Multi-omics analysis-based clinical and functional significance of a novel prognostic and immunotherapeutic gene signature derived from amino acid metabolism pathways in lung adenocarcinoma
BackgroundStudies have shown that tumor cell amino acid metabolism is closely associated with lung adenocarcinoma (LUAD) development and progression. However, the comprehensive multi-omics features and clinical impact of the expression of genes associated with amino acid metabolism in the LUAD tumor...
Saved in:
| Main Authors: | , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Frontiers Media S.A.
2024-12-01
|
| Series: | Frontiers in Immunology |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2024.1361992/full |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1846125947376369664 |
|---|---|
| author | Huihui Xiang Huihui Xiang Rika Kasajima Rika Kasajima Koichi Azuma Tomoyuki Tagami Asami Hagiwara Yoshiro Nakahara Yoshiro Nakahara Haruhiro Saito Yuka Igarashi Yuka Igarashi Feifei Wei Feifei Wei Tatsuma Ban Mitsuyo Yoshihara Mitsuyo Yoshihara Yoshiyasu Nakamura Yoshiyasu Nakamura Shinya Sato Shinya Sato Shinya Sato Shiro Koizume Shiro Koizume Tomohiko Tamura Tetsuro Sasada Tetsuro Sasada Yohei Miyagi Yohei Miyagi |
| author_facet | Huihui Xiang Huihui Xiang Rika Kasajima Rika Kasajima Koichi Azuma Tomoyuki Tagami Asami Hagiwara Yoshiro Nakahara Yoshiro Nakahara Haruhiro Saito Yuka Igarashi Yuka Igarashi Feifei Wei Feifei Wei Tatsuma Ban Mitsuyo Yoshihara Mitsuyo Yoshihara Yoshiyasu Nakamura Yoshiyasu Nakamura Shinya Sato Shinya Sato Shinya Sato Shiro Koizume Shiro Koizume Tomohiko Tamura Tetsuro Sasada Tetsuro Sasada Yohei Miyagi Yohei Miyagi |
| author_sort | Huihui Xiang |
| collection | DOAJ |
| description | BackgroundStudies have shown that tumor cell amino acid metabolism is closely associated with lung adenocarcinoma (LUAD) development and progression. However, the comprehensive multi-omics features and clinical impact of the expression of genes associated with amino acid metabolism in the LUAD tumor microenvironment (TME) are yet to be fully understood.MethodsLUAD patients from The Cancer Genome Atlas (TCGA) database were enrolled in the training cohort. Using least absolute shrinkage and selection operator Cox regression analysis, we developed PTAAMG-Sig, a signature based on the expression of tumor-specific amino acid metabolism genes associated with overall survival (OS) prognosis. We evaluated its predictive performance for OS and thoroughly explored the effects of the PTAAMG-Sig risk score on the TME. The risk score was validated in two Gene Expression Omnibus (GEO) cohorts and further investigated against an original cohort of chemotherapy combined with immune checkpoint inhibitors (ICIs). Somatic mutation, chemotherapy response, immunotherapy response, gene set variation, gene set enrichment, immune infiltration, and plasma-free amino acids (PFAAs) profile analyses were performed to identify the underlying multi-omics features.ResultsTCGA datasets based PTAAMG-Sig model consisting of nine genes, KYNU, PSPH, PPAT, MIF, GCLC, ACAD8, TYRP1, ALDH2, and HDC, could effectively stratify the OS in LUAD patients. The two other GEO-independent datasets validated the robust predictive power of PTAAMG-Sig. Our differential analysis of somatic mutations in the high- and low-risk groups in TCGA cohort showed that the TP53 mutation rate was significantly higher in the high-risk group and negatively correlated with OS. Prediction from transcriptome data raised the possibility that PTAAMG-Sig could predict the response to chemotherapy and ICIs therapy. Our