exosomes promoted angiogenesis via the repression of PTEN. Collectively, GC cell-derived exosomal miR-23a could promote angiogenesis and provide blood supply for growth of GC cells. This study contributes to advancement of miRNA-targeted therapeutics.
Copyright © 2020 Du, Liang, Li, Zhao, Wang and Lin.
KEYWORDS:
AKT pathway; PTEN; angiogenesis; exosome; gastric cancer; microRNA-23a
6.
Front Oncol. 2020 Mar 13;10:322. doi: 10.3389/fonc.2020.00322. eCollection 2020.
Autophagy Regulation by the Translation Machinery and Its Implications in Cancer.
Abstract
Various metabolic pathways and molecular processes in the cell act intertwined, and dysregulating the interplay between some of them may lead to cancer. It is only recently that defects in the translation process, i.e., the synthesis of proteins by the ribosome using a messenger (m)RNA as a template and translation factors, have begun to gain strong attention as a cause of autophagy dysregulation with effects in different maladies, including cancer. Autophagy is an evolutionarily conserved catabolic process that degrades cytoplasmic elements in lysosomes. It maintains cellular homeostasis and preserves cell viability under various stress conditions, which is crucial for all eukaryotic cells. In this review, we discuss recent advances shedding light on the crosstalk between the translation and the autophagy machineries and its impact on tumorigenesis. We also summarize how this interaction is being the target for novel therapies to treat cancer.
Copyright © 2020 Acevo-Rodríguez, Maldonado, Castro-Obregón and Hernández.
KEYWORDS:
ATG; PERK; autophagy; cancer; eIF2alpha; endoplasmic reticulum; mTOR; translation initiation
7.
Front Oncol. 2020 Mar 13;10:314. doi: 10.3389/fonc.2020.00314. eCollection 2020.
Tumor Mutational Burden Determined by Panel Sequencing Predicts Survival After Immunotherapy in Patients With Advanced Gastric Cancer.
Abstract
Objective: Panel-based sequencing is widely used to measure tumor mutational burden (TMB) in clinical trials and is ready to enter routine diagnostics. However, cut-off points to distinguish "TMB-high" from "TMB-low" tumors are not consistent and the clinical implications of TMB in predicting responses to immune checkpoint blockade (ICB) in gastric cancer are not clearly defined. We aimed to assess whether TMB is associated with the response to immunotherapy and to examine its relation with other biomarkers of immunotherapy response in advanced gastric cancer. Design: In total, 63 patients with advanced gastric cancer treated with ICB were included in the study. Panel-based TMB in gastric tumor samples, treatment responses to ICB, clinicopathological data, and time to progression were retrospectively analyzed. Microsatellite instability (MSI) status, Epstein-Barr virus (EBV) positivity, and programmed death-ligand 1 (PD-L1) combined positive score (CPS) were also analyzed. Results: TMB ranged from 0 to 446 mutations/megabase (mt/mb) and was significantly associated with MSI (P < 0.001), PD-L1 CPS (P = 0.022), response to ICB (P = 0.04), chemotherapy (P = 0.02) and older patient age (≥65 years; P = 0.0014). The cut-off point of 14.31 mt/mb determined by log-rank statistics for progression-free survival divided the tumors into eight (12.7%) TMB-high and 55 (87.3%) TMB-low tumors. The median TMB of the chemo-refractory group was significantly higher (8.43 mt/mb) compared to that of chemo-naïve group (3.42 mt/mb) (P = 0.02). Patients with TMB-high tumors showed prolonged progression-free survival in univariate [HR, 0.32; 95% confidence interval (CI), 0.12-0.90] and multivariate (HR, 0.21; 95% CI, 0.07-0.69) analyses. In area under the receiver operating curve (AUC) analysis of TMB, PD-L1, EBV, MSI, and their combination, the AUC value was the highest for EBV (0.97), followed by MSI (0.96), PD-L1 (0.81), the combination (0.78), and TMB (0.56). Conclusion: In addition to EBV, MSI, and PD-L1 CPS, TMB could be used as a predictive biomarker in patients with advanced gastric cancer treated with ICB and may aid clinical decision making.
