Genomic and transcriptomic profiling indicates the prognosis significance of mutational signature for TMB-high subtype in Chinese patients with gastric cancer
Introduction: Gastric cancer (GC)is the third leading cause of cancer-related deaths in China and immunotherapy emerging as a revolutionary treatment for GC recently. Tumor mutational burden (TMB) is a predictive biomarker of immunotherapy in multiple cancers. However, the prognostic significance an...
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| Format: | Article |
| Language: | English |
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Elsevier
2023-09-01
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| Series: | Journal of Advanced Research |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S209012322200248X |
| _version_ | 1797729981671931904 |
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| author | Yanan Cheng Dechao Bu Qiaoling Zhang Rebecca Sun Stephen Lyle Gang Zhao Li Dong Hui Li Yi Zhao Jinpu Yu Xishan Hao |
| author_facet | Yanan Cheng Dechao Bu Qiaoling Zhang Rebecca Sun Stephen Lyle Gang Zhao Li Dong Hui Li Yi Zhao Jinpu Yu Xishan Hao |
| author_sort | Yanan Cheng |
| collection | DOAJ |
| description | Introduction: Gastric cancer (GC)is the third leading cause of cancer-related deaths in China and immunotherapy emerging as a revolutionary treatment for GC recently. Tumor mutational burden (TMB) is a predictive biomarker of immunotherapy in multiple cancers. However, the prognostic significance and subtype of TMB in GC is not fully understood. Objectives: This study aims to evaluate the prognostic value of TMB in Chinese GC and further classify TMB-high GC (GCTMB-H) patients combing with mutational signatures. Methods: Genomic profiling of 435 cancer-gene panel was performed using 206 GC samples from Chinese people. Actionable genetic alterations were compared across all the samples to generate actionable subtyping. The prognostic value of TMB in Chinese GC was evaluated. Mutational signatures were analyzed on TMB-H subtype to stratify the prognosis of TMB. Transcriptomic analysis was applied to compare the distributed immunocytes among different subtypes. Results: 88.3% (182/206) of GC samples had at least one mutation, while 45.1% (93/206) had at least one somatic copy number alteration (SCNA). 29.6% (61/206) of GC samples were TMB-H, including 13 MSI-H and 48 MSS tumors. According to distinct genetic alteration profiles of 69 actionable genes, we classified GC samples into eight molecular subtypes, including TMB-H, ERBB2 amplified, ATM mutated, BRCA2 mutated, CDKN2A/B deleted, PI3KCA mutated, KRAS mutated, and less-mutated subtype. TMB-H subtype presented a remarkable immune-activated phenotype as determined by transcriptomic analysis that was further validated in the TCGA GC cohort. GCTMB-H patients exhibited significantly better survival (P = 0.047). But Signature 1-high GCTMB-H patients had relatively worse prognosis (P = 0.0209, HR = 2.571) than Signature 1-low GCTMB-H patients from Chinese GC cohort, also validated in TCGA GC cohort, presenting highly activated carbohydrate, fatty acid or lipid metabolism. Conclusion: The Signature 1-high GCTMB-H could be a marker of poor prognosis and is associated with metabolism disorder. |
| first_indexed | 2024-03-12T11:37:28Z |
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| id | doaj.art-8a089f979dcf4158a3517f704a3669a5 |
| institution | Directory Open Access Journal |
| issn | 2090-1232 |
| language | English |
| last_indexed | 2024-03-12T11:37:28Z |
| publishDate | 2023-09-01 |
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| spelling | doaj.art-8a089f979dcf4158a3517f704a3669a52023-09-01T05:01:02ZengElsevierJournal of Advanced Research2090-12322023-09-0151121134Genomic and transcriptomic profiling indicates the prognosis significance of mutational signature for TMB-high subtype in Chinese patients with gastric cancerYanan Cheng0Dechao Bu1Qiaoling Zhang2Rebecca Sun3Stephen Lyle4Gang Zhao5Li Dong6Hui Li7Yi Zhao8Jinpu Yu9Xishan Hao10Cancer Molecular Diagnostics Core, Tianjin Medical University Cancer Institute & Hospital, Key Laboratory of Cancer Prevention and Therapy, Key Laboratory of Cancer Immunology and Biotherapy, Tianjin, China; National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Tianjin, ChinaResearch Center for Ubiquitous Computing Systems, Key Laboratory of Intelligent Information Processing, Advanced Computer Research Center, Institute of Computing Technology, Chinese Academy of Sciences, Beijing, ChinaCancer Molecular Diagnostics Core, Tianjin Medical University Cancer Institute & Hospital, Key Laboratory of Cancer Prevention and Therapy, Key Laboratory of Cancer Immunology and Biotherapy, Tianjin, China; National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Tianjin, ChinaKEW, Inc., 303 Wyman Street, Waltham, MA, USAKEW, Inc., 303 Wyman Street, Waltham, MA, USADepartment of Gastrointestinal Cancer Biology, Tianjin Medical University Cancer Institute & Hospital, Tianjin, ChinaCancer Molecular Diagnostics Core, Tianjin Medical University Cancer Institute & Hospital, Key Laboratory of Cancer Prevention and Therapy, Key Laboratory of Cancer Immunology and Biotherapy, Tianjin, China; National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Tianjin, ChinaDepartment of Gastrointestinal Cancer Biology, Tianjin Medical University Cancer Institute & Hospital, Tianjin, ChinaResearch Center for Ubiquitous Computing Systems, Key Laboratory of Intelligent Information Processing, Advanced Computer Research Center, Institute of Computing Technology, Chinese Academy of Sciences, Beijing, China; Corresponding authors at: Institute of Computing Technology, Chinese Academy of