immunotherapy cohort confirmed the predictive ability of PTAAMG-Sig in the clinical response to ICIs therapy, which correlated with the infiltration of immune cells (e.g., T lymphocytes and nature killer cells). Corresponding to the concentrations of PFAAs, we discovered that the high PTAAMG-Sig risk score patients showed a significantly lower concentration of plasma-free α-aminobutyric acid.ConclusionIn patients with LUAD, the PTAAMG-Sig effectively predicted OS, drug sensitivity, and immunotherapy outcomes. These findings are expected to provide new targets and strategies for personalized treatment of LUAD patients. |
| format | Article |
| id | doaj-art-d732c09627bd42d4a3c49f52310aabb2 |
| institution | Kabale University |
| issn | 1664-3224 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj-art-d732c09627bd42d4a3c49f52310aabb22024-12-13T09:16:19ZengFrontiers Media S.A.Frontiers in Immunology1664-32242024-12-011510.3389/fimmu.2024.13619921361992Multi-omics analysis-based clinical and functional significance of a novel prognostic and immunotherapeutic gene signature derived from amino acid metabolism pathways in lung adenocarcinomaHuihui Xiang0Huihui Xiang1Rika Kasajima2Rika Kasajima3Koichi Azuma4Tomoyuki Tagami5Asami Hagiwara6Yoshiro Nakahara7Yoshiro Nakahara8Haruhiro Saito9Yuka Igarashi10Yuka Igarashi11Feifei Wei12Feifei Wei13Tatsuma Ban14Mitsuyo Yoshihara15Mitsuyo Yoshihara16Yoshiyasu Nakamura17Yoshiyasu Nakamura18Shinya Sato19Shinya Sato20Shinya Sato21Shiro Koizume22Shiro Koizume23Tomohiko Tamura24Tetsuro Sasada25Tetsuro Sasada26Yohei Miyagi27Yohei Miyagi28Molecular Pathology & Genetics Division, Kanagawa Cancer Center Research Institute, Yokohama, JapanDepartment of Pathology, Kanagawa Cancer Center, Yokohama, JapanMolecular Pathology & Genetics Division, Kanagawa Cancer Center Research Institute, Yokohama, JapanCenter for Cancer Genome Medicine, Kanagawa Cancer Center, Yokohama, JapanDepartment of Internal Medicine, Kurume University School of Medicine, Kurume, JapanResearch Institute for Bioscience Products and Fine Chemicals, Ajinomoto Co., Inc., Kanagawa, JapanResearch Institute for Bioscience Products and Fine Chemicals, Ajinomoto Co., Inc., Kanagawa, JapanDepartment of Thoracic Oncology, Kanagawa Cancer Center, Yokohama, Kanagawa, JapanDepartment of Respiratory Medicine, Kitasato University School of Medicine, Sagamihara, Kanagawa, JapanDepartment of Thoracic Oncology, Kanagawa Cancer Center, Yokohama, Kanagawa, JapanDivision of Cancer Immunotherapy, Kanagawa Cancer Center Research Institute, Yokohama, JapanCancer Vaccine and Immunotherapy Center, Kanagawa Cancer Center, Yokohama, JapanDivision of Cancer Immunotherapy, Kanagawa Cancer Center Research Institute, Yokohama, JapanCancer Vaccine and Immunotherapy Center, Kanagawa Cancer Center, Yokohama, Japan0Department of Immunology, Yokohama City University Graduate School of Medicine, Yokohama, JapanMolecular Pathology & Genetics Division, Kanagawa Cancer Center Research Institute, Yokohama, Japan1Morphological Analysis Laboratory, Kanagawa Cancer Center Research Institute, Yokohama, JapanMolecular Pathology & Genetics Division, Kanagawa Cancer Center Research Institute, Yokohama, Japan1Morphological Analysis Laboratory, Kanagawa Cancer Center Research Institute, Yokohama, JapanMolecular Pathology & Genetics Division, Kanagawa Cancer Center Research Institute, Yokohama, JapanDepartment of Pathology, Kanagawa Cancer Center, Yokohama, Japan1Morphological Analysis Laboratory, Kanagawa Cancer Center Research Institute, Yokohama, JapanMolecular Pathology & Genetics Division, Kanagawa