scholarly journals A Pan-Cancer Study of KMT2 Family as Therapeutic Targets in Cancer

2022 ◽  
Vol 2022 ◽  
pp. 1-10
Author(s):  
Jiamin Zhu ◽  
Zhili Liu ◽  
Xiao Liang ◽  
Lu Wang ◽  
Dan Wu ◽  
...  
Keyword(s):  
Overall Survival ◽  
Tumor Microenvironment ◽  
Patient Survival ◽  
Expression Patterns ◽  
Family Members ◽  
Cancer Type ◽  
Tumor Type ◽  
Histone Lysine ◽  
Cancer Types ◽  
Pan Cancer

Objective. Exome sequencing studies have shown that the histone-lysine N-methyltransferase 2 (KMT2) gene is one of the most commonly mutated genes in a range of human malignancies and is linked to some of the most common and deadly solid tumors. However, the connection between this gene family’s function and tumor type, immunological subtype, and molecular subtype dependency is still unknown. Methods. We examine the expression patterns of the histone-lysine N-methyltransferase 2 (KMT2) gene, as well as their relationship to patient survival. We also used a pan-cancer analysis to link their function to immunological subtypes, the tumor microenvironment, and treatment sensitivity. Results. Using the TCGA pan-cancer data, researchers looked at and examined KMT2 expression patterns and their links to patient survival and the tumor microenvironment in 33 cancer types. The expression of the KMT2 family changes significantly across and within cancer types, indicating significant inter- and intracancer heterogeneity. Patients’ overall survival was often linked to the expression of KMT2 family members. However, the direction of the link differed depending on the KMT2 isoform and cancer type studied. Notably, in all cancer types examined, nearly all KMT2 family members were substantially linked with overall survival in patients with renal clear cell carcinoma (KIRC). Furthermore, all KMT2 genes have a strong relationship with immune infiltrate subtypes, as well as varying degrees of stromal cell infiltration and tumor cell stemness. Finally, we discovered that higher expression of KMT2s, particularly KMT2F and KMT2G, was linked to greater chemotherapeutic sensitivity in several cell lines. Conclusions. The necessity to investigate each KMT2 member as a distinct entity inside each particular cancer type is highlighted by our comprehensive investigation of KMT2 gene expression and its relationship with immune infiltrates, tumor microenvironment, and cancer patient outcomes. Our research also confirmed the identification of KMT2 as a potential therapeutic target in cancer, but further laboratory testing is required.

scholarly journals Characterization of Class-3 Semaphorin Receptors, Neuropilins and Plexins, as Therapeutic Targets in a Pan-Cancer Study

Cancers ◽  
2020 ◽  
Vol 12 (7) ◽  
pp. 1816
Author(s):  
Xiaoli Zhang ◽  
Shuai Shao ◽  
Lang Li
Keyword(s):  
Patient Survival ◽  
Cancer Type ◽  
Dependent Manner ◽  
Metastatic Progression ◽  
Drug Responses ◽  
Signal Transducers ◽  
Surface Receptors ◽  
Downstream Signaling ◽  
Cancer Types ◽  
Pan Cancer

Class-3 semaphorins (SEMA3s), initially characterized as axon guidance cues, have been recognized as key regulators for immune responses, angiogenesis, tumorigenesis and drug responses. The functions of SEMA3s are attributed to the activation of downstream signaling cascades mainly mediated by cell surface receptors neuropilins (NRPs) and plexins (PLXNs), yet their roles in human cancers are not completely understood. Here, we provided a detailed pan-cancer analysis of NRPs and PLXNs in their expression, and association with key signal transducers, patient survival, tumor microenvironment (TME), and drug responses. The expression of NRPs and PLXNs were dysregulated in many cancer types, and the majority of them were further dysregulated in metastatic tumors, indicating a role in metastatic progression. Importantly, the expression of these genes was frequently associated with key transducers, patient survival, TME, and drug responses; however, the direction of the association varied for the particular gene queried and the specific cancer type/subtype tested. Specifically, NRP1, NRP2, PLXNA1, PLXNA3, PLXNB3, PLXNC1, and PLXND1 were primarily associated with aggressive phenotypes, whereas the rest were more associated with favorable prognosis. These data highlighted the need to study each as a separate entity in a cancer type- and subtype-dependent manner.

