Adenylate cyclase activates the cAMP signalling pathway to enhance platelet-rich plasma-treated Achilles tendon disease, a theoretical bioinformatics-based study.

The effectiveness of platelet-rich plasma (PRP) for the treatment of Achilles tendon disorders still needs to be evaluated through a series of prospective studies, but genomic analysis can reveal the existence of complementary PRP treatment options. Based on the 96 platelet activation-related genes in the Kyoto Encyclopedia of Genes and Genomes (KEGG) database, we performed Gene Ontology functional enrichment analysis and KEGG enrichment analysis, pathway correlation analysis, and enrichment mapping to determine the enrichment results of the gene set enrichment analysis and found that the cAMP signalling pathway may be the key to enhancing the effectiveness of PRP treatment. The cAMP signalling pathway interacts with the Rap1 signalling pathway and cGMP-PKG signalling pathway to mediate the entire pathophysiological process of Achilles tendon disease. Moreover, ADCY1-9 may be the key to the activation of the cAMP signalling network. Further based on the data in the Gene Expression Omnibus database, it was found that ADCY4 and ADCY7 may be the players that play a major role, associated with the STAT4-ADCY4-LAMA5 axis and the GRbeta-ADCY7-SEMA3C axis, which is expected to be a complementary target for enhancing the efficacy of PRP in the treatment of Achilles tendon disease.

Tumor mutation load better predicts the prognosis of patients treated with immune checkpoint inhibitors in upper gastrointestinal cancers: A systematic review and meta-analysis.

BACKGROUND: Tumor mutational load (TML) has emerged as a potential biomarker for multiple solid tumors. However, data on its prognostic impact on upper gastrointestinal (UGI) cancer are limited. Therefore, the aim of this systematic review and meta-analysis was to assess the prognostic value of TML for the survival of patients with UGI cancer. METHOD: A comprehensive search of the PubMed, Embase, Cochrane Library, and Web of Science databases was conducted up to February 13, 2023. Eleven studies met our inclusion criteria. Hazard ratios (HRs) for progression-free survival and overall survival and their 95% confidence intervals (CIs) were calculated. Subsequently, the combined HR and its 95% CI were calculated for UGI tract cancers in the high and low TML groups. I2 statistics and p-values were used to evaluate heterogeneity. Publication bias, sensitivity, and subgroup analyses were performed to determine sources of heterogeneity. RESULTS: In total, 932 patients with UGI tract cancer from 11 publications were included. The high TML group treated with immunotherapy showed significantly improved overall survival (HR = 0.68; 95% CI: 0.53, 0.86; p = .001) and progression-free survival (HR = 0.74; 95% CI: 0.58, 0.95; p = .020) compared with the low TML group. CONCLUSION: Our study demonstrated that patients with UGI tumors and higher TML have a better prognosis with immunotherapy, suggesting that TML is a promising predictive biomarker for immunotherapy. REGISTRATION: The study protocol was registered with the International Prospective Register of Systematic Reviews (PROSPERO Registration No: CRD42023405596).

Pan-cancer analysis of the tumorigenic role of Fanconi anemia complementation group D2 (FANCD2) in human tumors.

Monoubiquitination of FANCD2 is a central step in the activation of the Fanconi anemia (FA) pathway after DNA damage. Defects in the FA pathway centered around FANCD2 not only lead to genomic instability but also induce tumorigenesis. At present, few studies have investigated FANCD2 in tumors, and no pan-cancer research on FANCD2 has been conducted. We conducted a comprehensive analysis of the role of FANCD2 in cancer using public databases and other published studies. Moreover, we evaluated the role of FANCD2 in the proliferation, migration and invasion of lung adenocarcinoma cells through in vitro and in vivo experiments, and explored the role of FANCD2 in cisplatin chemoresistance. We investigated the regulatory effect of FANCD2 on the cell cycle of lung adenocarcinoma cells by flow cytometry, and verified this effect by western blotting. FANCD2 expression is elevated in most TCGA tumors and shows a strong positive correlation with poor prognosis in tumor patients. In addition, FANCD2 expression shows strong correlations with immune infiltration, immune checkpoints, the tumor mutation burden (TMB), and microsatellite instability (MSI), which are immune-related features, suggesting that it may be a potential target of tumor immunotherapy. We further found that FANCD2 significantly promotes the proliferation, invasion, and migration abilities of lung adenocarcinoma cells and that its ability to promote cancer cell proliferation may be achieved by modulating the cell cycle. The findings indicate that FANCD2 is a potential biomarker and therapeutic target in cancer treatment by analyzing the oncogenic role of FANCD2 in different tumors.