Cancer Center Research Institute, Yokohama, JapanDepartment of Pathology, Kanagawa Cancer Center, Yokohama, Japan0Department of Immunology, Yokohama City University Graduate School of Medicine, Yokohama, JapanDivision of Cancer Immunotherapy, Kanagawa Cancer Center Research Institute, Yokohama, JapanCancer Vaccine and Immunotherapy Center, Kanagawa Cancer Center, Yokohama, JapanMolecular Pathology & Genetics Division, Kanagawa Cancer Center Research Institute, Yokohama, JapanDepartment of Pathology, Kanagawa Cancer Center, Yokohama, JapanBackgroundStudies have shown that tumor cell amino acid metabolism is closely associated with lung adenocarcinoma (LUAD) development and progression. However, the comprehensive multi-omics features and clinical impact of the expression of genes associated with amino acid metabolism in the LUAD tumor microenvironment (TME) are yet to be fully understood.MethodsLUAD patients from The Cancer Genome Atlas (TCGA) database were enrolled in the training cohort. Using least absolute shrinkage and selection operator Cox regression analysis, we developed PTAAMG-Sig, a signature based on the expression of tumor-specific amino acid metabolism genes associated with overall survival (OS) prognosis. We evaluated its predictive performance for OS and thoroughly explored the effects of the PTAAMG-Sig risk score on the TME. The risk score was validated in two Gene Expression Omnibus (GEO) cohorts and further investigated against an original cohort of chemotherapy combined with immune checkpoint inhibitors (ICIs). Somatic mutation, chemotherapy response, immunotherapy response, gene set variation, gene set enrichment, immune infiltration, and plasma-free amino acids (PFAAs) profile analyses were performed to identify the underlying multi-omics features.ResultsTCGA datasets based PTAAMG-Sig model consisting of nine genes, KYNU, PSPH, PPAT, MIF, GCLC, ACAD8, TYRP1, ALDH2, and HDC, could effectively stratify the OS in LUAD patients. The two other GEO-independent datasets validated the robust predictive power of PTAAMG-Sig. Our differential analysis of somatic mutations in the high- and low-risk groups in TCGA cohort showed that the TP53 mutation rate was significantly higher in the high-risk group and negatively correlated with OS. Prediction from transcriptome data raised the possibility that PTAAMG-Sig could predict the response to chemotherapy and ICIs therapy. Our immunotherapy cohort confirmed the predictive ability of PTAAMG-Sig in the clinical response to ICIs therapy, which correlated with the infiltration of immune cells (e.g., T lymphocytes and nature killer cells). Corresponding to the concentrations of PFAAs, we discovered that the high PTAAMG-Sig risk score patients showed a significantly lower concentration of plasma-free α-aminobutyric acid.ConclusionIn patients with LUAD, the PTAAMG-Sig effectively predicted OS, drug sensitivity, and immunotherapy outcomes. These findings are expected to provide new targets and strategies for personalized treatment of LUAD patients.https://www.frontiersin.org/articles/10.3389/fimmu.2024.1361992/fullprognostic gene signatureamino acid metabolism pathwaylung adenocarcinomamulti-omics analysisTP53 mutationplasma-free α-aminobutyric acid |
