Mitochondrial-Related Transcriptome Feature Correlates with Prognosis, Vascular Invasion, Tumor Microenvironment, and Treatment Response in Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is the most common subtype of primary liver cancer, which was highly correlated with metabolic dysfunction. Nevertheless, the association between nuclear mitochondrial-related transcriptome and HCC remained unclear. A total of 147 nuclear mitochondrial-related genes (NMRGs) were downloaded from the MITOMAP: A Human Mitochondrial Genome Database. The training dataset was downloaded from The Cancer Genome Atlas (TCGA), while validation datasets were retrieved from the International Cancer Genome Consortium (ICGC) and Gene Expression Omnibus (GEO). The univariate and multivariate, and least absolute shrinkage and selection operator (LASSO) Cox regression analyses were applied to construct a NMRG signature, and the value of area under receiver operating characteristic curve (AUC) was utilized to assess the signature and nomogram. Then, data from the Genomics of Drug Sensitivity in Cancer (GDSC) were used for the evaluation of chemotherapy response in HCC. Functional enrichment of differentially expressed genes (DEGs) between HCC and paired normal tissue samples demonstrated that mitochondrial dysfunction was significantly associated with HCC development. Survival analysis showed a total of 35 NMRGs were significantly correlated with overall survival (OS) of HCC, and the LASSO Cox regression analysis further identified a 25-NMRG signature and corresponding prognosis score based on their transcriptional profiling. HCC patients were divided into high- and low-risk groups according to the median prognosis score, and high-risk patients had significantly worse OS (median OS: 27.50 vs. 83.18 months, P < 0.0001). The AUC values for OS at 1, 3, and 5 years were 0.79, 0.77, and 0.77, respectively. The prognostic capacity of NMRG signature was verified in the GSE14520 dataset and ICGC-HCC cohort. Besides, the NMRG signature outperformed each NMRG and clinical features in prognosis prediction and could also differentiate whether patients presented with vascular invasions (VIs) or not. Subsequently, a prognostic nomogram (C-index: 0.753, 95% CI: 0.703~0.804) by the integration of age, tumor metastasis, and NMRG prognosis score was constructed with the AUC values for OS at 1, 3, and 5 years were 0.82, 0.81, and 0.82, respectively. Notably, significant enrichment of regulatory and follicular helper T cells in high-risk group indicated the potential treatment of immune checkpoint inhibitors for these patients. Interestingly, the NMRG signature could also identify the potential responders of sorafenib or transcatheter arterial chemoembolization (TACE) treatment. Additionally, HCC patients in high-risk group appeared to be more sensitive to cisplatin, vorinostat, and methotrexate, reversely, patients in low-risk group had significantly higher sensitivity to paclitaxel and bleomycin instead. In summary, the development of NMRG signature provided a more comprehensive understanding of mitochondrial dysfunction in HCC, helped predict prognosis and tumor microenvironment, and provided potential targeted therapies for HCC patients with different NMRG prognosis scores.

Wang Y ，Song F ，Zhang X ，Yang C ... -  《-》

Overweight/obesity-related transcriptomic signature as a correlate of clinical outcome, immune microenvironment, and treatment response in hepatocellular carcinoma.

The pandemic of overweight and obesity (quantified by body mass index (BMI) ≥ 25) has rapidly raised the patient number of non-alcoholic fatty hepatocellular carcinoma (HCC), and several clinical trials have shown that BMI is associated with the prognosis of HCC. However, whether overweight/obesity is an independent prognostic factor is arguable, and the role of overweight/obesity-related metabolisms in the progression of HCC is scarcely known. In the present study, clinical information, mRNA expression profile, and genomic data were downloaded from The Cancer Genome Atlas (TCGA) as a training cohort (TCGA-HCC) for the identification of overweight/obesity-related transcriptome. Machine learning and the Cox regression analysis were conducted for the construction of the overweight/obesity-associated gene (OAG) signature. The Kaplan-Meier curve, receiver operating characteristic (ROC) curve, and the Cox regression analysis were performed to assess the prognostic value of the OAG signature, which was further validated in two independent retrospective cohorts from the International Cancer Genome Consortium (ICGC) and Gene Expression Omnibus (GEO). Subsequently, functional enrichment, genomic profiling, and tumor microenvironment (TME) evaluation were utilized to characterize biological activities associated with the OAG signature. GSE109211 and GSE104580 were retrieved to evaluate the underlying response of sorafenib and transcatheter arterial chemoembolization (TACE) treatment, respectively. The Genomics of Drug Sensitivity in Cancer (GDSC) database was employed for the evaluation of chemotherapeutic response. Overweight/obesity-associated transcriptome was mainly involved in metabolic processes and noticeably and markedly correlated with prognosis and TME of HCC. Afterward, a novel established OAG signature (including 17 genes, namely, GAGE2D, PDE6A, GABRR1, DCAF8L1, DPYSL4, SLC6A3, MMP3, RIBC2, KCNH2, HTRA3, PDX1, ATHL1, PRTG, SHC4, C21orf29, SMIM32, and C1orf133) divided patients into high and low OAG score groups with distinct prognosis (median overall survival (OS): 24.87 vs. 83.51 months, p < 0.0001), and the values of area under ROC curve (AUC) in predicting 1-, 2-, 3-, and 4-year OS were 0.81, 0.80, 0.83, and 0.85, respectively. Moreover, the OAG score was independent of clinical features and also exhibited a good ability for prognosis prediction in the ICGC-LIHC-JP cohort and GSE54236 dataset. Expectedly, the OAG score was also highly correlated with metabolic processes, especially oxidative-related signaling pathways. Furthermore, abundant enrichment of chemokines, receptors, MHC molecules, and other immunomodulators as well as PD-L1/PD-1 expression among patients with high OAG scores indicated that they might have better responses to immunotherapy. However, probably exclusion of T cells from infiltrating tumors resulting in lower infiltration of effective T cells would restrict immunotherapeutic effects. In addition, the OAG score was significantly associated with the response of sorafenib and TACE treatment. Overall, this study comprehensively disclosed the relationship between BMI-guided transcriptome and HCC. Moreover, the OAG signature had the potential clinical applications in the future to promote clinical management and precision medicine of HCC.