The role of organoids in cancer research.

Organoids are established through in vitro 3D culture, and they can mimic the structure and physiological functions of organs or tissues in vivo. Organoids have attracted much attention in recent years. They can provide a reliable technology platform for cancer research and treatment and are a valuable preclinical model for academic research and personalized medicine. A number of studies have confirmed that organoids have great application prospects in new drug development, drug screening, tumour mechanism research, and precision medicine. In this review, we mainly focus on recent advances in the application of organoids in cancer research. We also discussed the opportunities and challenges facing organoids, hoping to indicate directions for the development of organoids in the future.

Suppression of tumorigenesis in LUAD by LRP1B through regulation of the IL-6-JAK-STAT3 pathway.

Lung adenocarcinoma (LUAD) is the most common type of lung cancer. LRP1B was initially identified as a cancer suppressor in several cancers. However, the potential biological phenotypes and molecular mechanisms of LRP1B in LUAD have not been fully investigated. In our study, we showed that the expression of LRP1B in LUAD tissues was lower than that in normal tissues. Knockdown of LRP1B markedly enhanced malignancy of LUAD cells. Genomic analysis indicated that the population expressing low-levels of LRP1B had higher genomic instability, which accounted for a larger proportion of aneuploidy and inflammation subtyping. Enrichment analysis of bulk and cell-line transcriptomic data both showed that the low expression of LRP1B could induce the activation of IL-6-JAK-STAT3, chemokine, cytokine, and other inflammation signaling pathways. Moreover, our findings revealed that knockdown LRP1B enhanced the secretion of IL-6 and IL-8, as confirmed by ELISA assays. Further validation using PCR and WB confirmed that downregulation of LRP1B mRNA significantly upregulated the activity of the IL-6-JAK-STAT3 pathway. Collectively, this study highlights LRP1B as a tumor suppressor gene and reveals that LRP1B knockdown promotes malignant progression in LUAD by inducing inflammation through the IL-6-JAK-STAT3 pathway.

A narrative review of intraoperative use of indocyanine green fluorescence imaging in gastrointestinal cancer: situation and future directions.

Background and Objective: As a surgical tool, indocyanine green (ICG) is increasingly used in surgery, especially in gastric and colorectal surgery. The use of ICG fluorescence imaging can improve the accuracy of tumor resection and potentially improve surgical outcomes for cancer patients. However, there are still different opinions or controversies on the application of ICG in the literature and the administration of ICG is still not uniform. In this review, we summarize the current status of its application and ICG administration methods in gastrointestinal cancer and discuss its existing limitations and future research directions. Methods: Literature published in the PubMed database from 1969 to 2022 was searched for using the keywords "Indocyanine green or near-infrared imaging or ICG", "gastric cancer", "gastroesophageal junction cancer", and "colorectal cancer" to summarize the main applications of ICG in gastrointestinal cancers. Key Content and Findings: ICG guidance can rapidly determine tumor location and save operative time, and can also visualize lymph nodes (LNs) in real-time, helping surgeons to retrieve more LNs for better postoperative staging, but its use in identifying sentinel lymph node (SLN) in gastric cancer (GC) remains controversial due to false negatives. ICG fluorescent angiography has great potential in preventing colorectal anastomotic leakage, but there is a dearth of high-caliber research evidence. In addition, ICG has unique advantages in detecting colorectal liver micrometastasis. Notably, there is still no uniform administration method and dose of ICG. Conclusions: In this review, we summarize the current status of ICG application in gastrointestinal cancer, and the current literature suggests that it is safe and effective and has the potential to change the clinical outcome of patients. Therefore, ICG should be routinely used in gastrointestinal cancers to improve the surgical outcomes of patients. In addition, this review summarizes the ICG administration in the literature, and we expect future guidelines to unitize and standardize the administration of ICG.