| spellingShingle | Huihui Xiang Huihui Xiang Rika Kasajima Rika Kasajima Koichi Azuma Tomoyuki Tagami Asami Hagiwara Yoshiro Nakahara Yoshiro Nakahara Haruhiro Saito Yuka Igarashi Yuka Igarashi Feifei Wei Feifei Wei Tatsuma Ban Mitsuyo Yoshihara Mitsuyo Yoshihara Yoshiyasu Nakamura Yoshiyasu Nakamura Shinya Sato Shinya Sato Shinya Sato Shiro Koizume Shiro Koizume Tomohiko Tamura Tetsuro Sasada Tetsuro Sasada Yohei Miyagi Yohei Miyagi Multi-omics analysis-based clinical and functional significance of a novel prognostic and immunotherapeutic gene signature derived from amino acid metabolism pathways in lung adenocarcinoma Frontiers in Immunology prognostic gene signature amino acid metabolism pathway lung adenocarcinoma multi-omics analysis TP53 mutation plasma-free α-aminobutyric acid |
| title | Multi-omics analysis-based clinical and functional significance of a novel prognostic and immunotherapeutic gene signature derived from amino acid metabolism pathways in lung adenocarcinoma |
| title_full | Multi-omics analysis-based clinical and functional significance of a novel prognostic and immunotherapeutic gene signature derived from amino acid metabolism pathways in lung adenocarcinoma |
| title_fullStr | Multi-omics analysis-based clinical and functional significance of a novel prognostic and immunotherapeutic gene signature derived from amino acid metabolism pathways in lung adenocarcinoma |
| title_full_unstemmed | Multi-omics analysis-based clinical and functional significance of a novel prognostic and immunotherapeutic gene signature derived from amino acid metabolism pathways in lung adenocarcinoma |
| title_short | Multi-omics analysis-based clinical and functional significance of a novel prognostic and immunotherapeutic gene signature derived from amino acid metabolism pathways in lung adenocarcinoma |
| title_sort | multi omics analysis based clinical and functional significance of a novel prognostic and immunotherapeutic gene signature derived from amino acid metabolism pathways in lung adenocarcinoma |
| topic | prognostic gene signature amino acid metabolism pathway lung adenocarcinoma multi-omics analysis TP53 mutation plasma-free α-aminobutyric acid |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2024.1361992/full |
| work_keys_str_mv | AT huihuixiang multiomicsanalysisbasedclinicalandfunctionalsignificanceofanovelprognosticandimmunotherapeuticgenesignaturederivedfromaminoacidmetabolismpathwaysinlungadenocarcinoma AT huihuixiang multiomicsanalysisbasedclinicalandfunctionalsignificanceofanovelprognosticandimmunotherapeuticgenesignaturederivedfromaminoacidmetabolismpathwaysinlungadenocarcinoma AT rikakasajima multiomicsanalysisbasedclinicalandfunctionalsignificanceofanovelprognosticandimmunotherapeuticgenesignaturederivedfromaminoacidmetabolismpathwaysinlungadenocarcinoma AT rikakasajima multiomicsanalysisbasedclinicalandfunctionalsignificanceofanovelprognosticandimmunotherapeuticgenesignaturederivedfromaminoacidmetabolismpathwaysinlungadenocarcinoma AT koichiazuma multiomicsanalysisbasedclinicalandfunctionalsignificanceofanovelprognosticandimmunotherapeuticgenesignaturederivedfromaminoacidmetabolismpathwaysinlungadenocarcinoma AT tomoyukitagami multiomicsanalysisbasedclinicalandfunctionalsignificanceofanovelprognosticandimmunotherapeuticgenesignaturederivedfromaminoacidmetabolismpathwaysinlungadenocarcinoma AT asamihagiwara multiomicsanalysisbasedclinicalandfunctionalsignificanceofanovelprognosticandimmunotherapeuticgenesignaturederivedfromaminoacidmetabolismpathwaysinlungadenocarcinoma AT yoshironakahara multiomicsanalysisbasedclinicalandfunctionalsignificanceofanovelprognosticandimmunotherapeuticgenesignaturederivedfromaminoacidmetabolismpathwaysinlungadenocarcinoma AT yoshironakahara multiomicsanalysisbasedclinicalandfunctionalsignificanceofanovelprognosticandimmunotherapeuticgenesignaturederivedfromaminoacidmetabolismpathwaysinlungadenocarcinoma AT haruhirosaito