Copyright © 2020 Kim, Kim, Kang, Heo, Park, Kim, Kang, Lee and Kim.
KEYWORDS:
cut-off points; gastric cancer; immune checkpoint blockade; panel sequencing; tumor mutational burden
8.
Front Oncol. 2020 Mar 13;10:311. doi: 10.3389/fonc.2020.00311. eCollection 2020.
Chloroquine Inhibits Stemness of Esophageal Squamous Cell Carcinoma Cells Through Targeting CXCR4-STAT3 Pathway.
Yue D1,2, Zhang D1, Shi X1, Liu S1, Li A1, Wang D1,2, Qin G1,2, Ping Y1, Qiao Y1,2, Chen X1,2, Wang F2, Chen R3, Zhao S4, Wang L5, Zhang Y1,6,7.
Abstract
Esophageal squamous cell carcinoma (ESCC) is one of the most prevalent cancers worldwide. Recent studies have shown that cancer stem cells (CSCs) are present in ESCC, are thought to lead to aggressive tumor behavior and the prognosis. The CXC chemokine receptor 4 (CXCR4), is regarded as a putative CSCs marker in various malignancies. Here, we demonstrate that CXCR4 played a key role in ESCC progression and CXCR4 positive ESCC cells possessed stem-like properties. Furthermore, the anti-malarial agent chloroquine (CQ) targeted CXCR4-positive ESCC cells via STAT3 pathway. Therefore, CQ with anti-CSCs effects may be an effective adjunct to current ESCC chemotherapy regimens.
Copyright © 2020 Yue, Zhang, Shi, Liu, Li, Wang, Qin, Ping, Qiao, Chen, Wang, Chen, Zhao, Wang and Zhang.
KEYWORDS:
CXCR4; STAT3; cancer stem cells (CSCs); chloroquine (CQ); esophageal squamous cell carcinoma (ESCC)
9.
Front Oncol. 2020 Mar 13;10:310. doi: 10.3389/fonc.2020.00310. eCollection 2020.
Comparison of Fresh Frozen Tissue With Formalin-Fixed Paraffin-Embedded Tissue for Mutation Analysis Using a Multi-Gene Panel in Patients With Colorectal Cancer.
Abstract
Background: Next generation sequencing (NGS)-based multi-gene panel tests have been performed to predict the treatment response and prognosis in patients with colorectal cancer (CRC). Whether the multi-gene mutation results of formalin-fixed paraffin-embedded (FFPE) tissues are identical to those of fresh frozen tissues remains unknown. Methods: A 22-gene panel with 103 hotspots was used to detect mutations in paired fresh frozen tissue and FFPE tissue from 118 patients with CRC. Results: In our study, 117 patients (99.2%) had one or more variants, with 226 variants in FFPE tissue and 221 in fresh frozen tissue. Of the 129 variants identified in this study, 96 variants were present in both FFPE and fresh frozen tissues; 27 variants were found in FFPE tissues only; 6 variants were found only in fresh frozen tissues. The mutation results demonstrated >94.0% concordance in all variants, with Kappa coefficient >0.500 in 64.3% (83/129) of variants. At the gene level, concordance ranged from 73.8 to 100.0%, with Kappa coefficient >0.500 in 81.3% (13/16) of genes. Conclusions: The results of mutation analysis performed with a multi-gene panel and FFPE and fresh frozen tissue were highly concordant in patients with CRC, at both the variant and gene levels. There were, however, some important differences in mutation results between the two tissue types. Therefore, fresh frozen tissue should not routinely be replaced with FFPE tissue for mutation analysis with a multi-gene panel. Rather, FFPE tissue is a reasonable alternative for fresh frozen tissue when the latter is unavailable.
Copyright © 2020 Gao, Li, Gong, Yu, Liu, Hao, Liu, Bai and Zhang.
KEYWORDS:
colorectal cancer; formalin-fixed paraffin-embedded tissue; fresh frozen tissue; gene mutation; multi-gene panel
10.
