Identification of an m6A-Related Signature as Biomarker for Hepatocellular Carcinoma Prognosis and Correlates with Sorafenib and Anti-PD-1 Immunotherapy Treatment Response.

N6-methyladenosine (m6A) modification plays an essential role in diverse key biological processes and may take part in the development and progression of hepatocellular carcinoma (HCC). Here, we systematically analyzed the expression profiles and prognostic values of 13 widely reported m6A modification-related genes in HCC. The mRNA expression of 13 m6A modification-related genes and clinical parameters of HCC patients were downloaded from TCGA, ICGC, GSE109211, and GSE78220. Univariate and LASSO analyses were used to develop risk signature. Time-dependent ROC was performed to assess the predictive accuracy and sensitivity of risk signature. FTO, YTHDC1, YTHDC2, ALKBH5, KIAA1429, HNRNPC, METTL3, RBM15, YTHDF2, YTHDF1, and WTAP were significantly overexpressed in HCC patients. YTHDF1, HNRNPC, RBM15, METTL3, and YTHDF2 were independent prognostic factors for OS and DFS in HCC patients. Next, a risk signature was also developed and validated with five m6A modification-related genes in TCGA and ICGC HCC cohort. It could effectively stratify HCC patients into high-risk patients with shorter OS and DFS and low-risk patients with longer OS and DFS and showed good predictive efficiency in predicting OS and DFS. Moreover, significantly higher proportions of macrophages M0 cells, neutrophils, and Tregs were found to be enriched in HCC patients with high risk scores, while significantly higher proportions of memory CD4 T cells, gamma delta T cells, and naive B cells were found to be enriched in HCC patients with low scores. Finally, significantly lower risk scores were found at sorafenib treatment responders and anti-PD-1 immunotherapy responders compared to that in nonresponders, and anti-PD-1 immunotherapy-treated patients with lower risk scores had better OS than patients with higher risk scores. A risk signature developed with the expression of 5 m6A-related genes could improve the prediction of prognosis of HCC and correlated with sorafenib treatment and anti-PD-1 immunotherapy response.

Jiang H ，Ning G ，Wang Y ，Lv W ... -  《-》

m6A-Related Genes Contribute to Poor Prognosis of Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is one of the most common and lethal digestive system cancers worldwide. N6-methyladenosine (m6A) modification plays an essential role in diverse critical biological processes and may participate in the development and progression of HCC. We downloaded transcriptome data and clinical data from TCGA as the training set. COX and LASSO screened prognostic m6A genes. ROC and Kaplan-Meier curve analysis evaluated the effectiveness of the model. ICGC and our center data were used as verification sets. We include the "writer (METTL3, METTL14, WTAP, KIAA1429, RBM15, ZC3H13)," the "reader (YTHDC1, YTHDC2, YTHDF1, YTHDF2, HNRNPC)," and the "eraser (FTO, ALKBH5)" in the study. We obtained YTHDF2, YTHDF1, METTL3, and KIAA1429 through differential analysis, survival analysis, and LASSO regression analysis. The prediction model was established based on the expression of these 4 molecules. HCC patients were divided into "high-risk" and "low-risk" groups to compare survival differences. The model suggested a poor prognosis in the validation sets. The four-m6A-related-gene combination model was an independent prognostic factor of HCC and could improve the prediction of the prognosis of HCC.

Zou Y ，Jiang G ，Xie Y ，Li H ... -  《-》

Comprehensive Analysis of PD-L1 Expression, Immune Infiltrates, and m6A RNA Methylation Regulators in Esophageal Squamous Cell Carcinoma.