scholarly journals A Pan-Cancer Study of Epidermal Growth Factor-Like Domains 6/7/8 as Therapeutic Targets in Cancer

2020 ◽  
Vol 11 ◽  
Author(s):  
Shanping Shi ◽  
Ting Ma ◽  
Yang Xi
Keyword(s):  
Gene Expression ◽  
Growth Factor ◽  
Tumor Microenvironment ◽  
Epidermal Growth Factor ◽  
Patient Survival ◽  
Expression Profiles ◽  
Cancer Study ◽  
Cancer Types ◽  
Epidermal Growth ◽  
Pan Cancer

With highly homologous epidermal growth factor (EGF)-like (EGFL) domains, the members of the EGFL family play crucial roles in growth, invasion, and metastasis of tumors and are closely associated with the apoptosis of tumor cells and tumor angiogenesis. Furthermore, their contribution to immunoreaction and tumor microenvironment is highly known. In this study, a comprehensive analysis of EGFL6, −7, and −8 was performed on the basis of their expression profiles and their relationship with the rate of patient survival. Through a pan-cancer study, their effects were correlated with immune subtypes, tumor microenvironment, and drug resistance. Using The Cancer Genome Atlas pan-cancer data, expression profiles of EGFL6, −7, and −8, and their association with the patient survival rate and tumor microenvironment were analyzed in 33 types of cancers. The expression of the EGFL family was different in different cancer types, revealing the heterogeneity among cancers. The results showed that the expression of EGFL8 was lower than EGFL6 and EGFL7 among all cancer types, wherein EGFL7 had the highest expression. The univariate Cox proportional hazard regression model showed that EGFL6 and EGFL7 were the risk factors to predict poor prognosis of cancers. Survival analysis was then used to verify the relationship between gene expression and patient survival. Furthermore, EGFL6, EGFL7, and EGFL8 genes revealed a clear association with immune infiltrate subtypes; they were also related to the infiltration level of stromal cells and immune cells with different degrees. Moreover, they were negatively correlated with the characteristics of cancer stem cells measured by DNAs and RNAs. In addition, EGFL6, −7, and −8 were more likely to contribute to the resistance of cancer cells. Our systematic analysis of EGFL gene expression and their correlation with immune infiltration, tumor microenvironment, and prognosis of cancer patients emphasized the necessity of studying each EGFL member as a separate entity within each particular type of cancer. Simultaneously, EGFL6, −7, and −8 signals were verified as promising targets for cancer therapies, although further laboratory validation is still required.

Exploration of the MSI landscape in Chinese pan-cancer patient by Next-Generation Sequencing.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e14576-e14576
Author(s):  
Xinlu Liu ◽  
Jiasheng Xu ◽  
Jian Sun ◽  
Deng Wei ◽  
Xinsheng Zhang ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Correlation Analysis ◽  
Cancer Patients ◽  
Cancer Type ◽  
Multiple Tumor ◽  
Treatment Plans ◽  
Cancer Types ◽  
Chinese Cancer Patients ◽  
Colorectal Cancer Patients ◽  
Pan Cancer