Front Oncol. 2020 Mar 13;10:308. doi: 10.3389/fonc.2020.00308. eCollection 2020.
Regulation of Integrin Subunit Alpha 2 by miR-135b-5p Modulates Chemoresistance in Gastric Cancer.
Abstract
Chemotherapy has substantially improved gastric cancer (GC) patient outcomes in the past decades. However, the development of chemotherapy resistance has become the major cause of treatment failure. Although numerous molecules have been implicated in GC chemoresistance, its pathological mechanisms are still unclear. Here, we found that integrin subunit alpha 2 (ITGA2) is upregulated in chemoresistant GC cells and that increased ITGA2 levels correlated with the poor prognosis of GC patients who received chemotherapy. ITGA2 overexpression led to elevated chemotherapy resistance and drug-induced apoptosis inhibition in GC cells. ITGA2 knockdown resulted in restored chemosensitivity and increased apoptosis in chemoresistant GC cells both in vitro and in vivo. NanoString analysis revealed a unique signature of deregulated pathway expression in GC cells after ITGA2 silencing. The MAPK/ERK pathway and epithelial-mesenchymal transition (EMT) were found to be downregulated after ITGA2 knockdown. miR-135b-5p was identified as a direct upstream regulator of ITGA2. miR-135b-5p overexpression reduced chemoresistance and induced apoptosis in GC cells and attenuated ITGA2-induced chemoresistance and antiapoptotic effects by inhibiting MAPK signaling and EMT. In conclusion, this study underscored the role and mechanism of ITGA2 in GC and suggested the novel miR-135b-5p/ITGA2 axis as an epigenetic cause of chemoresistance with diagnostic and therapeutic implications.
Copyright © 2020 Wang, Cao, Guo, Zhou, Liu, Pan, Hou, Nie, Fan, Lu and Zhao.
KEYWORDS:
EMT; ITGA2; MAPK pathway; chemoresistance; gastric cancer; miR-135b-5p
11.
Front Oncol. 2020 Mar 13;10:294. doi: 10.3389/fonc.2020.00294. eCollection 2020.
MicroRNA-1224-5p Inhibits Metastasis and Epithelial-Mesenchymal Transition in Colorectal Cancer by Targeting SP1-Mediated NF-κB Signaling Pathways.
Li J1,2, Peng W1,2, Yang P1,2, Chen R1,2, Gu Q1,2, Qian W1,2, Ji D1,2, Wang Q1,2, Zhang Z1,2, Tang J1,2, Sun Y1,2.
Abstract
MicroRNAs (miRNAs) are small non-coding RNAs that play pivotal roles in cancer initiation and progression. However, the roles and molecular mechanisms of miRNAs in colorectal cancer (CRC) progression remain unclear. Here, we show that downregulation of miR-1224-5p in CRC is negatively correlated with SP1 expression and metastasis in patients and xenografted mouse models. Gain- and loss-of-function assays reveal that miR-1224-5p suppresses the migration, invasion, and epithelial-mesenchymal transition (EMT) of CRC cells in vitro and in vivo by directly targeting SP1. Moreover, SP1 promotes the phosphorylation of p65, which results in EMT progress in CRC cells. Clinical analysis reveals that miR-1224-5p and SP1 expression are remarkably associated with advanced clinical features and unfavorable prognosis of patients with CRC. Further study confirms that hypoxia accounts for the depletion of miR-1224-5p in CRC. The enhancement of hypoxia during epithelial-mesenchymal transition and metastasis of CRC cells is abolished by miR-1224-5p. Our findings provide the first evidence that miR-1224-5p is a potential therapeutic target and prognostic biomarker for patients with CRC.
Copyright © 2020 Li, Peng, Yang, Chen, Gu, Qian, Ji, Wang, Zhang, Tang and Sun.
KEYWORDS:
NF-κB; SP1; colorectal cancer; metastasis; miR-1224-5p; prognostic biomarker
12.
