Prognosis In Human Cancer Research Articles

Pan-Cancer Analysis of the Role of NCS1 in Immunotherapy and Prognosis of Human Cancer

Pan-Cancer Analysis of the Role of NCS1 in Immunotherapy and Prognosis of Human Cancer

The Role of Bitter Taste Receptors in Cancer: A Systematic Review.

Simple SummaryBitter taste receptors (TAS2Rs) are functionally expressed in various extra-oral cells eliciting non-gustatory functions. In the context of cancer, their functionality is less clear, despite growing interest in recent years. This is the first systematic review that summarizes the current knowledge on the role of TAS2Rs in cancer from different perspectives, from cellular mechanisms of cancer to sensory perception. Although the association between TAS2R-mediated bitterness sensitivity, dietary intake and cancer risk is so far inconclusive, the majority of studies provide evidence for the downregulated gene expression of some functional TAS2Rs in cancerous compared to non-cancerous cell lines and tissue samples. Additionally, the agonist-related activation and overexpression of TAS2Rs per se induced various anti-cancer effects, leading to the hypothesis that TAS2Rs impact carcinogenesis and could serve as a target in cancer therapy by interfering with typical capabilities of cancerous cells, known as the hallmarks of cancer.Background: Since it is known that bitter taste receptors (TAS2Rs) are expressed and functionally active in various extra-oral cells, their genetic variability and functional response initiated by their activation have become of broader interest, including in the context of cancer. Methods: A systematic research was performed in PubMed and Google Scholar to identify relevant publications concerning the role of TAS2Rs in cancer. Results: While the findings on variations of TAS2R genotypes and phenotypes and their association to the risk of developing cancer are still inconclusive, gene expression analyses revealed that TAS2Rs are expressed and some of them are predominately downregulated in cancerous compared to non-cancerous cell lines and tissue samples. Additionally, receptor-specific, agonist-mediated activation induced various anti-cancer effects, such as decreased cell proliferation, migration, and invasion, as well as increased apoptosis. Furthermore, the overexpression of TAS2Rs resulted in a decreased tumour incidence in an in vivo study and TAS2R activation could even enhance the therapeutic effect of chemotherapeutics in vitro. Finally, higher expression levels of TAS2Rs in primary cancerous cells and tissues were associated with an improved prognosis in humans. Conclusion: Since current evidence demonstrates a functional role of TAS2Rs in carcinogenesis, further studies should exploit their potential as (co-)targets of chemotherapeutics.

Thyroid Disease and Hepatocellular Carcinoma Survival: A Danish Nationwide Cohort Study

Introduction: Hepatocellular carcinoma (HCC) is the fourth leading cause of cancer mortality worldwide. Recent animal studies suggest that thyroid hormone treatment improves HCC prognosis. The aim of this study was to describe the association between thyroid disease and HCC prognosis in humans. Methods: We performed a nationwide cohort study including all persons with an HCC diagnosis from 2000 to 2018. Patients’ age, sex, HCC treatment, and diagnoses of thyrotoxicosis, nontoxic goiter, and myxedema were obtained from Danish national healthcare registries. We used regression models to examine the association between thyroid disease and mortality hazard and restricted mean survival time after HCC diagnosis, adjusting for confounding by sex and age. Results: We included 4,812 patients with HCC and 107 patients with thyroid disease. Median follow-up time was 5 months (total 5,985 person-years). The adjusted mortality hazard ratio was 0.68 (95% CI: 0.47–0.96) for thyrotoxicosis and 0.60 (95% CI: 0.41–0.88) for nontoxic goiter. The restricted mean survival time during the 5 years following HCC diagnosis was 6.8 months (95% CI: 1.1–12.6) longer for HCC patients with thyrotoxicosis than for patients without thyroid disease, and it was 6.9 months (95% CI: 0.9–12.9) longer for HCC patients with nontoxic goiter than for patients without thyroid disease. Conclusions: In this large nationwide cohort study, thyrotoxicosis and nontoxic goiter were associated with prolonged HCC survival.