e14576 Background: Clinically, MSI had been used as an important molecular marker for the prognosis of colorectal cancer and other solid tumors and the formulation of adjuvant treatment plans, and it had been used to assist in the screening of Lynch syndrome. However, there were currently few reports on the incidence of MSI-H in Chinese pan-cancer patients. This study described the occurrence of MSI in a large multi-center pan-cancer cohort in China, and explored the correlation between MSI and patients' TMB, age, PD-L1 expression and other indicators. Methods: The study included 8361 patients with 8 cancer types from multiple tumor centers. Use immunohistochemistry to detect the expression of MMR protein (MLH1, MSH2, MSH6 and PMS2) in patients with various cancer types to determine the MSI status and detect the expression of PD-L1 in patients. Through NGS technology, 831 genes of 8361 Chinese cancer patients were sequenced and the tumor mutation load of the patients was calculated. The MSI mutations of patients in 8 cancer types were analyzed and the correlation between MSI mutations of patients and the patient's age, TMB and PD-L1 expression was analyzed. Results: The test results showed that MSI patients accounted for 1.66% of pan-cancers. Among them, MSI-H patients accounted for the highest proportion in intestinal cancer, reaching 7.2%. The correlation analysis between MSI and TMB was performed on patients of various cancer types. The results showed that: in each cancer type, MSI-H patients had TMB greater than 10, and 26.83% of MSI-H patients had TMB greater than 100 in colorectal cancer patients. The result of correlation analysis showed that there was no significant correlation between the patient's age and the risk of MSI mutation ( P> 0.05). In addition to PAAD and LUAD, the expression of PD-L1 in MSI-H patients was higher than that in MSS patients in other cancer types( P< 0.05). The correlation analysis between PD-L1 expression and TMB in patients found that in colorectal cancer, the higher the expression of PD-L1, the higher the patient's TMB ( P< 0.05). Conclusions: In this study, we explored the incidence of MSI-H in pan-cancer patients in China and found that the TMB was greater than 10 in patients with MSI-H. Compared with MSS patients, MSI-H patients have higher PD-L1 expression, and the higher the PD-L1 expression in colorectal cancer, the higher the TMB value of patients.

scholarly journals Pan-cancer systematic identification of lncRNAs associated with cancer prognosis

2018 ◽  
Author(s):  
Matthew H. Ung ◽  
Evelien Schaafsma ◽  
Daniel E. Mattox ◽  
George L. Wang ◽  
Chao Cheng
Keyword(s):  
Drug Targets ◽  
Patient Survival ◽  
Cancer Prognosis ◽  
Rna Seq ◽  
Non Coding Rna ◽  
Cancer Types ◽  
Microarray Studies ◽  
Systematic Identification ◽  
Pan Cancer ◽  
Novel Associations

AbstractThe “dark matter” of the genome harbors several non-coding RNA species including IncRNAs, which have been implicated in neoplasias but remain understudied. RNA-seq has provided deep insights into the nature of lncRNAs in cancer but current RNA-seq data are rarely accompanied by longitudinal patient survival information. In contrast, a plethora of microarray studies have collected these clinical metadata that can be leveraged to identify novel associations between gene expression and clinical phenotypes. In this study, we developed an analysis framework that computationally integrates RNA-seq and microarray data to systematically screen 9,463 lncRNAs for association with mortality risk across 20 cancer types. In total, we identified a comprehensive list of associations between lncRNAs and patient survival and demonstrate that these prognostic lncRNAs are under selective pressure and may be functional. Our results provide valuable insights that facilitate further exploration of lncRNAs and their potential as cancer biomarkers and drug targets.

Role of DNA polymerases family members in cancer: The pan-cancer perspective.

2021 ◽  
Vol 39 (3_suppl) ◽  
pp. 475-475
Author(s):  
Zhiwen Luo ◽  
Xinyu Bi ◽  
Xingang Bi
Keyword(s):  
Expression Pattern ◽  
Drug Target ◽  
Dna Polymerases ◽  
Family Members ◽  
Prognostic Biomarkers ◽  
Cancer Type ◽  
Sequencing Data ◽  
Clinical Value ◽  
Bioinformatics Analyses ◽  
Pan Cancer