multiomicsanalysisbasedclinicalandfunctionalsignificanceofanovelprognosticandimmunotherapeuticgenesignaturederivedfromaminoacidmetabolismpathwaysinlungadenocarcinoma AT yukaigarashi multiomicsanalysisbasedclinicalandfunctionalsignificanceofanovelprognosticandimmunotherapeuticgenesignaturederivedfromaminoacidmetabolismpathwaysinlungadenocarcinoma AT yukaigarashi multiomicsanalysisbasedclinicalandfunctionalsignificanceofanovelprognosticandimmunotherapeuticgenesignaturederivedfromaminoacidmetabolismpathwaysinlungadenocarcinoma AT feifeiwei multiomicsanalysisbasedclinicalandfunctionalsignificanceofanovelprognosticandimmunotherapeuticgenesignaturederivedfromaminoacidmetabolismpathwaysinlungadenocarcinoma AT feifeiwei multiomicsanalysisbasedclinicalandfunctionalsignificanceofanovelprognosticandimmunotherapeuticgenesignaturederivedfromaminoacidmetabolismpathwaysinlungadenocarcinoma AT tatsumaban multiomicsanalysisbasedclinicalandfunctionalsignificanceofanovelprognosticandimmunotherapeuticgenesignaturederivedfromaminoacidmetabolismpathwaysinlungadenocarcinoma AT mitsuyoyoshihara multiomicsanalysisbasedclinicalandfunctionalsignificanceofanovelprognosticandimmunotherapeuticgenesignaturederivedfromaminoacidmetabolismpathwaysinlungadenocarcinoma AT mitsuyoyoshihara multiomicsanalysisbasedclinicalandfunctionalsignificanceofanovelprognosticandimmunotherapeuticgenesignaturederivedfromaminoacidmetabolismpathwaysinlungadenocarcinoma AT yoshiyasunakamura multiomicsanalysisbasedclinicalandfunctionalsignificanceofanovelprognosticandimmunotherapeuticgenesignaturederivedfromaminoacidmetabolismpathwaysinlungadenocarcinoma AT yoshiyasunakamura multiomicsanalysisbasedclinicalandfunctionalsignificanceofanovelprognosticandimmunotherapeuticgenesignaturederivedfromaminoacidmetabolismpathwaysinlungadenocarcinoma AT shinyasato multiomicsanalysisbasedclinicalandfunctionalsignificanceofanovelprognosticandimmunotherapeuticgenesignaturederivedfromaminoacidmetabolismpathwaysinlungadenocarcinoma AT shinyasato multiomicsanalysisbasedclinicalandfunctionalsignificanceofanovelprognosticandimmunotherapeuticgenesignaturederivedfromaminoacidmetabolismpathwaysinlungadenocarcinoma AT shinyasato multiomicsanalysisbasedclinicalandfunctionalsignificanceofanovelprognosticandimmunotherapeuticgenesignaturederivedfromaminoacidmetabolismpathwaysinlungadenocarcinoma AT shirokoizume multiomicsanalysisbasedclinicalandfunctionalsignificanceofanovelprognosticandimmunotherapeuticgenesignaturederivedfromaminoacidmetabolismpathwaysinlungadenocarcinoma AT shirokoizume multiomicsanalysisbasedclinicalandfunctionalsignificanceofanovelprognosticandimmunotherapeuticgenesignaturederivedfromaminoacidmetabolismpathwaysinlungadenocarcinoma AT tomohikotamura multiomicsanalysisbasedclinicalandfunctionalsignificanceofanovelprognosticandimmunotherapeuticgenesignaturederivedfromaminoacidmetabolismpathwaysinlungadenocarcinoma AT tetsurosasada multiomicsanalysisbasedclinicalandfunctionalsignificanceofanovelprognosticandimmunotherapeuticgenesignaturederivedfromaminoacidmetabolismpathwaysinlungadenocarcinoma AT tetsurosasada multiomicsanalysisbasedclinicalandfunctionalsignificanceofanovelprognosticandimmunotherapeuticgenesignaturederivedfromaminoacidmetabolismpathwaysinlungadenocarcinoma AT yoheimiyagi multiomicsanalysisbasedclinicalandfunctionalsignificanceofanovelprognosticandimmunotherapeuticgenesignaturederivedfromaminoacidmetabolismpathwaysinlungadenocarcinoma AT yoheimiyagi multiomicsanalysisbasedclinicalandfunctionalsignificanceofanovelprognosticandimmunotherapeuticgenesignaturederivedfromaminoacidmetabolismpathwaysinlungadenocarcinoma |