BCL11A promotes myeloid leukemogenesis by repressing PU.1 target genes

AbstractThe transcriptional repressor BCL11A is involved in hematological malignancies, B-cell development, and fetal-to-adult hemoglobin switching. However, the molecular mechanism by which it promotes the development of myeloid leukemia remains largely unknown. We find that Bcl11a cooperates with the pseudokinase Trib1 in the development of acute myeloid leukemia (AML). Bcl11a promotes the proliferation and engraftment of Trib1-expressing AML cells in vitro and in vivo. Chromatin immunoprecipitation sequencing analysis showed that, upon DNA binding, Bcl11a is significantly associated with PU.1, an inducer of myeloid differentiation, and that Bcl11a represses several PU.1 target genes, such as Asb2, Clec5a, and Fcgr3. Asb2, as a Bcl11a target gene that modulates cytoskeleton and cell-cell interaction, plays a key role in Bcl11a-induced malignant progression. The repression of PU.1 target genes by Bcl11a is achieved by sequence-specific DNA-binding activity and recruitment of corepressors by Bcl11a. Suppression of the corepressor components HDAC and LSD1 reverses the repressive activity. Moreover, treatment of AML cells with the HDAC inhibitor pracinostat and the LSD1 inhibitor GSK2879552 resulted in growth inhibition in vitro and in vivo. High BCL11A expression is associated with worse prognosis in humans with AML. Blocking of BCL11A expression upregulates the expression of PU.1 target genes and inhibits the growth of HL-60 cells and their engraftment to the bone marrow, suggesting that BCL11A is involved in human myeloid malignancies via the suppression of PU.1 transcriptional activity.

PARP1 as a prognostic biomarker for human cancers: a meta-analysis.

Aim: A comprehensive meta-analysis was carried out to evaluate the association between high PARP1 expression and clinical outcomes in diverse types of cancers. Materials & methods: The electronic databases for all articles about PARP1 expression and cancers were searched. Additionally, bioinformatics analysis was utilized to validate the results of the meta-analysis. Results: Fifty-two studies with a total of 7140 patients were included in the current meta-analysis. High PARP1 expression was found to be significantly associated with poor overall survival and recurrence in various cancers, which were further strengthened and complemented by the results of bioinformatic analysis. Furthermore, increased PAPR1 expression was also related to clinicopathological features. Conclusion: Our findings confirmed that PARP1 might be a promising biomarker for prognosis in human cancers.

MiR-155, miR-21, and let-7a Expressions in MCF-10A and MCF-7 Cell Lines after Low to High Dose Irradiation.

Objective Ionizing radiation is a tremendous risk factor for cancer development. MicroRNAs (miRNAs) are regulators that utilize cell pathways, which are implicated in human cancer prognosis. In addition, miRNAs respond to anti-cancer therapy and proliferation after irradiation. However, the changes in miRNA expression profiles in response to irradiation have not been comprehensively analysed. The present study was designed to assess potential changes that occur in miRNA expression following irradiation. Materials and Methods In this experimental study, we used quantitative real-time polymerase chain reaction (qRT- PCR) to measure the expressions of miR-155, miR-21, and let-7a in MCF-10A (normal breast cells) and MCF-7 (breast cancer cells) six hours after the cells were exposed to five different irradiation doses (50, 100, 400, 2000, and 4000 mGY). Results After irradiation from the low to high doses, we observed an upsurge in miR-155 (more than 100%) expression and reduction in let-7a (more than 87%) expression. However, there was an increase and a reduction in miR-21 expression (more than 100%). ConclusionIrradiation can play an important role in cancer development in normal breast cells (MCF-10A) at low dose irradiation. However, the results showed little difference at high doses of radiation.

Chromobox Homolog 8 (CBX8) in Human Tumor Carcinogenesis and Prognosis: A Pancancer Analysis Using Multiple Databases.

