Integrated analysis reveals a novel 5-fluorouracil resistance-based prognostic signature with promising implications for predicting the efficacy of chemotherapy and immunotherapy in patients with colorectal cancer
Background: 5-Fluorouracil (5-FU) has been used as a standard first-line treatment for colorectal cancer (CRC) patients. Although 5-FU-based chemotherapy and immune checkpoint blockade (ICB) have achieved success in treating CRC, drug resistance and low response rates remain substantial limitations....
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| Veröffentlicht in: | Apoptosis (London) 2024-08, Vol.29 (7-8), p.1126-1144 |
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| creator | Hou, Yufang Zhang, Fang Zong, Jinbao Li, Tiegang Gan, Wenqiang Lv, Silin Yan, Zheng Zeng, Zifan Yang, Liu Zhou, Mingxuan Zhao, Wenyi Yang, Min |
| description | Background: 5-Fluorouracil (5-FU) has been used as a standard first-line treatment for colorectal cancer (CRC) patients. Although 5-FU-based chemotherapy and immune checkpoint blockade (ICB) have achieved success in treating CRC, drug resistance and low response rates remain substantial limitations. Thus, it is necessary to construct a 5-FU resistance-related signature (5-FRSig) to predict patient prognosis and identify ideal patients for chemotherapy and immunotherapy. Methods: Using bulk and single-cell RNA sequencing data, we established and validated a novel 5-FRSig model using stepwise regression and multiple CRC cohorts and evaluated its associations with the prognosis, clinical features, immune status, immunotherapy, neoadjuvant therapy, and drug sensitivity of CRC patients through various bioinformatics algorithms. Unsupervised consensus clustering was performed to categorize the 5-FU resistance-related molecular subtypes of CRC. The expression levels of 5-FRSig, immune checkpoints, and immunoregulators were determined using quantitative real-time polymerase chain reaction (RT‒qPCR). Potential small-molecule agents were identified via Connectivity Map (CMap) and molecular docking. Results: The 5-FRSig and cluster were confirmed as independent prognostic factors in CRC, as patients in the low-risk group and Cluster 1 had a better prognosis. Notably, 5-FRSig was significantly associated with 5-FU sensitivity, chemotherapy response, immune cell infiltration, immunoreactivity phenotype, immunotherapy efficiency, and drug selection. We predicted 10 potential compounds that bind to the core targets of 5-FRSig with the highest affinity. Conclusion: We developed a valid 5-FRSig to predict the prognosis, chemotherapeutic response, and immune status of CRC patients, thus optimizing the therapeutic benefits of chemotherapy combined with immunotherapy, which can facilitate the development of personalized treatments and novel molecular targeted therapies for patients with CRC. |
| doi_str_mv | 10.1007/s10495-024-01981-2 |
| format | Article |
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Although 5-FU-based chemotherapy and immune checkpoint blockade (ICB) have achieved success in treating CRC, drug resistance and low response rates remain substantial limitations. Thus, it is necessary to construct a 5-FU resistance-related signature (5-FRSig) to predict patient prognosis and identify ideal patients for chemotherapy and immunotherapy. Methods: Using bulk and single-cell RNA sequencing data, we established and validated a novel 5-FRSig model using stepwise regression and multiple CRC cohorts and evaluated its associations with the prognosis, clinical features, immune status, immunotherapy, neoadjuvant therapy, and drug sensitivity of CRC patients through various bioinformatics algorithms. Unsupervised consensus clustering was performed to categorize the 5-FU resistance-related molecular subtypes of CRC. The expression levels of 5-FRSig, immune checkpoints, and immunoregulators were determined using quantitative real-time polymerase chain reaction (RT‒qPCR). Potential small-molecule agents were identified via Connectivity Map (CMap) and molecular docking. Results: The 5-FRSig and cluster were confirmed as independent prognostic factors in CRC, as patients in the low-risk group and Cluster 1 had a better prognosis. Notably, 5-FRSig was significantly associated with 5-FU sensitivity, chemotherapy response, immune cell infiltration, immunoreactivity phenotype, immunotherapy efficiency, and drug selection. We predicted 10 potential compounds that bind to the core targets of 5-FRSig with the highest affinity. Conclusion: We developed a valid 5-FRSig to predict the prognosis, chemotherapeutic response, and immune status of CRC patients, thus optimizing the therapeutic benefits of chemotherapy combined with immunotherapy, which can facilitate the development of personalized treatments and novel molecular targeted therapies for patients with CRC.