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Overweight/obesity-related transcriptomic signature as a correlate of clinical outcome, immune microenvironment, and treatment response in hepatocellular carcinoma
BACKGROUNDS: 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 overwe...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Frontiers Media S.A.
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9877416/ https://www.ncbi.nlm.nih.gov/pubmed/36714595 http://dx.doi.org/10.3389/fendo.2022.1061091 |
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author | Feng, Ning-Ning Du, Xi-Yue Zhang, Yue-Shan Jiao, Zhi-Kai Wu, Xiao-Hui Yang, Bao-Ming |
author_facet | Feng, Ning-Ning Du, Xi-Yue Zhang, Yue-Shan Jiao, Zhi-Kai Wu, Xiao-Hui Yang, Bao-Ming |
author_sort | Feng, Ning-Ning |
collection | PubMed |
description | BACKGROUNDS: 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. MATERIALS AND METHODS: 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. RESULTS: 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. CONCLUSIONS: 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. |
format | Online Article Text |
id | pubmed-9877416 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-98774162023-01-27 Overweight/obesity-related transcriptomic signature as a correlate of clinical outcome, immune microenvironment, and treatment response in hepatocellular carcinoma Feng, Ning-Ning Du, Xi-Yue Zhang, Yue-Shan Jiao, Zhi-Kai Wu, Xiao-Hui Yang, Bao-Ming Front Endocrinol (Lausanne) Endocrinology BACKGROUNDS: 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. MATERIALS AND METHODS: 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. RESULTS: 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. CONCLUSIONS: 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. Frontiers Media S.A. 2023-01-12 /pmc/articles/PMC9877416/ /pubmed/36714595 http://dx.doi.org/10.3389/fendo.2022.1061091 Text en Copyright © 2023 Feng, Du, Zhang, Jiao, Wu and Yang https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Endocrinology Feng, Ning-Ning Du, Xi-Yue Zhang, Yue-Shan Jiao, Zhi-Kai Wu, Xiao-Hui Yang, Bao-Ming Overweight/obesity-related transcriptomic signature as a correlate of clinical outcome, immune microenvironment, and treatment response in hepatocellular carcinoma |
title | Overweight/obesity-related transcriptomic signature as a correlate of clinical outcome, immune microenvironment, and treatment response in hepatocellular carcinoma |
title_full | Overweight/obesity-related transcriptomic signature as a correlate of clinical outcome, immune microenvironment, and treatment response in hepatocellular carcinoma |
title_fullStr | Overweight/obesity-related transcriptomic signature as a correlate of clinical outcome, immune microenvironment, and treatment response in hepatocellular carcinoma |
title_full_unstemmed | Overweight/obesity-related transcriptomic signature as a correlate of clinical outcome, immune microenvironment, and treatment response in hepatocellular carcinoma |
title_short | Overweight/obesity-related transcriptomic signature as a correlate of clinical outcome, immune microenvironment, and treatment response in hepatocellular carcinoma |
title_sort | overweight/obesity-related transcriptomic signature as a correlate of clinical outcome, immune microenvironment, and treatment response in hepatocellular carcinoma |
topic | Endocrinology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9877416/ https://www.ncbi.nlm.nih.gov/pubmed/36714595 http://dx.doi.org/10.3389/fendo.2022.1061091 |
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