Evolutionary genetic algorithm identifies IL2RB as a potential predictive biomarker for immune-checkpoint therapy in colorectal cancer.
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ABSTRACT:
SUBMITTER: Alderdice M
PROVIDER: S-EPMC8057496 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Somatostatin receptor 2 (SSTR2), the most abundant receptor of somatostatin (SST), possesses immunoreactivity and is altered in many cancers. However, the association between SSTR2 and efficacy of immune checkpoint inhibitors (ICIs) has not yet been reported. Immunohistochemistry (IHC) information across 20 cancers was collected from the Human Protein Atlas (HPA) and used to analyze the expression of SSTR2. Immune signatures collected from public databases, such as BioCarta or Reactome, were used to investigate the association between SSTR2 and the tumor microenviroment in the Cancer Genome Atlas (TCGA). Data from cohorts treated with ICIs were collected to assess whether SSTR2 is associated with benefits from ICIs treatment. In the HPA, we found the SSTR2 IHC-positive rate of 13 cancers to be above 50%. Five types of cancer express SSTR2 mildly (positive rate: 25%-50%), while the remaining two types of cancer barely stained SSTR2-positive (positive rate: 0%-24%). In TCGA analysis, immune cell signatures and immune function pathways were enriched in high SSTR2 expression groups in most cancers. In each ICIs treated cohort, patients with high SSTR2 expression experienced numerically superior objective response rate (Braun: 14.8% vs 13.4%, p = 0.85; Gide: 69.4% vs 40.5%, p = 0.025; Mariathasan: 22.4% vs 16.7%, p = 0.233; Miao: 37.5% vs 11.8%; Riaz: 32.0% vs 7.7%, p = 0.067) and overall survival (Braun: HR (95%CI): 0.80 [0.62-1.04], p = 0.80; Gide: HR (95%CI): 0.61 [0.29-1.30], p = 0.20; Mariathasan: HR (95%CI): 0.83 [0.64-1.08], p = 0.16; Miao: HR (95%CI): 0.24 [0.086-0.65], p = 0.0028; Nathanson cohort: HR (95%CI): 0 [0-inf], p = 0.18; Riaz: HR (95%CI): 0.24 [0.086-0.65], p = 0.028) than patients with low SSTR2 expression. In pooled cohort, we found these differences were significant (Pool: 24.6% vs 16.7%, p = 0.0077; HR (95% CI): 0.77 [0.65-0.91], p = 0.0018). Our results suggest that SSTR2 is a potential predictive biomarker for response to ICIs.
| S-EPMC8898825 | biostudies-literature
Project description:Background: Nuclear factor interleukin 3 (NFIL3) mainly focuses on the regulation of the circadian rhythm and immune system. However, the potential role of NFIL3 in human cancers has not been studied extensively. Methods: We retrieved original data from the TCGA, TARGET, and GTEx datasets via the UCSC Xena browser (http://genome.ucsc.edu/) and integrated them using R version 3.6.4. NFIL3 expression was assessed using resources such as UCSC, GEPIA (http://gepia.cancer-pku.cn/), Kaplan-Meier Plotter (KM Plotter; https://kmplot.com/), and the Human Protein Atlas (HPA; https://www.proteinatlas.org/) databases. To investigate the prognostic implications of NFIL3, we utilized GEPIA, Kaplan-Meier Plotter, and PrognoScan (http://www.abren.net/PrognoScan/) datasets. For a comprehensive analysis across multiple cancer types, we employed pan-cancer data from UCSC, examining associations between NFIL3 expression and genomic heterogeneity, tumor mutational burden (TMB), microsatellite instability (MSI), tumor purity, and neoantigens. Furthermore, we explored the relationships between NFIL3 expression and the infiltration of immune cells and the expression of immune checkpoint genes. In the context of ovarian cancer, we validated the expression and functional relevance of NFIL3. Cell Counting Kit 8 (CCK8) assays were conducted to assess cell proliferation, while scratch and transwell assays were employed to evaluate cell migration capabilities. We further examined the interaction between NFIL3 and the p53 signaling pathway through quantitative real-time polymerase chain reaction (qRT-PCR), Western blot analysis, immunofluorescence confocal, and Coimmunoprecipitation (Co-IP) assays. Results: In general, NFIL3 expression in cancerous tissues exhibited diminished levels when compared to normal tissue samples. Notably, NFIL3 expression demonstrated a robust correlation with several pivotal aspects, including prognosis, immune cell infiltration, immune checkpoint-related genes, TMB, MSI, tumor purity, and the presence of neoantigens. Experimental investigations involving scratch assays, transwell assays, and assessments of cell proliferation in ovarian cancer cells have provided indications that NFIL3 may exert influence over cell migration and proliferation processes. Moreover, a substantial association between NFIL3 and the p53 signaling pathway was discerned through Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis, with subsequent validation through qRT-PCR, Western blot analysis, immunofluorescence confocal, and co-immunoprecipitation (Co-IP) assays. Conclusions: Therefore, we concluded NFIL3 may serve as a possible prognostic and immunological pan-cancer biomarker.