</description><identifier>ISSN: 1360-8185</identifier><identifier>ISSN: 1573-675X</identifier><identifier>EISSN: 1573-675X</identifier><identifier>DOI: 10.1007/s10495-024-01981-2</identifier><identifier>PMID: 38824480</identifier><language>eng</language><publisher>New York: Springer US</publisher><subject>5-Fluorouracil ; Algorithms ; B cells ; Biochemistry ; Bioinformatics ; Biomarkers, Tumor - genetics ; Biomarkers, Tumor - immunology ; Biomarkers, Tumor - metabolism ; Biomedical and Life Sciences ; Biomedicine ; Cancer ; Cancer patients ; Cancer Research ; Cell Biology ; Chemotherapy ; Clustering ; Clusters ; Colorectal cancer ; Colorectal carcinoma ; Colorectal Neoplasms - drug therapy ; Colorectal Neoplasms - genetics ; Colorectal Neoplasms - immunology ; Drug resistance ; Drug Resistance, Neoplasm - drug effects ; Drug Resistance, Neoplasm - genetics ; Drug therapy ; Female ; Fluorouracil ; Fluorouracil - pharmacology ; Fluorouracil - therapeutic use ; Gene Expression Regulation, Neoplastic - drug effects ; Gene sequencing ; Health aspects ; Humans ; Immune checkpoint inhibitors ; Immune status ; Immune system ; Immunoreactivity ; Immunoregulation ; Immunotherapy ; Male ; Medical prognosis ; Medical research ; Medicine, Experimental ; Molecular docking ; Molecular Docking Simulation ; Oncology ; Patients ; Phenotypes ; Polymerase chain reaction ; Prognosis ; Real time ; Regression models ; Risk groups ; RNA sequencing ; Virology</subject><ispartof>Apoptosis (London), 2024-08, Vol.29 (7-8), p.1126-1144</ispartof><rights>The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2024. Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.</rights><rights>2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.</rights><rights>COPYRIGHT 2024 Springer</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><cites>FETCH-LOGICAL-c323t-da5154c4c2d7fcfcb39de5fa83ddad9f719451349b0c66a79c27da68a4c8d8763</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://link.springer.com/content/pdf/10.1007/s10495-024-01981-2$$EPDF$$P50$$Gspringer$$H</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1007/s10495-024-01981-2$$EHTML$$P50$$Gspringer$$H</linktohtml><link.rule.ids>314,776,780,27903,27904,41467,42536,51297</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/38824480$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Hou, Yufang</creatorcontrib><creatorcontrib>Zhang, Fang</creatorcontrib><creatorcontrib>Zong, Jinbao</creatorcontrib><creatorcontrib>Li, Tiegang</creatorcontrib><creatorcontrib>Gan, Wenqiang</creatorcontrib><creatorcontrib>Lv, Silin</creatorcontrib><creatorcontrib>Yan, Zheng</creatorcontrib><creatorcontrib>Zeng, Zifan</creatorcontrib><creatorcontrib>Yang, Liu</creatorcontrib><creatorcontrib>Zhou, Mingxuan</creatorcontrib><creatorcontrib>Zhao, Wenyi</creatorcontrib><creatorcontrib>Yang, Min</creatorcontrib><title>Integrated analysis reveals a novel 5-fluorouracil resistance-based prognostic signature with promising implications for predicting the efficacy of chemotherapy and immunotherapy in patients with colorectal cancer</title><title>Apoptosis (London)</title><addtitle>Apoptosis</addtitle><addtitle>Apoptosis</addtitle><description>Background: 5-Fluorouracil (5-FU) has been used as a standard first-line treatment for colorectal cancer (CRC) patients. Although 5-FU-based chemotherapy and immune checkpoint blockade (ICB) have achieved success in treating CRC, drug resistance and low response rates remain substantial limitations. Thus, it is necessary to construct a 5-FU resistance-related signature (5-FRSig) to predict patient prognosis and identify ideal patients for chemotherapy and immunotherapy. Methods: Using bulk and single-cell RNA sequencing data, we established and validated a novel 5-FRSig model using stepwise regression and multiple CRC cohorts and evaluated its associations with the prognosis, clinical features, immune status, immunotherapy, neoadjuvant therapy, and drug sensitivity of CRC patients through various bioinformatics algorithms. Unsupervised consensus clustering was performed to categorize the 5-FU resistance-related molecular subtypes of CRC. The expression levels of 5-FRSig, immune checkpoints, and immunoregulators were determined using quantitative real-time polymerase chain reaction (RT‒qPCR). Potential small-molecule agents were identified via Connectivity Map (CMap) and molecular docking. Results: The 5-FRSig and cluster were confirmed as independent prognostic factors in CRC, as patients in the low-risk group and Cluster 1 had a better prognosis. Notably, 5-FRSig was significantly associated with 5-FU sensitivity, chemotherapy response, immune cell infiltration, immunoreactivity phenotype, immunotherapy efficiency, and drug selection. We predicted 10 potential compounds that bind to the core targets of 5-FRSig with the highest affinity. Conclusion: We developed a valid 5-FRSig to predict the prognosis, chemotherapeutic response, and immune status of CRC patients, thus optimizing the therapeutic benefits of chemotherapy combined with immunotherapy, which can facilitate the development of personalized treatments and novel molecular targeted therapies for patients with CRC.</description><subject>5-Fluorouracil</subject><subject>Algorithms</subject><subject>B cells</subject><subject>Biochemistry</subject><subject>Bioinformatics</subject><subject>Biomarkers, Tumor - genetics</subject><subject>Biomarkers, Tumor - immunology</subject><subject>Biomarkers, Tumor - metabolism</subject><subject>Biomedical and Life Sciences</subject><subject>Biomedicine</subject><subject>Cancer</subject><subject>Cancer patients</subject><subject>Cancer Research</subject><subject>Cell Biology</subject><subject>Chemotherapy</subject><subject>Clustering</subject><subject>Clusters</subject><subject>Colorectal cancer</subject><subject>Colorectal carcinoma</subject><subject>Colorectal Neoplasms - drug therapy</subject><subject>Colorectal Neoplasms - genetics</subject><subject>Colorectal Neoplasms - immunology</subject><subject>Drug resistance</subject><subject>Drug Resistance, Neoplasm - drug effects</subject><subject>Drug Resistance, Neoplasm - genetics</subject><subject>Drug therapy</subject><subject>Female</subject><subject>Fluorouracil</subject><subject>Fluorouracil - pharmacology</subject><subject>Fluorouracil - therapeutic use</subject><subject>Gene Expression Regulation, Neoplastic - drug effects</subject><subject>Gene sequencing</subject><subject>Health aspects</subject><subject>Humans</subject><subject>Immune checkpoint inhibitors</subject><subject>Immune status</subject><subject>Immune system</subject><subject>Immunoreactivity</subject><subject>Immunoregulation</subject><subject>Immunotherapy</subject><subject>Male</subject><subject>Medical prognosis</subject><subject>Medical research</subject><subject>Medicine, Experimental</subject><subject>Molecular docking</subject><subject>Molecular Docking Simulation</subject><subject>Oncology</subject><subject>Patients</subject><subject>Phenotypes</subject><subject>Polymerase chain reaction</subject><subject>Prognosis</subject><subject>Real time</subject><subject>Regression models</subject><subject>Risk groups</subject><subject>RNA sequencing</subject><subject>Virology</subject><issn>1360-8185</issn><issn>1573-675X</issn><issn>1573-675X</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2024</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9Ustu1TAQjRCIlsIPsECW2LBJ8SuJs6wqHpUqsQGJXeRrj3NdJfbFdoruh_I_TEhpBULIC1tzHp4Znap6yeg5o7R7mxmVfVNTLmvKesVq_qg6ZU0n6rZrvj7Gt2hprZhqTqpnOd9QSoUS8ml1IpTiUip6Wv24CgXGpAtYooOejtlnkuAW9JSJJiHewkSa2k1LTHFJ2vgJYSQVHQzUO51ReEhxDDEXb0j2Y9BlSUC--7JfkdlnH0bi58PkjS4-hkxcTAiB9aasWNkDAecQNkcSHTF7mCMWkz4csSuL4nkJ9xUfyAGNIJS8_WLiFBOYoidi1rbS8-qJwwHgxd19Vn15_-7z5cf6-tOHq8uL69oILkptdcMaaaThtnPGmZ3oLTROK2Gttr3rWC8bJmS_o6Ztddcb3lndKi2NsqprxVn1ZvPFOb8tkMuA0xqYJh0gLnkQtBWyFbxRSH39F_UG94kbX1lK8I5K0T-wRj3B4IOLBXe-mg4XinL06_rV6_wfLDwWZm9iAOex_oeAbwKTYs4J3HBIftbpODA6rFkatiwNmKXhV5YGjqJXdx0vuxnsveR3eJAgNkJGKIyQHkb6j-1P9hvahg</recordid><startdate>20240801</startdate><enddate>20240801</enddate><creator>Hou, Yufang</creator><creator>Zhang, Fang</creator><creator>Zong, Jinbao</creator><creator>Li, Tiegang</creator><creator>Gan, Wenqiang</creator><creator>Lv, Silin</creator><creator>Yan, Zheng</creator><creator>Zeng, Zifan</creator><creator>Yang, Liu</creator><creator>Zhou, Mingxuan</creator><creator>Zhao, Wenyi</creator><creator>Yang, Min</creator><general>Springer