Front Oncol. 2020 Mar 13;10:292. doi: 10.3389/fonc.2020.00292. eCollection 2020.
Transcriptomic and Functional Screens Reveal MicroRNAs That Modulate Prostate Cancer Metastasis.
Abstract
Identifying new mechanisms that underlie the complex process of metastasis is vital to combat this fatal step in prostate cancer (PCa) progression. Small non-coding RNAs are emerging as important regulators of tumor cell biology. Here we take an integrative approach to elucidate the contribution of microRNAs to metastatic progression, combining transcriptomic analysis with functional screens for migration and morphology. We developed high-content microscopy, high-throughput functional screens for migration and morphology in PCa cells using a microRNA library. RNA-Seq analysis of paired epithelial and mesenchymal PCa cells identified differential expression of 200 microRNAs. Data integration identified two microRNAs that inhibited migration, induced an epithelial-like morphology and were increased in epithelial PCa cells. An overrepresentation of the AAGUGC seed sequence was detected in all three datasets. Analysis of published datasets of patients with PCa identified microRNAs of clinical relevance. The integration of high-throughput functional and expression analyses identifies microRNAs with clinical significance that modulate metastatic behavior in PCa.
Copyright © 2020 Rao, Howarth, Kratschmer, Snaith, Yapp, Ebner, Hamdy and Edwards.
KEYWORDS:
EMT - epithelial to mesenchymal transition; microRNA; migration screening; morphological analysis; prostate cancer; screening
13.
Front Oncol. 2020 Mar 13;10:272. doi: 10.3389/fonc.2020.00272. eCollection 2020.
Inferring Personalized and Race-Specific Causal Effects of Genomic Aberrations on Gleason Scores: A Deep Latent Variable Model.
Abstract
Extensive research has examined socioeconomic factors influencing prostate cancer (PCa) disparities. However, to what extent molecular and genetic mechanisms may also contribute to these inequalities still remains elusive. Although various in vitro, in vivo, and population studies have originated to address this issue, they are often very costly and time-consuming by nature. In this work, we attempt to explore this problem by a preliminary study, where a joint deep latent variable model (DLVM) is proposed to in silico quantify the personalized and race-specific effects that a genomic aberration may exert on the Gleason Score (GS) of each individual PCa patient. The core of the proposed model is a deep variational autoencoder (VAE) framework, which follows the causal structure of inference with proxies. Extensive experimental results on The Cancer Genome Atlas (TCGA) 270 European-American (EA) and 43 African-American (AA) PCa patients demonstrate that ERG fusions, somatic mutations in SPOP and ATM, and copy number alterations (CNAs) in ERG are the statistically significant genomic factors across all low-, intermediate-, and high-grade PCa that may explain the disparities between these two groups. Moreover, compared to a state-of-the-art deep inference method, our proposed method achieves much higher precision in causal effect inference in terms of the impact of a studied genomic aberration on GS. Further validation on an independent set and the assessment of the genomic-risk scores along with corresponding confidence intervals not only validate our results but also provide valuable insight to the observed racial disparity between these two groups regarding PCa metastasis. The pinpointed significant genomic factors may shed light on the molecular mechanism of cancer disparities in PCa and warrant further investigation.
Copyright © 2020 Chen, Edwards, Hicks and Zhang.
KEYWORDS:
Gleason scores; causal effect inference; deep latent variable model; genomic aberrations; prostate cancer; racial disparity
14.
Front Oncol. 2020 Mar 13;10:264. doi: 10.3389/fonc.2020.00264. eCollection 2020.
B7-Positive and B7-Negative Acute Myeloid Leukemias Display Distinct T Cell Maturation Profiles, Immune Checkpoint Receptor Expression, and European Leukemia Net Risk Profiles.
Antohe I1,2, Dǎscǎlescu A1,2, Dǎnǎilǎ C1,2, Titieanu A1,2, Zlei M3, Ivanov I4, Sireteanu A4, Pavel M5, Cianga P5.