Some emerging studies have suggested that chromobox homolog 8 (CBX8) may play a critical role in carcinogenesis and prognosis in human cancer. Based on The Cancer Genome Atlas (TCGA)’s available data and the Gene Expression Omnibus (GEO) database, we conducted a systematic analysis of the carcinogenic effects of the CBX8 gene. We used TIMER2, GEPIA2, UALCAN, cBioPortal, Kaplan-Meier plotter, OncoLnc, STRING, HPA, and Oncomine data analysis websites and R data analysis software to analyze available data. The results show that the level of expression of CBX8 was significantly different among 27 different types of tumors and adjacent normal tissues. Moreover, we found that CBX8 expression had a close relationship with prognosis in some kinds of cancers. The phosphorylation level of some protein sites (such as S256) was significantly increased in tumors. CD8 + T-cell, B-cell and cancer-associated fibroblast infiltration levels were associated with CBX8 expression. The results of enrichment analysis indicated that the main biological activities of CBX8 are connected to gene transcription and repair of DNA damage. In conclusion, the level of expression of CBX8 was closely related to carcinogenesis and prognosis of some kinds of tumors, which needs further experimental verification.

Construction of a ceRNA network and a genomic-clinicopathologic nomogram to predict survival for HBV-related HCC.

Some lncRNA-associated competing endogenous RNAs (ceRNAs) are considered as potential biomarkers for targeted therapies and prognosis in human cancer. In our present study, we aimed to construct a ceRNA network and establish a genomic-clinicopathologic nomogram to provide insights into the molecular mechanisms and predict survival for HBV-related HCC. The Cancer Genome Atlas (TCGA) database was applied to collect the data of LIHC RNA-seq dataset and miRNA-seq dataset as well as the clinicopathological information. Identification of differentially expressed RNAs (mRNAs, lncRNAs, and miRNAs) between HBV-related HCC samples and normal samples was conducted using Limma package in R. The Database for Annotation, Visualization, and Integrated Discovery (DAVID) was used for performing the functional enrichment analysis of differentially expressed mRNAs. The ceRNA network was carried out using Cytoscape. The LASSO-penalized Cox regression analysis was implemented to identify HCC-related lncRNAs, and the multivariate Cox regression analysis was conducted for the establishment of a genomic-clinicopathology nomogram. A total of 1859 DEmRNAs, 113 DElncRNAs, and 89 DEmiRNAs were screened out etween HBV-related HCC samples and normal samples. A ceRNA network including 44 DEmRNAs, 7 DElncRNAs, and 20 DEmiRNAs was constructed. 7 DElncRNAs (PVT1, LINC01138, LINC02499, AL355488.2, FGF14-AS2, MAFG-AS1 and LINC00261) were finally identified as prognostic indicators. The area under the curve reached 0.8169 for the 7-lncRNA signature. The predictive accuracy and clinical application value were remarkably high for the genomic-clinicopathologic nomogram integrating the histological grade and the 7-gene-based prognostic index. Taken together, we have established a ceRNA network with HBV-related HCC-specific DElncRNAs, DEmiRNAs, and DEmRNAs. Furthermore, the genome-wide data of lncRNA expression were analyzed using the TCGA database, and a 7-lncRNA signature was identified as a potential prognostic predictor for HBV-related HCC patients. Novel functional studies were provided by our current findings for elucidating the molecular mechanism of lncRNA in HBV-related HCC.

Identification of survival-related alternative splicing signatures in acute myeloid leukemia.

