A tumor microenvironment-specific gene expression signature predicts chemotherapy resistance in colorectal cancer patients

Abstract Studies have shown that tumor microenvironment (TME) might affect drug sensitivity and the classification of colorectal cancer (CRC). Using TME-specific gene signature to identify CRC subtypes with distinctive clinical relevance has not yet been tested. A total of 18 “bulk” RNA-seq datasets...

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Autores principales:	Xiaoqiang Zhu, Xianglong Tian, Linhua Ji, Xinyu Zhang, Yingying Cao, Chaoqin Shen, Ye Hu, Jason W. H. Wong, Jing-Yuan Fang, Jie Hong, Haoyan Chen
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
Acceso en línea:	https://doaj.org/article/c347240ed3e94a05aee507283d7dc3f6
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spelling	oai:doaj.org-article:c347240ed3e94a05aee507283d7dc3f62021-12-02T14:17:40ZA tumor microenvironment-specific gene expression signature predicts chemotherapy resistance in colorectal cancer patients10.1038/s41698-021-00142-x2397-768Xhttps://doaj.org/article/c347240ed3e94a05aee507283d7dc3f62021-02-01T00:00:00Zhttps://doi.org/10.1038/s41698-021-00142-xhttps://doaj.org/toc/2397-768XAbstract Studies have shown that tumor microenvironment (TME) might affect drug sensitivity and the classification of colorectal cancer (CRC). Using TME-specific gene signature to identify CRC subtypes with distinctive clinical relevance has not yet been tested. A total of 18 “bulk” RNA-seq datasets (total n = 2269) and four single-cell RNA-seq datasets were included in this study. We constructed a “Signature associated with FOLFIRI resistant and Microenvironment” (SFM) that could discriminate both TME and drug sensitivity. Further, SFM subtypes were identified using K-means clustering and verified in three independent cohorts. Nearest template prediction algorithm was used to predict drug response. TME estimation was performed by CIBERSORT and microenvironment cell populations-counter (MCP-counter) methods. We identified six SFM subtypes based on SFM signature that discriminated both TME and drug sensitivity. The SFM subtypes were associated with distinct clinicopathological, molecular and phenotypic characteristics, specific enrichments of gene signatures, signaling pathways, prognosis, gut microbiome patterns, and tumor lymphocytes infiltration. Among them, SFM-C and -F were immune suppressive. SFM-F had higher stromal fraction with epithelial-to-mesenchymal transition phenotype, while SFM-C was characterized as microsatellite instability phenotype which was responsive to immunotherapy. SFM-D, -E, and -F were sensitive to FOLFIRI and FOLFOX, while SFM-A, -B, and -C were responsive to EGFR inhibitors. Finally, SFM subtypes had strong prognostic value in which SFM-E and -F had worse survival than other subtypes. SFM subtypes enable the stratification of CRC with potential chemotherapy response thereby providing more precise therapeutic options for these patients.Xiaoqiang ZhuXianglong TianLinhua JiXinyu ZhangYingying CaoChaoqin ShenYe HuJason W. H. WongJing-Yuan FangJie HongHaoyan ChenNature PortfolioarticleNeoplasms. Tumors. Oncology. Including cancer and carcinogensRC254-282ENnpj Precision Oncology, Vol 5, Iss 1, Pp 1-14 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
spellingShingle	Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 Xiaoqiang Zhu Xianglong Tian Linhua Ji Xinyu Zhang Yingying Cao Chaoqin Shen Ye Hu Jason W. H. Wong Jing-Yuan Fang Jie Hong Haoyan Chen A tumor microenvironment-specific gene expression signature predicts chemotherapy resistance in colorectal cancer patients
description	Abstract Studies have shown that tumor microenvironment (TME) might affect drug sensitivity and the classification of colorectal cancer (CRC). Using TME-specific gene signature to identify CRC subtypes with distinctive clinical relevance has not yet been tested. A total of 18 “bulk” RNA-seq datasets (total n = 2269) and four single-cell RNA-seq datasets were included in this study. We constructed a “Signature associated with FOLFIRI resistant and Microenvironment” (SFM) that could discriminate both TME and drug sensitivity. Further, SFM subtypes were identified using K-means clustering and verified in three independent cohorts. Nearest template prediction algorithm was used to predict drug response. TME estimation was performed by CIBERSORT and microenvironment cell populations-counter (MCP-counter) methods. We identified six SFM subtypes based on SFM signature that discriminated both TME and drug sensitivity. The SFM subtypes were associated with distinct clinicopathological, molecular and phenotypic characteristics, specific enrichments of gene signatures, signaling pathways, prognosis, gut microbiome patterns, and tumor lymphocytes infiltration. Among them, SFM-C and -F were immune suppressive. SFM-F had higher stromal fraction with epithelial-to-mesenchymal transition phenotype, while SFM-C was characterized as microsatellite instability phenotype which was responsive to immunotherapy. SFM-D, -E, and -F were sensitive to FOLFIRI and FOLFOX, while SFM-A, -B, and -C were responsive to EGFR inhibitors. Finally, SFM subtypes had strong prognostic value in which SFM-E and -F had worse survival than other subtypes. SFM subtypes enable the stratification of CRC with potential chemotherapy response thereby providing more precise therapeutic options for these patients.
format	article
author	Xiaoqiang Zhu Xianglong Tian Linhua Ji Xinyu Zhang Yingying Cao Chaoqin Shen Ye Hu Jason W. H. Wong Jing-Yuan Fang Jie Hong Haoyan Chen
author_facet	Xiaoqiang Zhu Xianglong Tian Linhua Ji Xinyu Zhang Yingying Cao Chaoqin Shen Ye Hu Jason W. H. Wong Jing-Yuan Fang Jie Hong Haoyan Chen
author_sort	Xiaoqiang Zhu
title	A tumor microenvironment-specific gene expression signature predicts chemotherapy resistance in colorectal cancer patients
title_short	A tumor microenvironment-specific gene expression signature predicts chemotherapy resistance in colorectal cancer patients
title_full	A tumor microenvironment-specific gene expression signature predicts chemotherapy resistance in colorectal cancer patients
title_fullStr	A tumor microenvironment-specific gene expression signature predicts chemotherapy resistance in colorectal cancer patients
title_full_unstemmed	A tumor microenvironment-specific gene expression signature predicts chemotherapy resistance in colorectal cancer patients
title_sort	tumor microenvironment-specific gene expression signature predicts chemotherapy resistance in colorectal cancer patients
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/c347240ed3e94a05aee507283d7dc3f6
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A tumor microenvironment-specific gene expression signature predicts chemotherapy resistance in colorectal cancer patients

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