US</general><general>Springer</general><general>Springer Nature B.V</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7QL</scope><scope>7QP</scope><scope>7TK</scope><scope>7TM</scope><scope>7U9</scope><scope>C1K</scope><scope>H94</scope><scope>K9.</scope><scope>M7N</scope><scope>U9A</scope><scope>7X8</scope></search><sort><creationdate>20240801</creationdate><title>Integrated analysis reveals a novel 5-fluorouracil resistance-based prognostic signature with promising implications for predicting the efficacy of chemotherapy and immunotherapy in patients with colorectal cancer</title><author>Hou, Yufang ; Zhang, Fang ; Zong, Jinbao ; Li, Tiegang ; Gan, Wenqiang ; Lv, Silin ; Yan, Zheng ; Zeng, Zifan ; Yang, Liu ; Zhou, Mingxuan ; Zhao, Wenyi ; Yang, Min</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c323t-da5154c4c2d7fcfcb39de5fa83ddad9f719451349b0c66a79c27da68a4c8d8763</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2024</creationdate><topic>5-Fluorouracil</topic><topic>Algorithms</topic><topic>B cells</topic><topic>Biochemistry</topic><topic>Bioinformatics</topic><topic>Biomarkers, Tumor - genetics</topic><topic>Biomarkers, Tumor - immunology</topic><topic>Biomarkers, Tumor - metabolism</topic><topic>Biomedical and Life Sciences</topic><topic>Biomedicine</topic><topic>Cancer</topic><topic>Cancer patients</topic><topic>Cancer Research</topic><topic>Cell Biology</topic><topic>Chemotherapy</topic><topic>Clustering</topic><topic>Clusters</topic><topic>Colorectal cancer</topic><topic>Colorectal carcinoma</topic><topic>Colorectal Neoplasms - drug therapy</topic><topic>Colorectal Neoplasms - genetics</topic><topic>Colorectal Neoplasms - immunology</topic><topic>Drug resistance</topic><topic>Drug Resistance, Neoplasm - drug effects</topic><topic>Drug Resistance, Neoplasm - genetics</topic><topic>Drug therapy</topic><topic>Female</topic><topic>Fluorouracil</topic><topic>Fluorouracil - pharmacology</topic><topic>Fluorouracil - therapeutic use</topic><topic>Gene Expression Regulation, Neoplastic - drug effects</topic><topic>Gene sequencing</topic><topic>Health aspects</topic><topic>Humans</topic><topic>Immune checkpoint inhibitors</topic><topic>Immune status</topic><topic>Immune system</topic><topic>Immunoreactivity</topic><topic>Immunoregulation</topic><topic>Immunotherapy</topic><topic>Male</topic><topic>Medical prognosis</topic><topic>Medical research</topic><topic>Medicine, Experimental</topic><topic>Molecular docking</topic><topic>Molecular Docking Simulation</topic><topic>Oncology</topic><topic>Patients</topic><topic>Phenotypes</topic><topic>Polymerase chain reaction</topic><topic>Prognosis</topic><topic>Real time</topic><topic>Regression models</topic><topic>Risk groups</topic><topic>RNA sequencing</topic><topic>Virology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Hou, Yufang</creatorcontrib><creatorcontrib>Zhang, Fang</creatorcontrib><creatorcontrib>Zong, Jinbao</creatorcontrib><creatorcontrib>Li, Tiegang</creatorcontrib><creatorcontrib>Gan, Wenqiang</creatorcontrib><creatorcontrib>Lv, Silin</creatorcontrib><creatorcontrib>Yan, Zheng</creatorcontrib><creatorcontrib>Zeng, Zifan</creatorcontrib><creatorcontrib>Yang, Liu</creatorcontrib><creatorcontrib>Zhou, Mingxuan</creatorcontrib><creatorcontrib>Zhao, Wenyi</creatorcontrib><creatorcontrib>Yang, Min</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>Neurosciences Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Environmental Sciences and Pollution Management</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>MEDLINE - Academic</collection><jtitle>Apoptosis (London)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Hou, Yufang</au><au>Zhang, Fang</au><au>Zong, Jinbao</au><au>Li, Tiegang</au><au>Gan, Wenqiang</au><au>Lv, Silin</au><au>Yan, Zheng</au><au>Zeng, Zifan</au><au>Yang, Liu</au><au>Zhou, Mingxuan</au><au>Zhao, Wenyi</au><au>Yang, Min</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Integrated analysis reveals a novel 5-fluorouracil resistance-based prognostic signature with promising implications for predicting the efficacy of chemotherapy and immunotherapy in patients with colorectal cancer</atitle><jtitle>Apoptosis (London)</jtitle><stitle>Apoptosis</stitle><addtitle>Apoptosis</addtitle><date>2024-08-01</date><risdate>2024</risdate><volume>29</volume><issue>7-8</issue><spage>1126</spage><epage>1144</epage><pages>1126-1144</pages><issn>1360-8185</issn><issn>1573-675X</issn><eissn>1573-675X</eissn><abstract>Background: 5-Fluorouracil (5-FU) has been used as a standard first-line treatment for colorectal cancer (CRC) patients. Although 5-FU-based chemotherapy and immune checkpoint blockade (ICB) have achieved success in treating CRC, drug resistance and low response rates remain substantial limitations. Thus, it is necessary to construct a 5-FU resistance-related signature (5-FRSig) to predict patient prognosis and identify ideal patients for chemotherapy and immunotherapy. Methods: Using bulk and single-cell RNA sequencing data, we established and validated a novel 5-FRSig model using stepwise regression and multiple CRC cohorts and evaluated its associations with the prognosis, clinical features, immune status, immunotherapy, neoadjuvant therapy, and drug sensitivity of CRC patients through various bioinformatics algorithms. Unsupervised consensus clustering was performed to categorize the 5-FU resistance-related molecular subtypes of CRC. The expression levels of 5-FRSig, immune checkpoints, and immunoregulators were determined using quantitative real-time polymerase chain reaction (RT‒qPCR). Potential small-molecule agents were identified via Connectivity Map (CMap) and molecular docking. Results: The 5-FRSig and cluster were confirmed as independent prognostic factors in CRC, as patients in the low-risk group and Cluster 1 had a better prognosis. Notably, 5-FRSig was significantly associated with 5-FU sensitivity, chemotherapy response, immune cell infiltration, immunoreactivity phenotype, immunotherapy efficiency, and drug selection. We predicted 10 potential compounds that bind to the core targets of 5-FRSig with the highest affinity. Conclusion: We developed a valid 5-FRSig to predict the prognosis, chemotherapeutic response, and immune status of CRC patients, thus optimizing the therapeutic benefits of chemotherapy combined with immunotherapy, which can facilitate the development of personalized treatments and novel molecular targeted therapies for patients with CRC.</abstract><cop>New York</cop><pub>Springer US</pub><pmid>38824480</pmid><doi>10.1007/s10495-024-01981-2</doi><tpages>19</tpages></addata></record> |
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| subjects | 5-Fluorouracil Algorithms B cells Biochemistry Bioinformatics Biomarkers, Tumor - genetics Biomarkers, Tumor - immunology Biomarkers, Tumor - metabolism Biomedical and Life Sciences Biomedicine Cancer Cancer patients Cancer Research Cell Biology Chemotherapy Clustering Clusters Colorectal cancer Colorectal carcinoma Colorectal Neoplasms - drug therapy Colorectal Neoplasms - genetics Colorectal Neoplasms - immunology Drug resistance Drug Resistance, Neoplasm - drug effects Drug Resistance, Neoplasm - genetics Drug therapy Female Fluorouracil Fluorouracil - pharmacology Fluorouracil - therapeutic use Gene Expression Regulation, Neoplastic - drug effects Gene sequencing Health aspects Humans Immune checkpoint inhibitors Immune status Immune system Immunoreactivity Immunoregulation Immunotherapy Male Medical prognosis Medical research Medicine, Experimental Molecular docking Molecular Docking Simulation Oncology Patients Phenotypes Polymerase chain reaction Prognosis Real time Regression models Risk groups RNA sequencing Virology |
| title | Integrated analysis reveals a novel 5-fluorouracil resistance-based prognostic signature with promising implications for predicting the efficacy of chemotherapy and immunotherapy in patients with colorectal cancer |
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