ITGB1-mediated molecular landscape and cuproptosis phenotype induced the worse prognosis in diffuse gastric cancer.

Diffuse type gastric cancer was identified with relatively worse prognosis than other Lauren's histological classification. Integrin ß1 (ITGB1) was a member of integrin family which played a markedly important role in tumorigenesis and progression. However, the influence of ITGB1 in diffuse gastric cancer (DGC) remains uncertain. Here, we leveraged the transcriptomic and proteomic data to explore the association between ITGB1 expression and clinicopathologic information and biological process in DGC. Cell phenotype experiments combined with quantitative-PCR (q-PCR) and western blotting were utilized to identify the potential molecular mechanism underling ITGB1.Transcriptomics and proteomics both revealed that the higher ITGB1 expression was significantly associated with worse prognosis in DGC, but not in intestinal GC. Genomic analysis indicated that the mutation frequency of significantly mutated genes of ARID1A and COL11A1, and mutational signatures of SBS6 and SBS15 were markedly increased in the ITGB1 low expression subgroup. The enrichment analysis revealed diverse pathways related to dysregulation of ITGB1 in DGC, especially in cell adhesion, proliferation, metabolism reprogramming, and immune regulation alterations. Elevated activities of kinase-ROCK1, PKACA/PRKACA and AKT1 were observed in the ITGB1 high-expression subgroup. The ssGSEA analysis also found that ITGB1 low-expression had a higher cuproptosis score and was negatively correlated with key regulators of cuproptosis, including FDX1, DLAT, and DLST. We further observed that the upregulated expression of mitochondrial tricarboxylic acid (TCA) cycle in the ITGB1 low-expression group. Reduced expression of ITGB1 inhibited the ability of cell proliferation and motility and also potentiated the cell sensitive to copper ionophores via western blotting assay. Overall, this study revealed that ITGB1 was a protumorigenic gene and regulated tumor metabolism and cuproptosis in DGC.

CT-based radiomics nomogram for differentiating gastric hepatoid adenocarcinoma from gastric adenocarcinoma: a multicentre study.

BACKGROUND: To develop a CT-based radiomics nomogram for the high-precision preoperative differentiation of gastric hepatoid adenocarcinoma (GHAC) patients from gastric adenocarcinoma (GAC) patients. RESEARCH DESIGN AND METHODS: 108 patients with GHAC from 6 centers and 108 GAC patients matched by age, sex and T stage undergoing pathological examination were retrospectively reviewed. Patients from 5 centers were divided into two cohorts (training and internal validation) at a 7:3 ratio, the remaining patients were external test cohort. Venous-phase CT images were retrieved for tumor segmentation and feature extraction. A radiomics model was developed by the least absolute shrinkage and selection operator method. The nomogram was developed by clinical factors and the radiomics score. RESULTS: 1409 features were extracted and a radiomics model consisting of 19 features was developed, which showed a favorable performance in discriminating GHAC from GAC (AUCtraining cohort = 0.998, AUCinternal validation set = 0.942, AUCexternal test cohort = 0.731). The radiomics nomogram, including the radiomics score, AFP, and CA72_4, achieved good calibration and discrimination (AUCtraining cohort = 0.998, AUCinternal validation set = 0.954, AUCexternal test cohort = 0.909). CONCLUSIONS: The noninvasive CT-based nomogram, including radiomics score, AFP, and CA72_4, showed favorable predictive efficacy for differentiating GHAC from GAC and might be useful for clinical decision-making.

Machine learning-based identification of a novel prognosis-related long noncoding RNA signature for gastric cancer.