Aberrant RNA alternative splicing (AS) variants play critical roles in tumorigenesis and prognosis in human cancers. Here, we conducted a comprehensive profiling of aberrant AS events in acute myeloid leukemia (AML). RNA AS profile, including seven AS types, and the percent spliced in (PSI) value for each patient were generated by SpliceSeq using RNA-seq data from TCGA. Univariate followed by multivariate Cox regression analysis were used to identify survival-related AS events and develop the AS signatures. A nomogram was developed, and its predictive efficacy was assessed. About 27,892 AS events and 3,178 events were associated with overall survival (OS) after strict filtering. Parent genes of survival-associated AS events were mainly enriched in leukemia-associated processes including chromatin modification, autophagy, and T-cell receptor signaling pathway. The 10 AS signature based on seven types of AS events showed better efficacy in predicting OS of patients than those built on a single AS event type. The area under curve (AUC) value of the 10 AS signature for 3-year OS was 0.91. Gene set enrichment analysis (GSEA) confirmed that these survival-related AS events contribute to AML progression. Moreover, the nomogram showed good predictive performance for patient's prognosis. Finally, the correlation network of AS variants with splicing factor genes found potential important regulatory genes in AML. The present study presented a systematic analysis of survival-related AS events and developed AS signatures for predicting the patient’s survival. Further studies are needed to validate the signatures in independent AML cohorts and might provide a promising perspective for developing therapeutic targets.

Abstract 778: CD24 mutant p53 contribute to racial disparities in prostate cancer

Abstract African-American (AA) men have the highest rate of prostate cancer among racial or ethnic groups. CD24, a cell-surface protein anchored by glycosyl-phosphatidyl-inositol (GPI), often is over-expressed in cancers and serves as a marker for poor prognosis of human cancer, including prostate cancer. Using a functional analysis of prostate cancer cells, we found a CD24-dependent inactivation of mutant p53, but the clinical significance of this observation remained uncertain. Here, we validated these results with samples of human prostate cancer and explored the role of a CD24-p53 axis in racial disparities of prostate cancer. Our bioinformatics analysis of public datasets, including TCGA data, confirmed higher levels of CD24 mRNA expression in late-stage and metastatic prostate cancer. In the present study, we addressed the association of CD24 with mutant p53 and their differential expression between AA and European-American (EA) prostate cancers and assessed whether cells with CD24 and mutant p53 contribute to health disparities in prostate cancer. CD24, mutant p53, MDM2, and ARF proteins were expressed in 55%, 24%, 39%, and 68% of prostate cancer samples, respectively. CD24 and mutant p53 were present more frequently in late-stage and metastatic prostate cancer. The presence of CD24 was associated with a > 4-fold risk of metastasis, which included lymph node and distant metastases. H-score analysis showed positive correlations of CD24 expression with mutant p53 and MDM2. A racial disparity was evident for CD24 but not for mutant p53. In 32 CD24+/mutant p53+ cases, a TP53R273H mutation was found in five cases, but no TP53R175H mutation was found. The CD24-p53 axis may contribute to aggressive and metastatic prostate cancers, especially those of AAs. Citation Format: Xuelian Cui, Shuaibin Wang, Lizhong Wang. CD24 mutant p53 contribute to racial disparities in prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 778.

Co-regulation and function of FOXM1/RHNO1 bidirectional genes in cancer.

The FOXM1 transcription factor is an oncoprotein and a top biomarker of poor prognosis in human cancer. Overexpression and activation of FOXM1 is frequent in high-grade serous carcinoma (HGSC), the most common and lethal form of human ovarian cancer, and is linked to copy number gains at chromosome 12p13.33. We show that FOXM1 is co-amplified and co-expressed with RHNO1, a gene involved in the ATR-Chk1 signaling pathway that functions in the DNA replication stress response. We demonstrate that FOXM1 and RHNO1 are head-to-head (i.e., bidirectional) genes (BDG) regulated by a bidirectional promoter (BDP) (named F/R-BDP). FOXM1 and RHNO1 each promote oncogenic phenotypes in HGSC cells, including clonogenic growth, DNA homologous recombination repair, and poly-ADP ribosylase inhibitor resistance. FOXM1 and RHNO1 are one of the first examples of oncogenic BDG, and therapeutic targeting of FOXM1/RHNO1 BDG is a potential therapeutic approach for ovarian and other cancers.