475 Background: DNA polymerases family (DNA pols) has a lengthy reported significant influence on the initiation, development, and progress of cancer. However, the pan-cancer value of whole family members was poorly done. Our study intends to demonstrate the expression pattern and clinical cancer value of DNA pols members as prognostic biomarkers and a therapeutic target of pan-cancer. Methods: Comprehensive bioinformatics analyses were done using data from TCGA and CCLE. MultiCox regression was done to select tumor prognosis-related members. Nomogram was constructed to predict the overall survival (OS) across cancer patients. Transcription factor, GO, IPA, and GSEA enrichments were done to explore regulatory mechanisms and functions. Results: A total of 22 DNA pols were identified to have a potential to diagnostic value, and 10 DNA pols have a pan-cancer prognostic value under various stages, and cancer type, among which overexpression of 6 DNA-pols (POLA2, POLD1, POLD2, POLE2, POLE4, and POLQ) was found to be significantly related to worse outcomes regarding OS, while 4 DNA-pols (POLH, POLL, POLN, and REV1) significantly related to better outcomes. A 5-DNA pols based risk score (POLQ, POLD2, POLL, POLH, and REV1) was generated by MultiCox regression with a nomogram validated an accurate predictive efficacy. MYB Proto-Oncogene Like 2 (MYBL2) was identified as transcription factors of prognostic DNA pols in pan-cancer, and IPA mimic experiment reveals inhibiting MYBL2 could be a drug target to recover and balance the dysregulated expression pattern of DNA pols in pan-cancer. GO, IPA, and GSEA enrichments revealed functions and pathways altered by DNA pols in cancer, and the results were supported by pan-cancer cell sequencing data. Conclusions: DNA pols have a pan-cancer clinical value and can work as potential prognostic biomarkers. Furthermore, MYBL2 could be a drug target for pan-cancer.

scholarly journals Prognostic Indications of Elevated MCT4 and CD147 across Cancer Types: A Meta-Analysis

2015 ◽  
Vol 2015 ◽  
pp. 1-14 ◽  
Author(s):  
Cory D. Bovenzi ◽  
James Hamilton ◽  
Patrick Tassone ◽  
Jennifer Johnson ◽  
David M. Cognetti ◽  
...  
Keyword(s):  
Overall Survival ◽  
Tumor Microenvironment ◽  
Cancer Cells ◽  
Meta Analysis ◽  
Critical Role ◽  
Disease Free Survival ◽  
Free Survival ◽  
Cd147 Expression ◽  
Cancer Types ◽  
Disease Free

Background. Metabolism in the tumor microenvironment can play a critical role in tumorigenesis and tumor aggression. Metabolic coupling may occur between tumor compartments; this phenomenon can be prognostically significant and may be conserved across tumor types. Monocarboxylate transporters (MCTs) play an integral role in cellular metabolism via lactate transport and have been implicated in metabolic synergy in tumors. The transporters MCT1 and MCT4 are regulated via expression of their chaperone, CD147.Methods. We conducted a meta-analysis of existing publications on the relationship between MCT1, MCT4, and CD147 expression and overall survival and disease-free survival in cancer, using hazard ratios derived via multivariate Cox regression analyses.Results. Increased MCT4 expressions in the tumor microenvironment, cancer cells, or stromal cells were all associated with decreased overall survival and decreased disease-free survival (p<0.001for all analyses). Increased CD147 expression in cancer cells was associated with decreased overall survival and disease-free survival (p<0.0001for both analyses). Few studies were available on MCT1 expression; MCT1 expression was not clearly associated with overall or disease-free survival.Conclusion. MCT4 and CD147 expression correlate with worse prognosis across many cancer types. These results warrant further investigation of these associations.

scholarly journals From Genetic Alterations to Tumor Microenvironment: The Ariadne’s String in Pancreatic Cancer

Cells ◽  
2020 ◽  
Vol 9 (2) ◽  
pp. 309 ◽  
Author(s):  
Chiara Bazzichetto ◽  
Fabiana Conciatori ◽  
Claudio Luchini ◽  
Francesca Simionato ◽  
Raffaela Santoro ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Tumor Microenvironment ◽  
Current Knowledge ◽  
Myeloid Cells ◽  
Genetic Alterations ◽  
Molecular Characteristics ◽  
Precision Oncology ◽  
Cancer Type ◽  
Tumor Type ◽  
Driver Genes

