SHMT2 is Associated with Tumor Purity, CD8+ T Immune Cells Infiltration, and a Novel Therapeutic Target in Four Different Human Cancers.

AIMS: This study was launched to identify the SHMT2 associated Human Cancer subtypes. BACKGROUND: Cancer is the 2nd leading cause of death worldwide. Previous reports revealed the limited involvement of SHMT2 in human cancer. In the current study, we comprehensively analyzed the role of SHMT2 in 24 major subtypes of human cancers using in silico approach and identified a few subtypes that are mainly associated with SHMT2. OBJECTIVE: We aim to comprehensively analyze the role of SHMT2 in 24 major subtypes of human cancers using in silico approach and identified a few subtypes that are mainly associated with SHMT2. Earlier, limited knowledge exists in the medical literature regarding the involvement of Serine Hydroxymethyltransferase 2 (SHMT2) in human cancer. METHODS: In the current study, we comprehensively analyzed the role of SHMT2 in 24 major subtypes of human cancers using in silico approach and identified a few subtypes that are mainly associated with SHMT2. Pan-cancer transcriptional expression profiling of SHMT2 was done using UALCAN while further validation was performed using GENT2. For translational profiling of SHMT2, we utilized Human Protein Atlas (HPA) platform. Promoter methylation, genetic alteration, and copy number variations (CNVs) profiles were analyzed through MEXPRESS and cBioPortal. Survival analysis was carried out through Kaplan-Meier (KM) plotter platform. Pathway enrichment analysis of SHMT2 was performed using DAVID, while the gene-drug network was drawn through CTD and Cytoscape. Furthermore, in the tumor microenvironment, a correlation between tumor purity, CD8+ T immune cells infiltration, and SHMT2 expression was accessed using TIMER. RESULTS: SHMT2 was found overexpressed in 24 different subtypes of human cancers and its overexpression was significantly associated with the reduced Overall survival (OS) and Relapse-free survival durations of Breast cancer (BRCA), Kidney renal papillary cell carcinoma (KIRP), Liver hepatocellular carcinoma (LIHC), and Lung adenocarcinoma (LUAD) patients. This implies that SHMT2 plays a significant role in the development and progression of these cancers. We further noticed that SHMT2 was also up-regulated in BRCA, KIRP, LIHC, and LUAD patients of different clinicopathological features. Pathways enrichment analysis revealed the involvement of SHMT2 enriched genes in five diverse pathways. Furthermore, we also explored some interesting correlations between SHMT2 expression and promoter methylation, genetic alterations, CNVs, tumor purity, and CD8+ T immune cell infiltrates. CONCLUSION: Our results suggested that overexpressed SHMT2 is correlated with the reduced OS and RFS of the BRCA, KIRP, LIHC, and LUAD patients and can be a potential diagnostic and prognostic biomarker for these cancers.

Identification of Key Biomarkers for the Future Applications in Diagnostics and Targeted Therapy of Colorectal Cancer.

BACKGROUND: Colorectal cancer (CRC) is one of the most prevalent and deadliest malignancies in the world. INTRODUCTION: The microarray dataset GSE87211 has been re-analyzed in the present study through a multi-layered bioinformatics approach to identify the CRC associated hub genes. GSE87211 dataset was retrieved and GEO2R was implemented for the identification of differentially expressed genes (DEGs). STRING tool was used to construct the protein-protein interaction (PPI) network. Cytoscape was utilized to identify the top six hub genes. METHOD: KEGG analysis was performed using DAVID. Expression validation of the hub genes and exploration of the correlation between hub genes expression and various other parameters was done through UALCAN, GEPIA, GENT2, cBioportal, TIMER, RegNetwork, and CTD. The six identified hub genes (GAL, GALR1, SST, SSTR2, NPY, and NPY1R) were enriched in diverse cancer-driving pathways. GAL was significantly up-regulated while other 5 hub genes (GALR1, SST, SSTR2, NPY, and NPY1R) were significantly down-regulated in colon adenocarcinoma (COAD) patients relative to controls. RESULT: All these hub genes were hypermethylated and 5 out of 6 hub genes were found to be associated with the worst Overall survival (OS) of the COAD patients relative to control group. Furthermore, we explored some interesting associations between hub genes' expression and different other parameters including copy number variations (CNVs), CD+T immune cells infiltration, different other cancer states and crucial mutant genes across COAD samples. In addition, a few miRNAs (miR-27a-3p and miR-130a-3p) and drugs (triclosan, soman, reserpine, and isoproterenol, etc.) were found capable to alter the expression of hub genes and thus need to further be evaluated for their potential role in CRC treatment. CONCLUSION: In conclusion, the identified hub genes may provide new insight into the CRC biology and treatment.