Abstract
Acute myeloid leukemia (AML) is generally considered a poorly immunogenic malignancy, displaying a "non-inflamed" leukemia microenvironment (LME), leading to T cell tolerance. However, the immune landscape of AML is much more heterogeneous. Since B7 expression is regarded as a consequence of an interferon-mediated "inflammatory" phenotype, we have investigated by flow cytometry the B7 checkpoint ligands B7.1, B7.2, programmed death ligand 1 (PD-L1), PD-L2, ICOS-L, B7-H3, and B7-H4 on the AML blasts of 30 newly diagnosed patients and their corresponding receptors [cytotoxic T lymphocyte-associated protein 4 (CTLA-4), programmed death 1 (PD-1), and inducible T cell costimulator (ICOS)] on bone marrow (BM) T cell maturation populations. We could thus evidence B7-negative and B7-positive leukemias either with an isolated expression or part of eight different checkpoint ligand "signatures" that always included an inhibitory B7 molecule. B7-positive AMLs encompassed intermediate and adverse European Leukemia Net (ELN) risk cases and displayed mainly central memory CD4+ T cells with high ICOS levels and effector CD8+ T cells with high PD-1 expression. B7-negative cases were rather classified as AML with recurrent genetic anomalies and displayed predominantly naive T cells, with the exception of NPM1 mutated AMLs, which expressed B7-H3. These different B7 immune profiles suggest that specific immunotherapies are required to target the distinct immune evasion strategies of this genetically heterogeneous disease.
Copyright © 2020 Antohe, Dǎscǎlescu, Dǎnǎilǎ, Titieanu, Zlei, Ivanov, Sireteanu, Pavel and Cianga.
KEYWORDS:
B7 molecules; acute myeloid leukemia (AML); checkpoint ligand; immunotherapy; inducible T cell costimulator (ICOS); programmed death 1 (PD-1)
15.
Front Oncol. 2020 Mar 13;10:235. doi: 10.3389/fonc.2020.00235. eCollection 2020.
Predicting the Type of Tumor-Related Epilepsy in Patients With Low-Grade Gliomas: A Radiomics Study.
Wang Y1, Wei W2,3,4,5, Liu Z2,6, Liang Y1, Liu X7, Li Y1,7, Tang Z2,4, Jiang T1,7,8,9, Tian J2,4,5,6.
Abstract
Purpose: The majority of patients with low-grade gliomas (LGGs) experience tumor-related epilepsy during the disease course. Our study aimed to build a radiomic prediction model for LGG-related epilepsy type based on magnetic resonance imaging (MRI) data. Methods: A total of 205 cases with LGG-related epilepsy were enrolled in the retrospective study and divided into training and validation cohorts (1:1) according to their surgery time. Seven hundred thirty-four radiomic features were extracted from T2-weighted imaging, including six location features. Pearson correlation coefficient, univariate area under curve (AUC) analysis, and least absolute shrinkage and selection operator regression were adopted to select the most relevant features for the epilepsy type to build a radiomic signature. Furthermore, a novel radiomic nomogram was developed for clinical application using the radiomic signature and clinical variables from all patients. Results: Four MRI-based features were selected from the 734 radiomic features, including one location feature. Good discriminative performances were achieved in both training (AUC = 0.859, 95% CI = 0.787-0.932) and validation cohorts (AUC = 0.839, 95% CI = 0.761-0.917) for the type of epilepsy. The accuracies were 80.4 and 80.6%, respectively. The radiomic nomogram also allowed for a high degree of discrimination. All models presented favorable calibration curves and decision curve analyses. Conclusion: Our results suggested that the MRI-based radiomic analysis may predict the type of LGG-related epilepsy to enable individualized therapy for patients with LGG-related epilepsy.
Copyright © 2020 Wang, Wei, Liu, Liang, Liu, Li, Tang, Jiang and Tian.
KEYWORDS:
T2-weighted imaging; epilepsy type; low-grade gliomas; machine learning; radiomics
16.
Front Oncol. 2020 Mar 13;10:226. doi: 10.3389/fonc.2020.00226. eCollection 2020.