Gastric cancer (GC) is one of the most common malignancies with a poor prognosis. Immunotherapy has attracted much attention as a treatment for a wide range of cancers, including GC. However, not all patients respond to immunotherapy. New models are urgently needed to accurately predict the prognosis and the efficacy of immunotherapy in patients with GC. Long noncoding RNAs (lncRNAs) play crucial roles in the occurrence and progression of cancers. Recent studies have identified a variety of prognosis-related lncRNA signatures in multiple cancers. However, these studies have some limitations. In the present study, we developed an integrative analysis to screen risk prediction models using various feature selection methods, such as univariate and multivariate Cox regression, least absolute shrinkage and selection operator (LASSO), stepwise selection techniques, subset selection, and a combination of the aforementioned methods. We constructed a 9-lncRNA signature for predicting the prognosis of GC patients in The Cancer Genome Atlas (TCGA) cohort using a machine learning algorithm. After obtaining a risk model from the training cohort, we further validated the model for predicting the prognosis in the test cohort, the entire dataset and two external GEO datasets. Then we explored the roles of the risk model in predicting immune cell infiltration, immunotherapeutic responses and genomic mutations. The results revealed that this risk model held promise for predicting the prognostic outcomes and immunotherapeutic responses of GC patients. Our findings provide ideas for integrating multiple screening methods for risk modeling through machine learning algorithms.

A novel 3'tRNA-derived fragment tRF-Val promotes proliferation and inhibits apoptosis by targeting EEF1A1 in gastric cancer.

At present, it is commonly believed that tRFs and tiRNAs are formed by the specific and selective shear of tRNAs under certain pressure stimulation, rather than by random degradation of tRNA. tRFs and tiRNAs have been reported to contribute to the biological process of a variety of human cancers. However, the evidence for the mechanisms of tRFs and tiRNAs in the occurrence and development of gastric cancer (GC) is still insufficient. Here, we aimed to explore the carcinogenic roles of tRFs and tiRNAs in GC with RNA-sequencing technique, and found a novel 3'tRNA-derived fragment tRF-Val was significantly upregulated in GC tissues and cell lines. tRF-Val expression was positively correlated with tumor size and the depth of tumor invasion in GC tissues. Functionally, tRF-Val promoted proliferation and invasion, and inhibited apoptosis in GC cells. Mechanistically, tRF-Val directly bound to the chaperone molecule EEF1A1, mediated its transport into the nucleus and promoted its interaction with MDM2 (a specific p53 E3 ubiquitin ligase), thus inhibiting the downstream molecular pathway of p53 and promoting GC progression. These findings provided a new potential therapeutic target for GC and a new explanation for the occurrence of GC.

Deciphering the tumor microenvironment cell-infiltrating landscape reveals microenvironment subtypes and therapeutic potentials for nonsquamous NSCLC.

Recent studies highlighted the clinicopathologic importance of the tumor microenvironment (TME) in delineating molecular attributes and therapeutic potentials. However, the overall TME cell infiltration landscape in nonsquamous non-small cell lung cancer (NSCLC) has not been comprehensively characterized. In this study, we used consensus non-negative matrix factorization molecular subtyping to determine TME cell infiltration patterns and identified 3 TME clusters (TME-C1, -C2, -C3) characterized by distinct clinicopathologic features, infiltrating cells, and biological processes. Proteomics analyses revealed that cyclic GMP-AMP-stimulator of interferon genes immune signaling-mediated protein and phosphorylation levels were significantly upregulated in inflammation-related TME-C2 clusters. The score extracted from the TME-related signature (TMEsig-score) divided patients with NSCLC into high- and low-score subgroups, where a high score was associated with favorable prognosis and immune infiltration. The genomic landscape revealed that patients with low TMEsig-score harbored more somatic copy number alterations and higher mutation frequency of driver genes involving STK11, KEAP1, SMARCA4, and others. Drug sensitivity analyses suggested that tumors with high TMEsig-score were responsible for favorable clinical response to immune checkpoint inhibitor treatment. In summary, this study highlights that comprehensive recognizing of the TME cell infiltration landscape will contribute to enhancing our understanding of TME immune regulation and promote effectiveness of precision biotherapy strategies.

Naples prognostic score, a novel prognostic score for patients with high- and intermediate-risk gastrointestinal stromal tumours after surgical resection.