KIF18A knockdown reduces proliferation, migration, invasion and enhances radiosensitivity of esophageal cancer

Kinesin family member 18A (KIF18A) is significantly overexpressed and is related to the poor prognosis of human cancers. However, the function of KIF18A in esophageal cancer (EC) is still unclear. Human EC cell lines were used in this study. KIF18A expression in human tissues was assessed using Gene Expression Profiling Interactive Analysis 2.0 (GEPIA2). The expressions of KIF18A or IGF2BP3 in EC cells were detected using qRT-PCR or WB. Cells were transfected using si-KIF18A, si-IGF2BP3, and plasmid IGF2BP3. The abilities of proliferation, migration, and invasion were detected by EdU, wound-healing, and transwell assay. The interaction between KIF18A and IGF2BP3 was predicted by starBase v3.0 and studied by RIP and RNA stability assay. Colony formation assay was used to reflect the changes of radiosensitivity in EC cells. KIF18A was upregulated in EC, and KIF18A knockdown inhibited EC cell proliferation, migration, invasion, and radioresistance. The prediction in starBase and RIP assay results showed that KIF18A mRNA could bind to IGF2BP3 protein in EC cells. RNA stability assay was performed to confirm that IGF2BP3 affects mRNA stability of KIF18A. Further studies also showed that IGF2BP3 could positively regulate KIF18A on proliferation, migration, invasion, and radioresistance. Our findings first revealed an oncogenic effect of KIF18A in human EC progression. KIF18A expression was associated with radioresistance of EC cells. The binding relationship between KIF18A and IGF2BP3 might influence the mRNA stability of KIF18A in EC cell lines.

Albumin-to-alkaline phosphatase ratio as a promising indicator of prognosis in human cancers: is it possible?

BackgroundThe impact of albumin-to-alkaline phosphatase ratio (AAPR) on prognosis in cancer patients remains uncertain, despite having multiple relevant studies in publication.MethodsWe systemically compiled literatures from 3 databases (Cochrane Library, PubMed, and Web of Science) updated to May 24th, 2020. Hazard ratios (HRs) and 95% confidence intervals (CIs) were computed and synthesized using STATA 14, values were then pooled and utilized in order to assess the overall impact of AAPR on patient’s prognosis.ResultsIn total, 18 studies involving 25 cohorts with 7019 cases were incorporated. Pooled results originated from both univariate and multivariate analyses (HR = 2.14, 95%CI:1.83–2.51, random-effects model; HR = 1.93, 95%CI:1.75–2.12, fixed-effects model; respectively) suggested that decreased AAPR had adverse effect on overall survival (OS). Similarly, pooled results from both univariate and multivariate analysis of fixed-effects model, evinced that decreased AAPR also had adverse effect on disease-free survival (DFS) (HR = 1.81, 95%CI:1.60–2.04, I2 = 29.5%, P = 0.174; HR = 1.69, 95%CI:1.45–1.97, I2 = 13.0%, P = 0.330; respectively), progression-free survival (PFS) (HR = 1.71, 95%CI:1.31–2.22, I2 = 0.0%, P = 0.754; HR = 1.90, 95%CI:1.16–3.12, I2 = 0.0%, P = 0.339; respectively), and cancer-specific survival (CSS) (HR = 2.22, 95%CI:1.67–2.95, I2 = 5.6%, P = 0.347; HR = 1.88, 95%CI:1.38–2.57, I2 = 26.4%, P = 0.244; respectively). Admittedly, heterogeneity and publication bias existed, but stratification of univariate meta-analytic results, as well as adjusted meta-analytic results via trim and fill method, all showed that AAPR still significantly correlated with poor OS despite of confounding factors.ConclusionsIn summary, decreased AAPR had adverse effect on prognosis in cancer patients. As an inexpensive and convenient ratio derived from liver function test, AAPR might become a promising indicator of prognosis in human cancers.

Long non-coding RNA FTX predicts a poor prognosis of human cancers: a meta-analysis.