| S-EPMC10861811 | biostudies-literature
Project description:Immune checkpoint inhibitors (ICIs) therapy elicits admirable anti-tumor responses across many types of cancer. Growing evidence point to a link to Mediator complex subunit 12 (MED12) and DNA damage repair (DDR) and TGF-β signing, while the clinical data on the association of MED12 and ICIs response are lacking. In this study, clinical and whole-exome sequencing (WES) data from published studies were merged as a WES cohort to explore the association between MED12 mutation (MED12-Mut) and ICIs efficiency across cancers. Then, Memorial Sloan Kettering Cancer Center (MSKCC) cohort was used for validating our findings. The Cancer Genome Atlas (TCGA) cohort was used to perform anti-tumor immunity and prognosis analysis. In the WES cohort (n = 474), significant differences were detected between MED12-Mut and MED12-wildtype (MED12-Wt) patients regarding durable clinical benefit (DCB, 80.00% vs. 53.67%, P = 0.022). In addition, significantly prolonged PFS was observed in MED12-Mut patients (mPFS: not reached, NR vs. 5.87 months, HR: 0.38, 95% CI 0.17-0.85, log-rank P = 0.015), After taking into account age, gender, metastasis, treatment and TMB status, the result of multivariable Cox proportional hazards regression showed significantly better PFS (HR:0.40, 95% CI 0.18-0.92; P = 0.031). In the MSKCC cohort (n = 1513), overall survival advantage was achieved in MED12-Mut patients (mOS: 41 vs. 19 months, HR:0.54, 95%CI 0.34-0.85; log-rank P = 0.007), after taking into account same factors in WES cohort, this link still existed (HR: 0.60, 95% CI: 0.38-0.96, P = 0.033), Notably, TMB was also found significantly higher in MED12-Mut patients in both WES and MSKCC cohort. Further tumor-infiltrating lymphocytes and DDR-related gene analysis revealed anti-tumor immunity in MED12-Mut patients. Totally, MED12-Mut successfully predicted better clinical outcomes in ICIs-treated pan-cancer cohort, indicating that MED12-Mut could serve as a potential predictive biomarker for immune checkpoint inhibitors in pan-cancer.
| S-EPMC9618186 | biostudies-literature
Project description:Objective: 5-fluorouracil- and oxaliplatin-based FOLFOX regimens are mainstay chemotherapeutics for colorectal cancer (CRC) but drug resistance represents a major therapeutic challenge. To improve patient survival, there is a need to identify resistance genes to better understand the mechanisms underlying chemotherapy resistance. Methods: Transcriptomic datasets were retrieved from the Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases and combined with our own microarray data. Weighted gene co-expression network analysis (WGCNA) was used to dissect the functional networks and hub genes associated with FOLFOX resistance and cancer recurrence. We then conducted analysis of prognosis, profiling of tumor infiltrating immune cells, and pathway overrepresentation analysis to comprehensively elucidate the biological impact of the identified hub gene in CRC. Results: WGCNA analysis identified the complement component 3 (C3) gene as the only hub gene associated with both FOLFOX chemotherapy resistance and CRC recurrence after FOLFOX chemotherapy. Subsequent survival analysis confirmed that high C3 expression confers poor progression-free survival, disease-free survival, and recurrence-free survival. Further correlational analysis revealed significant negative association of C3 expression with sensitivity to oxaliplatin, but not 5-fluorouracil. Moreover, in silico analysis of tumor immune cell infiltration suggested the change of C3 expression could affect tumor microenvironment. Finally, gene set enrichment analysis (GSEA) revealed a hyperactivation of pathways contributing to invasion, metastasis, lymph node spread, and oxaliplatin resistance in CRC samples with C3 overexpression. Conclusion: Our results suggest that high C3 expression is a debilitating factor for FOLFOX chemotherapy, especially for oxaliplatin sensitivity, and C3 may represent a novel biomarker for treatment decision of CRC.
