TP53 Mutational Status-Based Genomic Signature for Prognosis and Predicting Therapeutic Response in Pancreatic Cancer
TP53 mutation is a critical driver mutation that affects the carcinogenesis and prognosis of patients with pancreatic cancer (PC). Currently, there is no driver mutation-derived signature based on TP53 mutational status for prognosis and predicting therapeutic response in PC. In the present study, w...
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| Format: | Article |
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Frontiers Media S.A.
2021-05-01
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| Series: | Frontiers in Cell and Developmental Biology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fcell.2021.665265/full |
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| author | Feng Zhang Feng Zhang Wenhui Zhong Wenhui Zhong Honghao Li Kaijun Huang Min Yu Yubin Liu |
| author_facet | Feng Zhang Feng Zhang Wenhui Zhong Wenhui Zhong Honghao Li Kaijun Huang Min Yu Yubin Liu |
| author_sort | Feng Zhang |
| collection | DOAJ |
| description | TP53 mutation is a critical driver mutation that affects the carcinogenesis and prognosis of patients with pancreatic cancer (PC). Currently, there is no driver mutation-derived signature based on TP53 mutational status for prognosis and predicting therapeutic response in PC. In the present study, we characterized the TP53 mutational phenotypes in multiple patient cohorts and developed a prognostic TP53-associated signature based on differentially expressed genes between PC samples with mutated TP53 and wild-type TP53. Comprehensive investigations were carried out in prognostic stratification, genetic variation, immune cell infiltration, and efficacy prediction of chemotherapy and targeted therapy. We found that TP53 mutation commonly occurred as a survival-related driver mutation in PC. In total, 1,154 differentially expressed genes were found between two distinct TP53 mutational phenotypes. A five-gene TP53-associated signature was constructed in The Cancer Genome Atlas (TCGA) cohort by least absolute shrinkage and selection operator (LASSO)–Cox analysis and proven to be a robust prognostic predictor, which performed well in three independent Gene Expression Omnibus (GEO) validating cohorts. Remarkably, patients in the low-risk group were characterized with decreased tumor mutation burden and activity of immunity, with favorable prognosis. Higher fractions of macrophages M0 and impaired CD8 + T cells were observed in patients in the high-risk group, suggesting immunosuppression with poor survival. Patients in the high-risk group also demonstrated enhanced response to specific chemotherapeutic agents, including gemcitabine and paclitaxel. Several targeted inhibitors, like histamine receptor inhibitor, were screened out as promising drugs for PC treatment. Collectively, the TP53-associated signature is a novel prognostic biomarker and predictive indicator of PC. The signature could contribute to optimizing prognostic stratification and guide effective PC treatments. |
| first_indexed | 2024-12-19T02:03:58Z |
| format | Article |
| id | doaj.art-c8b25a95ef6f407b84b2fd796cb7d6a2 |
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| issn | 2296-634X |
| language | English |
| last_indexed | 2024-12-19T02:03:58Z |
| publishDate | 2021-05-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Cell and Developmental Biology |
| spelling | doaj.art-c8b25a95ef6f407b84b2fd796cb7d6a22022-12-21T20:40:59ZengFrontiers Media S.A.Frontiers in Cell and Developmental Biology2296-634X2021-05-01910.3389/fcell.2021.665265665265TP53 Mutational Status-Based Genomic Signature for Prognosis and Predicting Therapeutic Response in Pancreatic CancerFeng Zhang0Feng Zhang1Wenhui Zhong2Wenhui Zhong3Honghao Li4Kaijun Huang5Min Yu6Yubin Liu7Department of General Surgery, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Guangzhou, ChinaShantou University Medical College, Shantou, ChinaDepartment of General Surgery, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Guangzhou, ChinaShantou University Medical College, Shantou, ChinaThe Sixth Affiliated Hospital, Sun Yat-sen University Guangdong Gastrointestinal Hospital, Guangzhou, ChinaDepartment of General Surgery, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Guangzhou, ChinaDepartment of General Surgery, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Guangzhou, ChinaDepartment of General Surgery, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Guangzhou, ChinaTP53 mutation is a critical driver mutation that affects the carcinogenesis and prognosis of patients with pancreatic cancer (PC). Currently, there is no driver mutation-derived signature based on TP53 mutational status for prognosis and predicting therapeutic response in PC. In the present study, we characterized the TP53 mutational phenotypes in multiple patient cohorts and developed a prognostic TP53-associated signature based on differentially expressed genes between PC samples with mutated TP53 and wild-type TP53. Comprehensive investigations were carried out in prognostic stratification, genetic variation, immune cell infiltration, and efficacy prediction of chemotherapy and targeted therapy. We found that TP53 mutation commonly occurred as a survival-related driver mutation in PC. In total, 1,154 differentially expressed genes were found between two distinct TP53 mutational phenotypes. A five-gene TP53-associated signature was constructed in The Cancer Genome Atlas (TCGA) cohort by least absolute shrinkage and selection operator (LASSO)–Cox analysis and proven to be a robust prognostic predictor, which performed well in three independent Gene Expression Omnibus (GEO) validating cohorts. Remarkably, patients in the low-risk group were characterized with decreased tumor mutation burden and activity of immunity, with favorable prognosis. Higher fractions of macrophages M0 and impaired CD8 + T cells were observed in patients in the high-risk group, suggesting immunosuppression with poor survival. Patients in the high-risk group also demonstrated enhanced response to specific chemotherapeutic agents, including gemcitabine and paclitaxel. Several targeted inhibitors, like histamine receptor inhibitor, were screened out as promising drugs for PC treatment. Collectively, the TP53-associated signature is a novel prognostic biomarker and predictive indicator of PC. The signature could contribute to optimizing prognostic stratification and guide effective PC treatments.https://www.frontiersin.org/articles/10.3389/fcell.2021.665265/fullTP53 mutationpancreatic cancersignatureprognosistherapeutic responses |
| spellingShingle | Feng Zhang Feng Zhang Wenhui Zhong Wenhui Zhong Honghao Li Kaijun Huang Min Yu Yubin Liu TP53 Mutational Status-Based Genomic Signature for Prognosis and Predicting Therapeutic Response in Pancreatic Cancer Frontiers in Cell and Developmental Biology TP53 mutation pancreatic cancer signature prognosis therapeutic responses |
| title | TP53 Mutational Status-Based Genomic Signature for Prognosis and Predicting Therapeutic Response in Pancreatic Cancer |
| title_full | TP53 Mutational Status-Based Genomic Signature for Prognosis and Predicting Therapeutic Response in Pancreatic Cancer |
| title_fullStr | TP53 Mutational Status-Based Genomic Signature for Prognosis and Predicting Therapeutic Response in Pancreatic Cancer |
| title_full_unstemmed | TP53 Mutational Status-Based Genomic Signature for Prognosis and Predicting Therapeutic Response in Pancreatic Cancer |
| title_short | TP53 Mutational Status-Based Genomic Signature for Prognosis and Predicting Therapeutic Response in Pancreatic Cancer |
| title_sort | tp53 mutational status based genomic signature for prognosis and predicting therapeutic response in pancreatic cancer |
| topic | TP53 mutation pancreatic cancer signature prognosis therapeutic responses |
| url | https://www.frontiersin.org/articles/10.3389/fcell.2021.665265/full |
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