Background: Several studies have assessed the relationship between long non-coding RNA five prime to Xist (FTX) expression, clinicopathological features, and survival outcomes in patients with cancer with conflicting results. This meta-analysis synthesized existing data to clarify the association between FTX with cancer prognosis.Methods: PubMed, Embase, Cochrane library, Web of Science, Chinese CNKI, and the Chinese WanFang databases were used to search for relevant studies. The role of FTX in cancers was evaluated by pooled odds ratios (ORs) and hazard ratios (HRs) with 95% confidence intervals (CIs).Results: Eleven studies comprising 1210 participants including colorectal cancer (CRC), hepatocellular carcinoma (HCC), gastric cancer (GC), renal cell carcinoma (RCC), osteosarcoma (OSC), and glioma were enrolled in this analysis. The meta-analysis showed that high FTX expression was significantly associated with several clinicopathological characteristics, including lymph node metastasis in patients with CRC, GC, HCC, and RCC, distant metastasis in patients with CRC, GC, HCC, and OSC, larger tumor size in patients with CRC, GC, HCC, RCC, and OSC, and subsequently TNM/clinical stage in patients with CRC, GC, HCC, OSC, and glioma. The pooled results from the survival analysis revealed a significant correlation between high FTX expression and shorter OS in patients with HCC, CRC, GC, OSC, and glioma. Further, FTX overexpression could be an independent predictive marker for shorter OS in patients with CRC, HCC, OSC, and glioma.Conclusions: FTX may be a potential oncogene, with high FTX expression being associated with a poorer prognosis in patients with CRC, HCC, OSC, and glioma.

Immunological Role and Prognostic Potential of CLEC10A in Pan-Cancer

CLEC10A is expressed in a variety of cells, involved in a variety of biological pathways including immune response, and is closely related to the development of tumor immune response. However, the role of CLEC10A from a pan-cancer perspective has not yet been analyzed, and its role in human cancer prognosis and immunology remains largely unclear.We studied the expression levels of CLEC10A and investigated its prognostic value in various cancers across distinct datasets including Oncomine, cBioPortal, and TCGA, and conducted immunohistochemical experiments using fresh bladder cancer and breast cancer samples to verify the results. In addition, we also performed GSEA of CLEC10A and explored the relationship between CLEC10A expression and immune infiltration, immune checkpoints, immune activation genes, immunosuppressive genes, chemokines and chemokine receptors.The results showed that the expression level of CLEC10A in most tumors was significantly lower compared with non-cancerous tissue, and the decreased expression was related to poor prognosis and more advanced cancer stages. We also found that the expression of CLEC10A was significantly related to the immunomodulatory interaction between lymph and non-lymphocytes. Furthermore, the expression of CLEC10A was not only significantly correlated with the level of infiltration of CD4+T cells and CD8+T cells, but also closely related to immune checkpoints, immune activation genes, immunosuppressive genes, chemokines, and chemokine receptors. Importantly, our analysis of the relationship between CLEC10A and TMB and MSI also confirmed the speculation that CLEC10A may influence antitumor immunity by regulating the composition and immune mechanisms of the tumor microenvironment.In conclusion, CLEC10A may serve as a new target for tumor immunotherapy and has great potential as a molecular biomarker for predicting pan-cancer prognosis and immune infiltration.

The Clinical Prognostic Value of lncRNA SBF2-AS1 in Cancer Patients: A Meta-Analysis.