BACKGROUND: A novel multidimensional inflammatory and nutritional assessment system named the Naples prognostic score could serve as an independent prognostic indicator. However, its significance in patients with high- and intermediate-risk gastrointestinal stromal tumours remains unclear. METHODS: We performed this retrospective cohort study based on a prospectively collected database of gastrointestinal stromal tumours (GISTs) between March 2010 and December 2019. The Kaplan-Meier method and log-rank test were used for survival analyses. Least absolute shrinkage and selection operator (LASSO) and Cox proportional hazards regression analysis was used for univariate and multivariate analyses. Time-dependent receiver operating characteristic curves were generated to evaluate the discriminatory ability of the prognostic scoring systems. Differences in the areas under the curve were further compared. RESULTS: A total of 405 patients with regular follow-up were included and analysed in this study. Significant differences in progression-free survival and overall survival were observed between the groups (P < 0.001). Multivariate analysis demonstrated that the NPS was a significant predictor of poor progression-free survival (1 vs 0, HR = 4.622, P = 0.001; 2 vs 0, HR = 12.770, P < 0.001) and overall survival (2 vs 0, HR = 5.535, P = 0.002). Furthermore, time-dependent AUC analyses showed that the NPS was more accurate than other haematologic prognostic systems. CONCLUSIONS: The present study demonstrates that the NPS could independently predict disease progression and survival among patients with high- and intermediate-risk GISTs. The NPS might be regarded and applied as one of the most convenient and effective preoperative risk stratification tools in the future, which should be validated by large-scale multicentre prospective cohort studies.

CCDC12 promotes tumor development and invasion through the Snail pathway in colon adenocarcinoma.

Integrative expression Quantitative Trait Loci (eQTL) analysis found that rs8180040 was significantly associated with Coiled-coil domain containing 12 (CCDC12) in colon adenocarcinoma (COAD) patients. Immunohistochemical staining and western blotting confirmed CCDC12 was highly expressed in COAD tissues, which was consistent with RNA-Seq data from the TCGA database. Knockdown of CCDC12 could significantly reduce proliferation, migration, invasion, and tumorigenicity of colon cancer cells, while exogenous overexpression of CCDC12 had the opposite effect. Four plex Isobaric Tags for Relative and Absolute Quantitation assays were performed to determine its function and potential regulatory mechanism and demonstrated that overexpression of CCDC12 would change proteins on the adherens junction pathway. Overexpressed Snail and knocked down CCDC12 subsequently in SW480 cells, and we found that overexpression of Snail did not significantly change CCDC12 levels in SW480 cells, while knockdown of CCDC12 reduced that of Snail. CCDC12 plays a significant role in tumorigenesis, development, and invasion of COAD and may affect the epithelial to mesenchymal transformation process of colon cancer cells by regulating the Snail pathway.

Clinicopathological characteristics and longterm survival of patients with synchronous multiple primary gastrointestinal stromal tumors: A propensity score matching analysis.

BACKGROUND: Multiple gastrointestinal stromal tumors (MGISTs) are specific and rare. Little is known about the impact of MGISTs on the survival of patients with gastrointestinal stromal tumors (GIST). The diagnosis, treatment and follow-up strategies of MGISTs is not specifically described in guidelines. AIM: To compare the clinicopathological characteristics and prognosis of MGISTs and solitary GISTs (SGISTs). METHODS: Patients diagnosed with primary GISTs from March 2010 to January 2020 were included. Due to the inhomogeneous distribution of several baseline characteristics and uneven MGIST and SGIST group sizes, propensity score matching was performed according to comorbidities, body mass index, tumor location, mitotic index, sex, age and American Society of Anesthesiologists score. Differences in clinicopathological characteristics and prognosis between patients with MGISTs and patients with SGISTs were compared. RESULTS: Among the entire cohort of 983 patients, the incidence of MGISTs was 4.17%. Before matching, patients with MGISTs and those with SGISTs had disparities in body mass index, surgical approach, tumor size and mitotic index. After 1:4 ratio matching, the clinical baseline data were comparable. The 5-year progression-free survival rate was 52.17% in the MGIST group and 75.00% in the SGIST group (P = 0.031). On multivariate analysis, tumor location, tumor size, mitotic index, imatinib treatment and MGISTs (hazard ratio = 2.431, 95% confidence interval = 1.097-5.386, P = 0.029) were identified as independent prognostic factors of progression-free survival. However, overall survival was similar between the SGIST and MGIST groups. CONCLUSION: Patients with MGISTs had poorer progression-free survival than patients with SGISTs. Risk criteria and diagnostic and treatment strategies should be developed to achieve personalized precision therapy and maximize the survival benefit.