A pan-cancer analysis of GINS complex subunit 4 to identify its potential role as a biomarker in multiple human cancers.

This study was initiated to explore the expression variation, clinical significance, and biological importance of the GINS complex subunit 4 (GINS4) in different human cancers as a shared biomarker via pan-cancer analysis through different platforms including UALCAN, Kaplan Meier (KM) plotter, TNMplot, GENT2, GEPIA, DriverDBv3, Human Protein Atlas (HPA), MEXPRESS, cBioportal, STRING, DAVID, MuTarge, Enrichr, TIMER, and CTD. Our findings have verified the up-regulation of GINS4 in 24 major subtypes of human cancers, and its overexpression was found to be substantially associated with poor overall survival (OS), relapse-free survival (RFs), and metastasis in ESCA, KIRC, LIHC, LUAD, and UCEC. This suggested that GINS4 plays a significant role in the development and progression of these five cancers. Furthermore, we noticed that GINS4 is also overexpressed in ESCA, KIRC, LIHC, LUAD, and UCEC patients with different clinicopathological characteristics. Enrichment analysis revealed the involvement of GINS4 associated genes in a variety of diverse GO and KEGG terms. We also explored few significant correlations between GINS4 expression and promoter methylation, genetic alterations, CNVs, other mutant genes, tumor purity, and immune cells infiltration. In conclusion, our results elucidated that GINS4 can serve as a shared diagnostic, prognostic biomarker, and a potential therapeutic target in ESCA, KIRC, LIHC, LUAD, and UCEC patients with different clinicopathological characteristics.

Breast Cancer Risk and Human Papillomavirus Infection: A Bradford Hill Criteria Based Evaluation.

BACKGROUND: The association between human papillomavirus (HPV) and human breast cancer (BC) has already been thoroughly studied worldwide with contradictory findings. Although the researchers have tried to minimize the conflict using statistical meta-analysis because of its shortcomings, there is still a need to evaluate the correlation between HPV and BC using any additional method. OBJECTIVES: This study was launched to investigate the correlation between HPV and BC through the application of Bradford Hill criteria postulates. METHODS: Population-wide studies associating HPV with BC were searched using the PubMed database. Then, the information of HPV burden in BC, normal/benign samples was analyzed, and ultimately Bradford Hill criteria postulates were applied on the collected evidence to explore the relationship between HPV and BC. In addition, to make the outcomes more authentic, we also reviewed the methodologies of previous studies to address the propensity of false results. RESULTS: After a careful evaluation of the obtained data against major Bradford Hill criteria postulates, it was noted that all these postulates, including strength, consistency, biological gradient, temporality, plausibility, experiment, specificity, and analogy were not fulfilled. CONCLUSION: The results of the present study have failed to establish a causal association between HPV and BC, but they did suggest HPV as a cause-effective agent or at least a co-participant in the pathogenesis of BC. Because of the weakness of association, particularly the lack of consistency between studies and the lack of effect specificity, more research into Bradford Hill criteria postulates is required.