Deletion of Btg1 Induces Prmt1-Dependent Apoptosis and Increased Stemness in Shh-Type Medulloblastoma Cells Without Affecting Tumor Frequency.
Abstract
About 30% of medulloblastomas (MBs), a tumor of the cerebellum, arise from cerebellar granule cell precursors (GCPs) undergoing transformation following activation of the Sonic hedgehog (Shh) pathway. To study this process, we generated a new MB model by crossing Patched1 heterozygous (Ptch1 +/-) mice, which develop spontaneous Shh-type MBs, with mice lacking B-cell translocation gene 1 (Btg1), a regulator of cerebellar development. In MBs developing in Ptch1 +/- mice, deletion of Btg1 does not alter tumor and lesion frequencies, nor affect the proliferation of neoplastic precursor cells. However, in both tumors and lesions arising in Ptch1 +/- mice, ablation of Btg1 increases by about 25% the apoptotic neoplastic precursor cells, as judged by positivity to activated caspase-3. Moreover, although Btg1 ablation in early postnatal GCPs, developing in the external granule cell layer, leads to a significant increase of proliferation, and decrease of differentiation, relative to wild-type, no synergy occurs with the Ptch1 +/- mutation. However, Btg1 deletion greatly increases apoptosis in postnatal GCPs, with strong synergy between Btg1-null and Ptch1 +/- mutations. That pronounced increase of apoptosis observed in Ptch1 +/- /Btg1 knockout young or neoplastic GCPs may be responsible for the lack of effect of Btg1 ablation on tumorigenesis. This increased apoptosis may be a consequence of increased expression of protein arginine methyltransferase 1 (Prmt1) protein that we observe in Btg1 knockout/Ptch1 +/- MBs. In fact, apoptotic genes, such as BAD, are targets of Prmt1. Moreover, in Btg1-null MBs, we observed a two-fold increase of cells positive to CD15, which labels tumor stem cells, raising the possibility of activation of quiescent tumor cells, known for their role in long-term resistance to treatment and relapses. Thus, Btg1 appears to play a role in cerebellar tumorigenesis by regulating the balance between apoptosis and proliferation during MB development, also influencing the number of tumor stem cells.
Copyright © 2020 Ceccarelli, D'Andrea, Micheli and Tirone.
KEYWORDS:
B-cell translocation gene 1 (Btg1); Sonic hedgehog (Shh); apoptosis; cerebellum neurogenesis; medulloblastoma; neoplastic granule cell precursors; proliferation; protein arginine methyltransferase 1 (Prmt1)
17.
Front Oncol. 2020 Mar 13;10:186. doi: 10.3389/fonc.2020.00186. eCollection 2020.
Humanizing Big Data: Recognizing the Human Aspect of Big Data.
Abstract
The term "big data" refers broadly to large volumes of data, often gathered from several sources, that are then analyzed, for example, for predictive analytics. Combining and mining genetic data from varied sources including clinical genetic testing, for example, electronic health records, what might be termed as "recreational" genetic testing such as ancestry testing, as well as research studies, provide one type of "big data." Challenges and cautions in analyzing big data include recognizing the lack of systematic collection of the source data, the variety of assay technologies used, the potential variation in classification and interpretation of genetic variants. While advanced technologies such as microarrays and, more recently, next-generation sequencing, that enable testing an individual's DNA for thousands of genes and variants simultaneously are briefly discussed, attention is focused more closely on challenges to analysis of the massive data generated by these genomic technologies. The main theme of this review is to evaluate challenges associated with big data in general and specifically to bring the sophisticated technology of genetic/genomic testing down to the individual level, keeping in mind the human aspect of the data source and considering where the impact of the data will be translated and applied. Considerations in this "humanizing" process include providing adequate counseling and consent for genetic testing in all settings, as well as understanding the strengths and limitations of assays and their interpretation.
Copyright © 2020 Helzlsouer, Meerzaman, Taplin and Dunn.
KEYWORDS:
big data; cancer risk prediction; clinical genetics/genomics; data sharing; direct-to-consumer testing; precision medicine; predictive analytics
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