| S-EPMC8554154 | biostudies-literature
Project description:BackgroundA critical and challenging process in immunotherapy is to identify cancer patients who could benefit from immune checkpoint inhibitors (ICIs). Exploration of predictive biomarkers could help to maximize the clinical benefits. Eph receptors have been shown to play essential roles in tumor immunity. However, the association between EPH gene mutation and ICI response is lacking.MethodsClinical data and whole-exome sequencing (WES) data from published studies were collected and consolidated as a discovery cohort to analyze the association between EPH gene mutation and efficacy of ICI therapy. Another independent cohort from Memorial Sloan Kettering Cancer Center (MSKCC) was adopted to validate our findings. The Cancer Genome Atlas (TCGA) cohort was used to perform anti-tumor immunity and pathway enrichment analysis.ResultsAmong fourteen EPH genes, EPHA7-mutant (EPHA7-MUT) was enriched in patients responding to ICI therapy (FDR adjusted P < 0.05). In the discovery cohort (n = 386), significant differences were detected between EPHA7-MUT and EPHA7-wildtype (EPHA7-WT) patients regarding objective response rate (ORR, 52.6% vs 29.1%, FDR adjusted P = 0.0357) and durable clinical benefit (DCB, 70.3% vs 42.7%, FDR adjusted P = 0.0200). In the validation cohort (n = 1144), significant overall survival advantage was observed in EPHA7-MUT patients (HR = 0.62 [95% confidence interval, 0.39 to 0.97], multivariable adjusted P = 0.0367), which was independent of tumor mutational burden (TMB) and copy number alteration (CNA). Notably, EPHA7-MUT patients without ICI therapy had significantly worse overall survival in TCGA cohort (HR = 1.33 [95% confidence interval, 1.06 to 1.67], multivariable adjusted P = 0.0139). Further gene set enrichment analysis revealed enhanced anti-tumor immunity in EPHA7-MUT tumor.ConclusionsEPHA7-MUT successfully predicted better clinical outcomes in ICI-treated patients across multiple cancer types, indicating that EPHA7-MUT could serve as a potential predictive biomarker for immune checkpoint inhibitors.
| S-EPMC7852135 | biostudies-literature
Project description:BackgroundThe ten-eleven translocation 1 (TET1), which is essential for active DNA demethylation, plays a multifaceted role in the pathogenesis of colorectal cancer. The study has demonstrated the association of TET1 mutations with a high response to immune checkpoint inhibitors (ICIs) in diverse cancers. However, the relationship between TET1 mutations and the response to ICIs in colon cancer is still lacking.MethodsThe prognosis, predictive markers, immune characteristics, mutation number of DNA damage repair (DDR) pathways, pathway enrichment, and drug sensitivity conditions were all compared between TET1-mutated and wild-type patients with colon adenocarcinoma (COAD).ResultsThe overall survival of patients with TET1 mutations in the ICI-treated cohort was significantly longer than those without (p = 0.0059). Compared with the wild-type patients, TET1-mutated patients had higher tumor mutational burden and neoantigen load, enhanced abundance of tumor-infiltrating immune cells, increased expression of immune-related genes, and mutation number of DDR pathways. Additionally, the patients with TET1 mutations were found to be more sensitive to lapatinib and 5-fluorouracil.ConclusionThese findings suggest that TET1 mutations may serve as a potential biomarker for the response to ICIs in COAD patients.
| S-EPMC8991851 | biostudies-literature
Project description:Colorectal cancer is one of the most common malignant tumors and, hence, has become one of the most important public health issues in the world. Treatment with immune checkpoint inhibitors (ICIs) successfully improves the survival rate of patients with melanoma, non-small-cell lung cancer, and other malignancies, and its application in metastatic colorectal cancer is being actively explored. However, a few patients develop drug resistance. Predictive molecular markers are important tools to precisely screen patient groups that can benefit from treatment with ICIs. The current article focused on certain important predictive molecular markers for ICI treatment in colorectal cancer, including not only some of the mature molecular markers, such as deficient mismatch repair (d-MMR), microsatellite instability-high (MSI-H), tumor mutational burden (TMB), programmed death-ligand-1 (PD-L1), tumor immune microenvironment (TiME), and tumor-infiltrating lymphocytes (TILs), but also some of the novel molecular markers, such as DNA polymerase epsilon (POLE), polymerase delta 1 (POLD1), circulating tumor DNA (ctDNA), and consensus molecular subtypes (CMS). We have reviewed these markers in-depth and presented the results from certain important studies, which suggest their applicability in CRC and indicate their advantages and disadvantages. We hope this article is helpful for clinicians and researchers to systematically understand these markers and can guide the treatment of colorectal cancer.