Integrative analysis reveals methylenetetrahydrofolate dehydrogenase 1-like as an independent shared diagnostic and prognostic biomarker in five different human cancers.

BACKGROUND: Defects in methylenetetrahydrofolate dehydrogenase 1-like (MTHFD1L) expression have earlier been examined in only a few human cancers. OBJECTIVES: Multi-omics profiling of MTHFD1L as a shared biomarker in distinct subtypes of human cancers. METHODS: In the current study, for the multi-omics analysis of MTHFD1L in 24 major subtypes of human cancers, a comprehensive in silico approach was adopted to mine different open access online databases including UALCAN, Kaplan-Meier (KM) plotter, LOGpc, GEPIA, Human Protein Atlas (HPA), Gene Expression across Normal and Tumor tissue (GENT2), MEXPRESS, cBioportal, STRING, DAVID, TIMER, and Comparative Toxicogenomics Database (CTD). RESULTS: We noticed that the expression of MTHFD1L was significantly higher in all the analyzed 24 subtypes of human cancers as compared with the normal controls. Moreover, MTHDF1L overexpression was also found to be significantly associated with the reduced overall survival (OS) duration of Bladder urothelial cancer (BLCA), Head and neck cancer (HNSC), Kidney renal papillary cell carcinoma (KIRP), Lung adenocarcinoma (LUAD), and Uterine corpus endometrial carcinoma (UCEC). This implies that MTHFD1L plays a significant role in the development and progression of these cancers. We further noticed that MTHFD1L was also overexpressed in BLCA, HNSC, KIRP, LUAD, and UCEC patients of different clinicopathological features. Pathways enrichment analysis revealed the involvement of MTHFD1L-associated genes in five diverse pathways. We also explored few interesting correlations between MTHFD1L expression and its promoter methylation, genetic alterations, CNVs, and between CD8+ T immune cells level. CONCLUSION: In conclusion, our results elucidated that MTHFD1L can serve as a shared diagnostic and prognostic biomarker in BLCA, HNSC, KIRP, LUAD, and UCEC patients of different clinicopathological features.

CTHRC1 expression is a novel shared diagnostic and prognostic biomarker of survival in six different human cancer subtypes.

According to the previous reports, the collagen triple helix repeat containing 1 (CTHRC1) causes tumorigenesis by modulating the tumor microenvironment, however, the evidence is limited to a few human cancer subtypes. In the current study, we analyzed and validated the CTHRC1 expression variations in 24 different human cancer tissues paired with normal tissues using publically available databases. We observed that CTHRC1 was overexpressed in all the 24 major subtypes of human cancers and its overexpression was significantly associated with the reduced overall survival (OS) duration of head and neck squamous cell carcinoma (HNSC), kidney renal clear cell carcinoma (KIRC), liver hepatocellular carcinoma (LIHC), Lung adenocarcinoma (LUAD), stomach adenocarcinoma (STAD), and Uterine corpus endometrial carcinoma (UCEC). This implies that CTHRC1 plays a significant role in the development and progression of these cancers. We further noticed that CTHRC1 was also overexpressed in HNSC, KIRC, LIHC, LUAD, STAD, and UCEC patients of different clinicopathological features. Pathways enrichment analysis revealed the involvement of CTHRC1 associated genes in seven diverse pathways. We also explored few interesting correlations between CTHRC1 expression and promoter methylation, genetic alterations, CNVs, CD8+ T immune cells infiltration, and tumor purity. In conclusion, CTHRC1 can serve as a shared diagnostic and prognostic biomarker in HNSC, KIRC, LIHC, LUAD, STAD, and UCEC patients of different clinicopathological features.

Multi-Omics Analysis Identified TMED2 as a Shared Potential Biomarker in Six Subtypes of Human Cancer.