Background:The mortality and recurrence of patients with cancer is of high prevalence. SET-binding factor 2 (SBF2) antisense RNA1 (lncRNA-SBF2-AS1) is a promising long non-coding RNA. There is increasing evidence that SBF2-AS1 is abnormally expressed in various tumors and is associated with cancer prognosis. However, the identification of the effect of lncRNA SBF2-AS1 in tumors remains necessary.Materials and Methods:Up to November 2, 2020, electronic databases, including PubMed, Cochrane Library, EMBASE, Medline, and Web of Science, were searched. The results were evaluated by pooled odds ratios (ORs) and hazard ratios (HRs) with 95% confidence intervals (CIs).Results:A total of 11 literatures on cancer patients were included for the present meta-analysis. The combined results revealed that high expression of SBF2-AS1 was significantly associated with unfavorable overall survival (OS) (HR = 1.48, 95% CI: 1.34-1.62, P < 0.00001) in a variety of cancers. In additional, the increase in SBF2-AS1 expression was also correlated with tumor size ((larger vs. smaller) OR = 2.34, 95% CI: 1.47-3.70, P = 0.0003), advanced TNM stage ((III/IV vs. I/II) OR = 2.78, 95% CI: 1.75-4.41, P < 0.0001), lymph node metastasis ((Positive vs. Negative) OR = 3.06, 95% CI: 1.93-4.86, P < 0.00001), and histological grade ((poorly vs. well/moderately) OR = 2.58, 95% CI: 1.47-4.52, P = 0.001) in patients with cancer. Furthermore, The Cancer Genome Atlas (TCGA) dataset valuated that SBF2-AS1 was upregulated in a variety of tumors, and predicted the worse prognosis.Conclusions:Our results of this meta-analysis demonstrate that high SBF2-AS1 expression may become a potential target for predicting the prognosis of human cancers.

Prognostic Value of Long Noncoding RNA SNHG12 in Various Carcinomas: A Meta-Analysis.

Background Numerous recent studies suggested that overexpression of the long noncoding RNA small nucleolar RNA host gene 12 (SNHG12) exhibited prooncogenic activity in multiple cancers. However, results regarding the prognostic value of SNHG12 in cancers still remained controversial. Therefore, we conducted a meta-analysis complemented with bioinformatics analysis to elucidate the clinical significance of SNHG12 in cancer patients. Methods PubMed, Embase, Cochrane Library, Chinese National Knowledge Infrastructure, Wanfang, and Weipu databases were searched for eligible studies until July 2020. Additionally, bioinformatics analysis was applied to verify the results of meta-analysis. Results Twenty-three related studies consisting of 1389 cancer patients were enrolled in the current meta-analysis. Elevated SNHG12 expression was found to be significantly associated with poor overall survival (OS) (HR = 1.81; 95% CI: 1.53-2.13; P < 0.001) and disease-free survival (DFS) (HR = 1.40; 95% CI: 1.12-1.76; P = 0.004) in multiple cancers, which were also verified by the results of bioinformatics analysis. Moreover, overexpression of SNHG12 was also related to clinicopathological characteristics including LNM, distant metastasis, high clinical stage, large tumor size, and poor tumor differentiation in diverse types of cancers. Conclusion The present findings indicated that SNHG12 might act as a novel biomarker for diagnosis or prognosis in human cancers.

CD25-Treg-depleting antibodies preserving IL-2 signaling on effector T cells enhance effector activation and antitumor immunity.

Intratumoral regulatory T cell (Treg) abundance associates with diminished anti-tumor immunity and poor prognosis in human cancers. Recent work demonstrates that CD25, the high affinity receptor subunit for IL-2, is a selective target for Treg depletion in mouse and human malignancies; however, anti-human CD25 antibodies have failed to deliver clinical responses against solid tumors due to bystander IL-2 receptor signaling blockade on effector T cells, which limits their anti-tumor activity.Here we demonstrate potent single-agent activity of anti-CD25 antibodies optimized to deplete Tregs whilst preserving IL-2-STAT5 signaling on effector T cells, and demonstrate synergy with immune checkpoint blockade in vivo. Pre-clinical evaluation of an anti-human CD25 (RG6292) antibody with equivalent features demonstrates, in both non-human primates and humanized mouse models, efficient Treg depletion with no overt immune-related toxicities. Our data supports the clinical development of RG6292 and evaluation of novel combination therapies incorporating non-IL-2 blocking anti-CD25 antibodies in clinical studies.