Esophageal squamous cell carcinoma (ESCC) is one of the most common cancer types and represents a threat to global public health. N6-Methyladenosine (m6A) methylation plays a key role in the occurrence and development of many tumors, but there are still few studies investigating ESCC. This study attempts to construct a prognostic signature of ESCC based on m6A RNA methylation regulators and to explore the potential association of these regulators with the tumor immune microenvironment (TIME). The transcriptome sequencing data and clinical information of 20 m6A RNA methylation regulators in 453 patients with ESCC (The Cancer Genome Atlas [TCGA] cohort, n = 95; Gene Expression Omnibus [GEO] cohort, n = 358) were obtained. The differing expression levels of m6A regulators between ESCC and normal tissue were evaluated. Based on the expression of these regulators, consensus clustering was performed to investigate different ESCC clusters. PD-L1 expression, immune score, immune cell infiltration and potential mechanisms among different clusters were examined. LASSO Cox regression analysis was utilized to obtain a prognostic signature based on m6A RNA methylation modulators. The relationship between the risk score based on the prognostic signature and the TIME of ESCC patients was studied in detail. Six m6A regulators (METTL3, WTAP, IGF2BP3, YTHDF1, HNRNPA2B1 and HNRNPC) were observed to be significantly highly expressed in ESCC tissues. Two molecular subtypes (clusters 1/2) were determined by consensus clustering of 20 m6A modulators. The expression level of PD-L1 in ESCC tissues increased significantly and was significantly negatively correlated with the expression levels of YTHDF2, METL14 and KIAA1429. The immune score, CD8 T cells, resting mast cells, and regulatory T cells (Tregs) in cluster 2 were significantly increased. Gene set enrichment analysis (GSEA) shows that this cluster involves multiple hallmark pathways. We constructed a five-gene prognostic signature based on m6A RNA methylation, and the risk score based on the prognostic signature was determined to be an independent prognostic indicator of ESCC. More importantly, the prognostic value of the prognostic signature was verified using another independent cohort. m6A regulators are related to TIME, and their copy-number alterations will dynamically affect the number of tumor-infiltrating immune cells. Our study established a strong prognostic signature based on m6A RNA methylation regulators; this signature was able to accurately predict the prognosis of ESCC patients. The m6A methylation regulator may be a key mediator of PD-L1 expression and immune cell infiltration and may strongly affect the TIME of ESCC.

Guo W ，Tan F ，Huai Q ，Wang Z ，Shao F ，Zhang G ，Yang Z ，Li R ，Xue Q ，Gao S ，He J ... -  《Frontiers in Immunology》

Ahypoxia-related signature enhances the prediction of the prognosis in hepatocellular carcinoma patients and correlates with sorafenib treatment response.

Hepatocellular carcinoma (HCC) is one of the leading cancer death and is the primary malignancy of the liver. Tumor hypoxia is the stressor that is involved in tumorigenesis and significantly increased the aggressiveness of HCC. Here, we systematically analyzed the expression profiles and prognostic values of 84 hypoxia associated genes in HCC. mRNA expression of 84 hypoxia associated genes and clinical parameters of HCC patients were downloaded from TCGA, GSE14520, GSE109211 and ICGC. Consensus clustering analysis was performed for unsupervised classes on the basis of 84 hypoxia associated genes. Univariate and LASSO analysis were used to develop the risk signature. A risk signature was developed, including the expression of APEX1, ATR, CTSA, DNAJC5, ENO1, EPO, HMOX1, LDHA, NDRG1, and PER1, and found to be significantly related with OS and DFS of HCC patients. We stratified HCC patients into the high-risk group and low-risk group by means of the risk signature. Patients of high-risk group had shorter OS and DFS, while that of the low-risk group had longer OS and DFS. The risk signature showed better predictive efficiency than the TNM staging in predicting OS and DFS. Also, macrophage M0 cells, regulatory T cells, and neutrophils were found to be significantly enriched in patients of high-risk group. Next, we validated the discrimination and prognostic value of the risk signature in GSE14520 and the ICGC HCC cohort. Finally, significantly lower risk scores were found in sorafenib treatment responders of GSE109211 cohort, and the AUC for predicting sorafenib treatment response was 0.881. In conclusion, a risk signature developed with the expression of 10 hypoxia associated genes improved the prognosis prediction of HCC and correlated with sorafenib treatment response.

Jiang HY ，Ning G ，Wang YS ，Lv WB ... -  《American Journal of Translational Research》

A novel mitochondrial unfolded protein response-related risk signature to predict prognosis, immunotherapy and sorafenib sensitivity in hepatocellular carcinoma.

Zhang S ，Guo H ，Wang H ，Liu X ，Wang M ，Liu X ，Fan Y ，Tan K ... -  《-》