Examination of the differences between sulforaphane and sulforaphene in colon cancer: A study based on next-generation sequencing.

Sulforaphane and sulforaphene are isothiocyanate compounds derived from cruciferous vegetables that have demonstrated antiproliferative properties against colon cancer. However, the underlying mechanism of action of these two compounds has yet to be elucidated. The aim of the present study was to examine the effects of sulforaphane and sulforaphene on colon cancer using next-generation sequencing (NGS). The SW480 colon cancer cell line was cultured with 25 µmol/l sulforaphane or sulforaphene. Total RNA was extracted from the cells following 48 h of incubation with these compounds, and NGS was performed. Pearson's correlation and principal component analyses were performed on the NGS data in order to determine sample homogeneity followed by hierarchical clustering, chromosomal location, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses. A total of 873 probes in the sulforaphene group were differentially expressed compared with the control group. Similarly, 959 probes in the sulforaphane group were differentially expressed compared with the control group. The differentially expressed genes were dispersed on the chromosomes, across 22 pairs of autosomes, as well as the X and Y chromosomes. GO and KEGG analyses demonstrated that both drugs affected the 'p53 signaling pathway', 'MAPK signaling pathway', 'FOXO signaling pathway' and 'estrogen signaling pathway', while 'Wnt signaling pathway' was enriched in the sulforaphane group, and 'ubiquitin mediated proteolysis' and 'estrogen signaling pathway' in the sulforaphene group. Thus, sulforaphane and sulforaphene exhibited similar biological activities on colon cancer cells. Sulforaphane and sulforaphene may be associated with Wnt and estrogen signaling, respectively.

Prognostic Value of Lateral Pelvic Lymph Node Dissection for Rectal Cancer: A Meta-Analysis.

BACKGROUND AND AIMS: The benefit of lateral pelvic lymph node dissection (LPLD) for locally advanced rectal cancer remains controversial. This meta-analysis aimed to evaluate the prognostic value of LPLD in patients with locally advanced rectal cancer. METHODS: We performed a systematic search in PubMed, Embase, and the Cochrane Library for publications comparing radical resection plus LPLD (LPLD group) with single radical resection (non-LPLD group) for locally advanced rectal cancer. A total of 15 studies satisfied our inclusion criteria and were assessed. Random-effects and fixed-effects meta-analytical models were used where indicated, and between-study heterogeneity was assessed. RESULTS: LPLD significantly increased grade 3-4 postoperative complications (odds ratio [OR]1.44, 95% CI 1.03-2.02; P = 0.03) compared with non-LPLD. There were no significant differences in 5-y overall survival (hazard ratio = 0.90, 95% CI 0.77-1.05; P = 0.17), 5-y disease-free survival (hazard ratio 1.12, 95% CI 0.60-2.09; P = 0.73), local recurrence (OR 0.89, 95% CI 0.53-1.51; P = 0.68) or distant recurrence (OR 0.85, 95% CI 0.64-1.12; P = 0.24). CONCLUSIONS: We found that LPLD significantly increased grade 3-4 postoperative complications but did not increase 5-y overall survival or 5-y disease-free survival compared with single radical resection for locally advanced rectal cancer. Furthermore, it did not decrease the local recurrence or distant recurrence rates. Thus, more multicenter large-scale randomized controlled trials should be conducted to further explore whether the long-term survival benefits of LPLD truly exist.

The role and application of small extracellular vesicles in gastric cancer.