The threatening notoriety of pancreatic cancer mainly arises from its negligible early diagnosis, highly aggressive progression, failure of conventional therapeutic options and consequent very poor prognosis. The most important driver genes of pancreatic cancer are the oncogene KRAS and the tumor suppressors TP53, CDKN2A, and SMAD4. Although the presence of few drivers, several signaling pathways are involved in the oncogenesis of this cancer type, some of them with promising targets for precision oncology. Pancreatic cancer is recognized as one of immunosuppressive phenotype cancer: it is characterized by a fibrotic-desmoplastic stroma, in which there is an intensive cross-talk between several cellular (e.g., fibroblasts, myeloid cells, lymphocytes, endothelial, and myeloid cells) and acellular (collagen, fibronectin, and soluble factors) components. In this review; we aim to describe the current knowledge of the genetic/biological landscape of pancreatic cancer and the composition of its tumor microenvironment; in order to better direct in the intrinsic labyrinth of this complex tumor type. Indeed; disentangling the genetic and molecular characteristics of cancer cells and the environment in which they evolve may represent the crucial step towards more effective therapeutic strategies

Thyroid dysfunction and immune checkpoint inhibitor outcomes.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e15103-e15103
Author(s):  
Mitchell S. von Itzstein ◽  
Rong Lu ◽  
Sadia Ali ◽  
Donglu Xie ◽  
Jennifer Cai ◽  
...  
Keyword(s):  
Overall Survival ◽  
Thyroid Function ◽  
Median Survival ◽  
Immune Checkpoint ◽  
Thyroid Dysfunction ◽  
Cancer Type ◽  
Thyroid Function Tests ◽  
Function Tests ◽  
Cancer Types ◽  
Thyroid Abnormalities

e15103 Background: Immune checkpoint inhibitors (ICI) frequently cause thyroid dysfunction. We performed a longitudinal analysis of thyroid function tests in a large, single-center cohort of patients with multiple cancer types receiving ICI. Methods: We performed a retrospective medical records review of consecutive patients treated with ICI from 1/1/2005 to 12/31/2018. We collected demographic and clinical data, including serial thyroid function tests. We compared overall survival between patients with normal and abnormal thyroid stimulating hormone (TSH) at baseline and after ICI initiation using Kaplan-Meier curves, log-rank tests, and multivariate Cox proportional hazards model. Results: A total of 910 patients were included: 63% male, 82% white, median age 67. The most common cancer types were lung (26%), kidney (18%), and melanoma (17%). ICI types were anti-PD1/L1 (78%), anti-CTLA-4 (7%), and combination ICI (15%). Normal baseline TSH and abnormal post-treatment TSH was associated with longer overall survival (median survival 26 months) compared to all other TSH permutations (median survival < 10 months) ( P< 0.001). This finding persisted after multivariate Cox regression adjustment for age, gender and cancer type (P < 0. 001), and also after sensitivity analysis censoring patients who died within 2 months after starting ICI. Conversely, abnormal TSH at baseline was associated with lower overall survival (median 8 months) compared to normal TSH at baseline (median 18 months) ( P< 0.001), which also persisted in multivariate analysis ( P< 0.001). Kidney and head and neck cancers (71% and 69%) were associated with increased development of thyroid dysfunction compared to melanoma, lung and other urological cancers (52%, 50% and 35%) ( P< 0.01). Conclusions: Although abnormal thyroid function after ICI initiation was associated with improved overall survival, pre-treatment thyroid abnormalities were associated with worse overall survival. Given the prevalence of thyroid abnormalities in the general population, further research into these observations is warranted.

scholarly journals Integrative analyses of the RNA modification machinery reveal tissue- and cancer-specific signatures