Abstract PO-111: Identifying epigenetic mechanisms for proliferation and self-renewal of tumor-propagating cells (TPC) in lung cancer

Abstract Lung cancer is a leading cause of death worldwide and lung adenocarcinoma (LUAD) is the most common subtype. LUAD tumors have a functional heterogeneity in regard to tumor-propagating capacity. Cells with an increased capacity to sustain tumor growth are called tumor-propagating cells (TPC or cancer stem cells) and they have been associated with chemoresistance and tumor relapse. A TPC population identified in a mouse model of LUAD (Kras G12D/wt/p53 fl/fl)(KP) sustain growth in serial orthotopic transplantations and are distinguished by expression of Notch receptors. Furthermore, TPCs gene expression signature is associated with a worse prognosis in human cancer. My hypothesis is the TPCs gene expression may be regulated by global chromatin alterations driven by epigenetic regulators. In LUAD, secondary tumors derived from TPC or non-TPC sorted populations regenerated both TPC and non-TPC populations, recapitulating the heterogeneity of the original tumor, suggesting TPC plasticity and supporting an epigenetic regulation. The main goal of my work is to identify and understand epigenetic mechanisms of TPC maintenance in LUAD and determine their relevance for other cancers. TPC and non-TPC populations show dramatic differential protein expression of H3K4me3 and H4K16ac histone modifications associated with transcription activation. To better understand how these histone marks alter the genome of TPCs, I performed ATAC-seq (Assay for Transposase-Accessible Chromatin followed by sequencing) and CARM (CRISPR/Cas9-assisted removal of mitochondrial DNA) to remove mitochondrial DNA prior to sequencing in both TPC and non-TPC populations from primary cells of KP mouse models. I have identified unique open chromatin regions in TPCs which were associated to the closest gene. For TPCs, the main enriched cluster of pathways included Notch signaling pathway and pathways associated with remodeling of the tumor microenvironment. In parallel, I am customizing an epigenetic short hairpin RNA (shRNA) library to screen epigenetic regulators implicated in plasticity and self-renewal ability of TPCs and I will evaluate them whether function through Notch signaling. Citation Format: Eunice Lopez Fuentes, Alejandro Sweet-Cordero. Identifying epigenetic mechanisms for proliferation and self-renewal of tumor-propagating cells (TPC) in lung cancer [abstract]. In: Proceedings of the AACR Virtual Special Conference on Tumor Heterogeneity: From Single Cells to Clinical Impact; 2020 Sep 17-18. Philadelphia (PA): AACR; Cancer Res 2020;80(21 Suppl):Abstract nr PO-111.

Genomic analysis of the prognostic effect of tumor-associated neutrophil-related genes across 15 solid cancer types: an immune perspective.

BackgroundTumor-associated neutrophils (TANs) have been a research hotspot in recent years. However, the role and relevant mechanisms of TANs in the tumor microenvironment (TME) have not yet been elucidated.MethodThe ribonucleic acid (RNA) expression levels of fucosyltransferase 4 (FUT4) and elastase, neutrophil expressed (ELANE) in samples from The Cancer Genome Atlas (TCGA) (n=4,538) were analyzed. Receiver operating characteristic (ROC) curves were used to calculate the critical cutoff values, and different data were defined as high and low expression. The tumor microenvironment immune type (TMIT) was defined according to the activation state of TAN, and the samples were classified into three TMITs based on their cut-off values. Mutational datasets and overall survival were compared according to the TMITs.ResultsThe prognostic significance of FUT4, ELANE, and myeloperoxidase (MPO) was different among the 15 cancers, and the prognostic significance of different TMITs varied across the different tumors. Compared with the other groups, TMIT 3 had a favorable prognostic effect, which was most prominent in lung adenocarcinoma (LUAD) [hazard ratio (HR) =0.292, 95% confidence interval (CI): 0.185–0.459, P<0.001].ConclusionsOur study demonstrated that highly-activated TANs predicted a favorable prognosis in humans using genomic analyses for the first time. This provides a realistic basis for further exploring the role of TANs in the immune microenvironment and provides real world data for tumor immunotherapy.