Gastric cancer (GC) is a common tumour that affects humans worldwide, is highly malignant and has a poor prognosis. Small extracellular vesicles (sEVs), especially exosomes, are nanoscale vesicles released by various cells that deliver bioactive molecules to recipient cells, affecting their biological characteristics, changing the tumour microenvironment and producing long-distance effects. In recent years, many studies have clarified the mechanisms by which sEVs function with regard to the initiation, progression, angiogenesis, metastasis and chemoresistance of GC. These molecules can function as mediators of cell-cell communication in the tumour microenvironment and might affect the efficacy of immunotherapy. Due to their unique physiochemical characteristics, sEVs show potential as effective antitumour vaccines as well as drug carriers. In this review, we summarize the roles of sEVs in GC and highlight the clinical application prospects in the future.

m6A regulator-based methylation modification patterns characterized by distinct tumor microenvironment immune profiles in colon cancer.

Recent studies have highlighted the biological significance of RNA N6-methyladenosine (m6A) modification in tumorigenicity and progression. However, it remains unclear whether m6A modifications also have potential roles in immune regulation and tumor microenvironment (TME) formation. Methods: In this study, we curated 23 m6A regulators and performed consensus molecular subtyping with NMF algorithm to determine m6A modification patterns and the m6A-related gene signature in colon cancer (CC). The ssGSEA and CIBERSORT algorithms were employed to quantify the relative infiltration levels of various immune cell subsets. An PCA algorithm based m6Sig scoring scheme was used to evaluate the m6A modification patterns of individual tumors with an immune response. Results: Three distinct m6A modification patterns were identified among 1307 CC samples, which were also associated with different clinical outcomes and biological pathways. The TME characterization revealed that the identified m6A patterns were highly consistent with three known immune profiles: immune-inflamed, immune-excluded, and immune-desert, respectively. Based on the m6Sig score, which was extracted from the m6A-related signature genes, CC patients can be divided into high and low score subgroups. Patients with lower m6Sig score was characterized by prolonged survival time and enhanced immune infiltration. Further analysis indicated that lower m6Sig score also correlated with greater tumor mutation loads, PD-L1 expression, and higher mutation rates in SMGs (e.g., PIK3CA and SMAD4). In addition, patients with lower m6Sig scores showed a better immune responses and durable clinical benefits in three independent immunotherapy cohorts. Conclusions: This study highlights that m6A modification is significantly associated with TME diversity and complexity. Quantitatively evaluating the m6A modification patterns of individual tumors will strengthen our understanding of TME characteristics and promote more effective immunotherapy strategies.

Association of clock-like mutational signature with immune checkpoint inhibitor outcome in patients with melanoma and NSCLC.

Immune checkpoint inhibitor (ICI) therapy has achieved remarkable clinical benefit in melanoma and non-small cell lung cancer (NSCLC). Tumor mutational signatures are the fingerprints of endogenous and exogenous factors that have acted throughout tumorigenesis and heterogeneity; however, their association with immune response in ICI-treated samples remains unclear. Here, we leveraged whole-exome sequencing (WES)-based mutational profiles combined with clinicopathologic characteristics from melanoma and NSCLC datasets to examine whether tumor genomic features contribute to clinical benefit of ICI treatment. Mutational data acquired from targeted next-generation sequencing (NGS) assays (MSK-IMPACT panels) were also employed for further corroboration. A mutational signature (known as age-related clock-like processing) characterized by enrichment of C>T mutations at NpCpG trinucleotides were identified to be associated with a worse prognosis and lower tumor mutation load (TML) in both WES and targeted NGS immunotherapy cohorts. We also analyzed gene transcriptomic profiles and identified immune regulation-related gene pathways that were significantly altered in samples with different clock-like signature grouping. Leucocyte subset analysis further revealed that clock-like signature was associated with the reduction of cytotoxic cell infiltration and elevation of regulatory T cells. Overall, our work re-annotated that the age-related clock-like signature was associated with worse prognosis and lower immune activity, offering opportunities to stratify patients into optimal immunotherapy plans based on genomic subtyping.