2019 ◽  
Author(s):  
Oguzhan Begik ◽  
Morghan C. Lucas ◽  
Huanle Liu ◽  
Jose Miguel Ramirez ◽  
John S. Mattick ◽  
...  
Keyword(s):  
Cancer Research ◽  
Expression Patterns ◽  
Rna Modification ◽  
Cancer Type ◽  
Evolutionary Analysis ◽  
Rna Modifications ◽  
Human Samples ◽  
Mammalian Tissues ◽  
Normal Human ◽  
Cancer Types

ABSTRACTBackgroundRNA modifications play central roles in cellular fate and differentiation. These features have placed the epitranscriptome in the forefront of developmental biology and cancer research. However, the machinery responsible for placing, removing and recognizing more than 170 RNA modifications remains largely uncharacterized and poorly annotated, and we currently lack integrative studies that identify which RNA modification–related proteins (RMPs) may be dysregulated in each cancer type.ResultsHere we have performed a comprehensive annotation and evolutionary analysis of human RMPs as well as an integrative analysis of their expression patterns across 32 tissues, 10 species and 13,358 paired tumor-normal human samples. Our analysis reveals an unanticipated heterogeneity of RMP expression patterns across mammalian tissues, with a vast proportion of duplicated enzymes displaying testis-specific expression, suggesting a key role for RNA modifications in sperm formation and possibly intergenerational inheritance. Moreover, through the analysis of paired tumor-normal human samples we uncover many RMPs that are dysregulated in various types of cancer, and whose expression levels are predictive of cancer progression. Surprisingly, we find that several commonly studied RNA modification enzymes such as METTL3 or FTO, are not significantly up-regulated in most cancer types, once the sample is properly scaled and normalized to the full dataset, whereas several less-characterized RMPs, such as LAGE3 and HENMT1, are dysregulated in many cancers.ConclusionsOur analyses reveal an unanticipated heterogeneity in the expression patterns of RMPs across mammalian tissues, and uncover a large proportion of dysregulated RMPs in multiple cancer types. We provide novel targets for future cancer research studies targeting the human epitranscriptome, as well as foundations to understand cell type-specific behaviours that are orchestrated by RNA modifications.

scholarly journals Multi-cancer classification; an analysis of neural network complexity

2022 ◽  
Author(s):  
James W. Webber ◽  
Kevin M. Elias
Keyword(s):  
Neural Network ◽  
The Body ◽  
Cancer Classification ◽  
Control Group ◽  
Specific Information ◽  
Cancer Type ◽  
Feed Forward ◽  
Cancer Prediction ◽  
Cancer Types ◽  
Pan Cancer

Background: Cancer identification is generally framed as binary classification, normally discrimination of a control group from a single cancer group. However, such models lack any cancer-specific information, as they are only trained on one cancer type. The models fail to account for competing cancer risks. For example, an ostensibly healthy individual may have any number of different cancer types, and a tumor may originate from one of several primary sites. Pan-cancer evaluation requires a model trained on multiple cancer types, and controls, simultaneously, so that a physician can be directed to the correct area of the body for further testing. Methods: We introduce novel neural network models to address multi-cancer classification problems across several data types commonly applied in cancer prediction, including circulating miRNA expression, protein, and mRNA. In particular, we present an analysis of neural network depth and complexity, and investigate how this relates to classification performance. Comparisons of our models with state-of-the-art neural networks from the literature are also presented. Results: Our analysis evidences that shallow, feed-forward neural net architectures offer greater performance when compared to more complex deep feed-forward, Convolutional Neural Network (CNN), and Graph CNN (GCNN) architectures considered in the literature. Conclusion: The results show that multiple cancers and controls can be classified accurately using the proposed models, across a range of expression technologies in cancer prediction. Impact: This study addresses the important problem of pan-cancer classification, which is often overlooked in the literature. The promising results highlight the urgency for further research.

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