| S-EPMC8761449 | biostudies-literature
Project description:With the advent of targeted therapies, there has been a revolution in the treatment of cancer across multiple histologies. Immune checkpoint blockade has made it possible to take advantage of receptor-ligand interactions between immune and tumor cells in a wide spectrum of malignancies. Toxicity in healthy tissue, however, can limit our use of these agents. Immune checkpoint blockade has been approved in advanced melanoma, renal cell cancer, non-small cell lung cancer, relapsed refractory Hodgkin's lymphoma, and urothelial cancer. Though FDA-approved indications for use of some of these novel agents depend on current protein-based programmed death 1 (PD-1) and programmed death ligand 1 (PD-L1) assays, detection methods come with several caveats. Additional predictive tools must be interrogated to discern responders from non-responders. Some of these include measurement of microsatellite instability, PD-L1 amplification, cluster of differentiation 8 (CD8) infiltrate density, and tumor mutational burden. This review serves to synthesize biomarker detection at the DNA, RNA, and protein level to more accurately forecast benefit from these novel agents.
| S-EPMC5385298 | biostudies-other
Project description:BackgroundImmune checkpoint inhibitor (ICI) therapy is highly effective in metastatic mismatch repair-deficient (MMR-D) colorectal cancer (CRC). In this study, we evaluated molecular and clinical predictors of ICI response in MMR-D CRC.Materials and methodsPatient databases at four cancer institutions were queried. The Fisher exact test was performed to test the association of clinical and molecular markers. The Kaplan-Meier method was used to estimate progression-free survival (PFS) and compared by the log-rank test. Twelve- and 24-month PFS rates were compared by the Z test.ResultsA total of 60 patients with CRC with MMR-D/microsatellite instability-high who previously received ICIs were identified. Patients with liver metastasis had a lower overall response rate as compared with other sites of metastasis (36.4% vs. 68.7%; p = .081). Patients with MLH1/PMS2 loss had worse 1-year and 2-year PFS rates compared with patients with MSH2/MSH6 loss (84.2% vs. 57.8% and 78.2% vs. 54.2%, respectively; p < .001). There were improved 1-year and 2-year PFS rates in patients with wild-type BRAF when compared with patients with BRAF V600E mutation (73.3% vs. 40%, and 73.3% vs. 26.7%; respectively; p < .001). Patients aged >65 had significantly worse PFS rates as compared with patients aged ≤65 (p < .001).ConclusionBRAF V600E mutation, MLH1 and/or PMS2 loss, as well as age >65 years and liver metastasis, may be predictive of duration of ICI response in patients with MMR-D CRC. Larger cohorts are needed to confirm our findings.Implications for practiceThe results of this study reveal clinically important biomarkers that potentially predict immune checkpoint inhibitor response in patients with mismatch repair-deficient colorectal cancer.
| S-EPMC8342606 | biostudies-literature
Project description:The application of immune checkpoint inhibitors (ICIs) in non-small cell lung cancer has significantly improved patient survival. However, most patients fail to respond to ICIs or develop drug resistance during treatment. Therefore, novel biomarkers are needed to predict the efficacy of ICIs or provide clues on how to overcome drug resistance. Here, it was revealed that cell division cycle 25C (CDC25C) expression was upregulated in lung adenocarcinoma (LUAD) compared to that of normal lung tissue in multiple databases. This was further verified by q-PCR. Furthermore, higher CDC25C expression was associated with shorter overall survival and worse pathological stage. Most importantly, a higher CDC25C expression was associated with shorter progression-free survival in LUAD patients treated with nivolumab, suggesting the role of the cell cycle in immunotherapy. In addition, CDC25C expression was significantly associated with immune cell infiltration and immune-related signatures in the LUAD tumor microenvironment. Moreover, CDC25C was differentially expressed and correlated with overall survival in multiple tumors, indicating that CDC25C is a broad-spectrum biomarker. Taken together, our study demonstrates that CDC25C is a prognostic biomarker for LUAD patients, especially for patients treated with ICIs. Our study also provides strong evidence for the role of the cell cycle in ICIs therapy and tumor microenvironment.
| S-EPMC9104567 | biostudies-literature