INTRODUCTION: Cancer is one of the most common malignancies and the leading cause of death worldwide. As a member of the transmembrane emp24 domain (Tmed)/p24 family of proteins, TMED2 expression variations have been documented earlier in only a few subtypes of human cancers, and the multi-omics profiling of TMED2 as a shared biomarker in different other subtypes of human cancers remains to be uncovered. METHODS: In the current study, TMED2 multi-omics analysis in 24 major subtypes of human cancer was performed using different authentic online databases and bioinformatics analysis including UALCAN, Kaplan-Meier (KM) plotter, Human Protein Atlas (HPA), GENT2, MEXPRESS, cBioportal, STRING, DAVID, TIMER, and CTD. RESULTS: In general, the TMED2 expression in 24 major subtypes of human cancers was higher relative to normal controls and was also strongly associated with the lower overall survival (OS) and relapse-free survival (RFS) duration of CESC, ESCA, HNSC, KIRC, LIHC, and LUAD patients. This implies that TMED2 plays a significant role in the development and progression of these cancers. Furthermore, the TMED2 overexpression was also correlated with different clinicopathological features of CESC, ESCA, HNSC, KIRC, LIHC, and LUAD patients. TMED2-associated genes network was involved in 3 diverse pathways, and finally, few stronger correlations were also explored between TMED2 expression and its promoter methylation level, genetic alterations, and CD8+ T immune cells level. CONCLUSION: In conclusion, via this in silico study, we have elucidated that TMED2 can serve as a shared diagnostic and prognostic biomarker in CESC, ESCA, HNSC, KIRC, LIHC, and LUAD patients of different clinicopathological features but, further in vitro and in vivo research should be carried out to confirm these findings.

Does human papillomavirus cause human colorectal cancer? Applying Bradford Hill criteria postulates.

The role of human papillomavirus (HPV) in human colorectal cancer (CRC) has already been widely investigated worldwide with conflicting results. Although researchers have tried to establish the link between HPV and CRC through a statistical meta-analysis of the previous studies associating HPV with CRC, they failed to establish a more reliable link due to the shortcomings of the statistical meta-analysis. In the present study, we identified population-wide studies relating HPV with CRC through the PubMed search engine. Then, we examined the available data of HPV prevalence in CRC and normal/benign samples and applied the postulates of Bradford Hill criteria on the available evidence to investigate the association between HPV and CRC. The Bradford Hill criteria are very old, reliable and widely accepted for establishing a link between the cause and disease. In addition, to further enhance the reliability of the outcomes, we have also evaluated the methodologies of the previous studies to address the possibility of false-negative and false-positive results. After a careful evaluation of the extracted data against the postulates of Bradford Hill criteria, it was observed that none of the studies fulfil all the major postulates of Bradford Hill criteria for causation including temporality, consistency, biological gradient, experiment, coherence, specificity and analogy. Hence, no causal relationship has been suggested between HPV and CRC patients of the any included population. The results failed to prove the causal relationship between HPV and CRC and suggested HPV as a coparticipant in the pathogenesis of CRC.

Risk Factors and Epidemiology of Gastric Cancer in Pakistan.

Gastric cancer is the 2nd most common cause of death among all cancers and is the 4th most common cancer in the world. The number of deaths due to gastric cancer is about 800,000 annually. Gastric cancer is more common in men as compared to women and is 3rd most common cancer after colorectal and breast cancers in women. A progressive rise in the incidence rate has been observed in females over the last 5 years. The highest incidence of stomach cancer is in China, South America and Eastern Europe. The incidence of gastric cancer has 20 fold variation worldwide. Global variation is linked by two factors which play important role in developing gastric cancer. One is infection with Helicobacter pylori and the 2nd is diet. South Asia is a region with low risk, despite a high prevalence of H.pylori. Gastric carcinoma is common in southern region of India. Gastric cancer is more readily treated if diagnosed early. This study aims to provide awareness about gastric cancer as well as an updated knowledge about risk factors and epidemiology of gastric cancer in Pakistan.