Sciences, No.6 Kexueyuan South Road Zhongguancun, Haidian District, Beijing 100190, China (Y. Zhao). Tianjin Medical University Cancer Institute and Hospital, Huanhuxi Road, Ti-Yuan-Bei, Hexi District, Tianjin 300060, China (J. Yu). Tianjin Medical University Cancer Institute and Hospital, Huanhuxi Road, Ti-Yuan-Bei, Hexi District, Tianjin 300060, China (X. Hao).Cancer Molecular Diagnostics Core, Tianjin Medical University Cancer Institute & Hospital, Key Laboratory of Cancer Prevention and Therapy, Key Laboratory of Cancer Immunology and Biotherapy, Tianjin, China; National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Tianjin, China; Corresponding authors at: Institute of Computing Technology, Chinese Academy of Sciences, No.6 Kexueyuan South Road Zhongguancun, Haidian District, Beijing 100190, China (Y. Zhao). Tianjin Medical University Cancer Institute and Hospital, Huanhuxi Road, Ti-Yuan-Bei, Hexi District, Tianjin 300060, China (J. Yu). Tianjin Medical University Cancer Institute and Hospital, Huanhuxi Road, Ti-Yuan-Bei, Hexi District, Tianjin 300060, China (X. Hao).Cancer Molecular Diagnostics Core, Tianjin Medical University Cancer Institute & Hospital, Key Laboratory of Cancer Prevention and Therapy, Key Laboratory of Cancer Immunology and Biotherapy, Tianjin, China; National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Tianjin, China; Corresponding authors at: Institute of Computing Technology, Chinese Academy of Sciences, No.6 Kexueyuan South Road Zhongguancun, Haidian District, Beijing 100190, China (Y. Zhao). Tianjin Medical University Cancer Institute and Hospital, Huanhuxi Road, Ti-Yuan-Bei, Hexi District, Tianjin 300060, China (J. Yu). Tianjin Medical University Cancer Institute and Hospital, Huanhuxi Road, Ti-Yuan-Bei, Hexi District, Tianjin 300060, China (X. Hao).Introduction: Gastric cancer (GC)is the third leading cause of cancer-related deaths in China and immunotherapy emerging as a revolutionary treatment for GC recently. Tumor mutational burden (TMB) is a predictive biomarker of immunotherapy in multiple cancers. However, the prognostic significance and subtype of TMB in GC is not fully understood. Objectives: This study aims to evaluate the prognostic value of TMB in Chinese GC and further classify TMB-high GC (GCTMB-H) patients combing with mutational signatures. Methods: Genomic profiling of 435 cancer-gene panel was performed using 206 GC samples from Chinese people. Actionable genetic alterations were compared across all the samples to generate actionable subtyping. The prognostic value of TMB in Chinese GC was evaluated. Mutational signatures were analyzed on TMB-H subtype to stratify the prognosis of TMB. Transcriptomic analysis was applied to compare the distributed immunocytes among different subtypes. Results: 88.3% (182/206) of GC samples had at least one mutation, while 45.1% (93/206) had at least one somatic copy number alteration (SCNA). 29.6% (61/206) of GC samples were TMB-H, including 13 MSI-H and 48 MSS tumors. According to distinct genetic alteration profiles of 69 actionable genes, we classified GC samples into eight molecular subtypes, including TMB-H, ERBB2 amplified, ATM mutated, BRCA2 mutated, CDKN2A/B deleted, PI3KCA mutated, KRAS mutated, and less-mutated subtype. TMB-H subtype presented a remarkable immune-activated phenotype as determined by transcriptomic analysis that was further validated in the TCGA GC cohort. GCTMB-H patients exhibited significantly better survival (P = 0.047). But Signature 1-high GCTMB-H patients had relatively worse prognosis (P = 0.0209, HR = 2.571) than Signature 1-low GCTMB-H patients from Chinese GC cohort, also validated in TCGA GC cohort, presenting highly activated carbohydrate, fatty acid or lipid metabolism. Conclusion: The Signature 1-high GCTMB-H could be a marker of poor prognosis and is associated with metabolism disorder.http://www.sciencedirect.com/science/article/pii/S209012322200248XGastric cancerComprehensive genomic profilingTMBMutational signatureTumor metabolism |
| spellingShingle | Yanan Cheng Dechao Bu Qiaoling Zhang Rebecca Sun Stephen Lyle Gang Zhao Li Dong Hui Li Yi Zhao Jinpu Yu Xishan Hao Genomic and transcriptomic profiling indicates the prognosis significance of mutational signature for TMB-high subtype in Chinese patients with gastric cancer Journal of Advanced Research Gastric cancer Comprehensive genomic profiling TMB Mutational signature Tumor metabolism |
| title | Genomic and transcriptomic profiling indicates the prognosis significance of mutational signature for TMB-high subtype in Chinese patients with gastric cancer |
| title_full | Genomic and transcriptomic profiling indicates the prognosis significance of mutational signature for TMB-high subtype in Chinese patients with gastric cancer |
| title_fullStr | Genomic and transcriptomic profiling indicates the prognosis significance of mutational signature for TMB-high subtype in Chinese patients with gastric cancer |
| title_full_unstemmed | Genomic and transcriptomic profiling indicates the prognosis significance of mutational signature for TMB-high subtype in Chinese patients with gastric cancer |
| title_short | Genomic and transcriptomic profiling indicates the prognosis significance of mutational signature for TMB-high subtype in Chinese patients with gastric cancer |
| title_sort | genomic and transcriptomic profiling indicates the prognosis significance of mutational signature for tmb high subtype in chinese patients with gastric cancer |
| topic | Gastric cancer Comprehensive genomic profiling TMB Mutational signature Tumor metabolism |
| url | http://www.sciencedirect.com/science/article/pii/S209012322200248X |
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