Feng NN ，Du XY ，Zhang YS ，Jiao ZK ，Wu XH ，Yang BM ... -  《Frontiers in Endocrinology》

Comprehensive FGFR3 alteration-related transcriptomic characterization is involved in immune infiltration and correlated with prognosis and immunotherapy response of bladder cancer.

Bladder cancer (BC) threatens the health of human beings worldwide because of its high recurrence rate and mortality. As an actionable biomarker, fibroblast growth factor receptor 3 (FGFR3) alterations have been revealed as a vital biomarker and associated with favorable outcomes in BC. However, the comprehensive relationship between the FGFR3 alteration associated gene expression profile and the prognosis of BC remains ambiguous. Genomic alteration profile, gene expression data, and related clinical information of BC patients were downloaded from The Cancer Genomics database (TCGA), as a training cohort. Subsequently, the Weighted Gene Co-expression Network Analysis (WGCNA) was conducted to identify the hub modules correlated with FGFR3 alteration. The univariate, multivariate, and least absolute shrinkage and selection operator (LASSO) Cox regression analyses were used to obtain an FGFR3 alteration-related gene (FARG) prognostic signature and FARG-based nomogram. The receiver operating characteristic (ROC) curve analysis was used for evaluation of the ability of prognosis prediction. The FARG signature was validated in four independent datasets, namely, GSE13507, GSE31684, GSE32548, and GSE48075, from Gene Expression Omnibus (GEO). Then, clinical feature association analysis, functional enrichment, genomic alteration enrichment, and tumor environment analysis were conducted to reveal differential clinical and molecular characterizations in different risk groups. Lastly, the treatment response was evaluated in the immunotherapy-related dataset of the IMvigor210 cohort and the frontline chemotherapy dataset of GSE48276, and the chemo-drug sensitivity was estimated via Genomics of Drug Sensitivity in Cancer (GDSC). There were a total of eleven genes (CERCAM, TPST1, OSBPL10, EMP1, CYTH3, NCRNA00201, PCDH10, GAP43, COLQ, DGKB, and SETBP1) identified in the FARG signature, which divided BC patients from the TCGA cohort into high- and low-risk groups. The Kaplan-Meier curve analysis demonstrated that BC patients in the low-risk group have superior overall survival (OS) than those in the high-risk group (median OS: 27.06 months vs. 104.65 months, p < 0.0001). Moreover, the FARG signature not only showed a good performance in prognosis prediction, but also could distinguish patients with different neoplasm disease stages, notably whether patients presented with muscle invasive phenotype. Compared to clinicopathological features, the FARG signature was found to be the only independent prognostic factor, and subsequently, a FARG-based prognostic nomogram was constructed with better ability of prognosis prediction, indicated by area under ROC curve (AUC) values for 1-, 3-, and 5-year OS of 0.69, 0.71, and 0.79, respectively. Underlying the FARG signature, multiple kinds of metabolism- and immune-related signaling pathways were enriched. Genomic alteration enrichment further identified that FGFR3 alterations, especially c.746C>G (p.Ser249Cys), were more prevalent in the low-risk group. Additionally, FARG score was positively correlated with ESTIMATE and TIDE scores, and the low-risk group had abundant enrichment of plasma B cells, CD8+ T cells, CD4+ naive T cells, and helper follicular T cells, implying that patients in the low-risk group were likely to make significant responses to immunotherapy, which was further supported by the analysis in the IMvigor210 cohort as there was a significantly higher response rate among patients with lower FARG scores. The analysis of the GDSC database finally demonstrated that low-risk samples were more sensitive to methotrexate and tipifarnib, whereas those in the high-risk group had higher sensitivities in cisplatin, docetaxel, and paclitaxel, instead. The novel established FARG signature based on a comprehensive FGFR3 alteration-related transcriptomic profile performed well in prognosis prediction and was also correlated with immunotherapy and chemotherapy treatment responses, which had great potential in future clinical applications.

Xu T ，Xu W ，Zheng Y ，Li X ，Cai H ，Xu Z ，Zou Q ，Yu B ... -  《Frontiers in Immunology》

Transcriptomic correlates of cell cycle checkpoints with distinct prognosis, molecular characteristics, immunological regulation, and therapeutic response in colorectal adenocarcinoma.

Wang H ，Wang W ，Wang Z ，Li X ... -  《Frontiers in Immunology》

Identification of a Liver Progenitor Cell-Related Genes Signature Predicting Overall Survival for Hepatocellular Carcinoma.

Li X ，Lin J ，Pan Y ，Cui P ，Xia J ... -  《-》