Decoding the molecular landscape: HER2 and PD-L1 in advanced gastric cancer
IntroductionEpidermal growth factor receptor 2 (HER2) and programmed cell death ligand 1 (PD-L1) are pivotal therapeutic targets for advanced gastric cancer (GC). Nevertheless, the correlation between them, along with the clinical and genomic characteristics and prognosis differences across distinct...
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Frontiers Media S.A.
2025-05-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2025.1567308/full |
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| author | Jun Yao Qiang Sun Han Wu Xiaokai Zhao Pengmin Yang Xiaozhi Wang Xintao Wang Meiping Gu Jieyi Li Yuansi Zheng Ziying Gong Daoyun Zhang Weijun Wang |
| author_facet | Jun Yao Qiang Sun Han Wu Xiaokai Zhao Pengmin Yang Xiaozhi Wang Xintao Wang Meiping Gu Jieyi Li Yuansi Zheng Ziying Gong Daoyun Zhang Weijun Wang |
| author_sort | Jun Yao |
| collection | DOAJ |
| description | IntroductionEpidermal growth factor receptor 2 (HER2) and programmed cell death ligand 1 (PD-L1) are pivotal therapeutic targets for advanced gastric cancer (GC). Nevertheless, the correlation between them, along with the clinical and genomic characteristics and prognosis differences across distinct molecular subtypes, remains elusive.MethodsIn this retrospective study, 390 advanced GC patients provided both tumor tissue and paired blood samples for Next-Generation Sequencing (NGS) of 639 tumor-related genes, along with PD-L1 immunohistochemical staining. HER2 amplification was further validated using FISH in 254 patients. We analyzed the clinical and molecular characteristics of the subgroups based on HER2 amplification and PD-L1 CPS scores.Results and discussionThe highest consistency with FISH for HER2 amplification was observed when the positive threshold for NGS detection was set to 2.5. TP53 mutation rate peaked at 59%, which was significantly higher in cases with HER2 amplification (P<0.01). Patients with both HER2 amplification and TP53 mutations exhibited notably shorter survival rates than cases with only TP53 mutations (P<0.05). Furthermore, HER2 amplification did not correlate with PD-L1 expression. A stratified analysis of PD-L1 expression revealed distinct clinical and molecular features. When the CPS threshold is set at 5, 10, and 20, PD-L1 positive patients have a significantly higher proportion of high tumor mutational burden (TMB-H) and high microsatellite instability (MSI-H) status compared to PD-L1 negative patients. Additionally, patients with PD-L1 CPS ≥5 demonstrate an enrichment of mutations in key signaling pathways, such as PI3K, TGFβ, and Wnt/β-catenin.ConclusionOverall, our study highlights the prognostic significance of HER2 amplification and TP53 mutations in patients with advanced GC. Stratified analysis of PD-L1 expression may help to identify candidates for targeted immunotherapy in this patient population. |
| format | Article |
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| institution | OA Journals |
| issn | 1664-3224 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | Frontiers Media S.A. |
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| series | Frontiers in Immunology |
| spelling | doaj-art-ea0a1658169e46d7858dcfd4890601a42025-08-20T02:34:50ZengFrontiers Media S.A.Frontiers in Immunology1664-32242025-05-011610.3389/fimmu.2025.15673081567308Decoding the molecular landscape: HER2 and PD-L1 in advanced gastric cancerJun Yao0Qiang Sun1Han Wu2Xiaokai Zhao3Pengmin Yang4Xiaozhi Wang5Xintao Wang6Meiping Gu7Jieyi Li8Yuansi Zheng9Ziying Gong10Daoyun Zhang11Weijun Wang12Department of Gastrointestinal Surgery, Changzheng Hospital, Naval Medical University, Shanghai, ChinaDepartment of Gastrointestinal Surgery, Changzheng Hospital, Naval Medical University, Shanghai, ChinaDepartment of Gastrointestinal Surgery, Changzheng Hospital, Naval Medical University, Shanghai, ChinaJiaxing Key Laboratory of Precision Medicine and Companion Diagnostics, Jiaxing Yunying Medical Inspection Co., Ltd., Jiaxing, ChinaJiaxing Key Laboratory of Precision Medicine and Companion Diagnostics, Jiaxing Yunying Medical Inspection Co., Ltd., Jiaxing, ChinaJiaxing Key Laboratory of Precision Medicine and Companion Diagnostics, Jiaxing Yunying Medical Inspection Co., Ltd., Jiaxing, ChinaJiaxing Key Laboratory of Precision Medicine and Companion Diagnostics, Jiaxing Yunying Medical Inspection Co., Ltd., Jiaxing, ChinaJiaxing Key Laboratory of Precision Medicine and Companion Diagnostics, Jiaxing Yunying Medical Inspection Co., Ltd., Jiaxing, ChinaJiaxing Key Laboratory of Precision Medicine and Companion Diagnostics, Jiaxing Yunying Medical Inspection Co., Ltd., Jiaxing, ChinaDepartment of Pathology, Zhejiang Cancer Hospital, Hangzhou, Zhejiang, ChinaJiaxing Key Laboratory of Precision Medicine and Companion Diagnostics, Jiaxing Yunying Medical Inspection Co., Ltd., Jiaxing, ChinaJiaxing Key Laboratory of Precision Medicine and Companion Diagnostics, Jiaxing Yunying Medical Inspection Co., Ltd., Jiaxing, ChinaDepartment of Gastrointestinal Surgery, Changzheng Hospital, Naval Medical University, Shanghai, ChinaIntroductionEpidermal growth factor receptor 2 (HER2) and programmed cell death ligand 1 (PD-L1) are pivotal therapeutic targets for advanced gastric cancer (GC). Nevertheless, the correlation between them, along with the clinical and genomic characteristics and prognosis differences across distinct molecular subtypes, remains elusive.MethodsIn this retrospective study, 390 advanced GC patients provided both tumor tissue and paired blood samples for Next-Generation Sequencing (NGS) of 639 tumor-related genes, along with PD-L1 immunohistochemical staining. HER2 amplification was further validated using FISH in 254 patients. We analyzed the clinical and molecular characteristics of the subgroups based on HER2 amplification and PD-L1 CPS scores.Results and discussionThe highest consistency with FISH for HER2 amplification was observed when the positive threshold for NGS detection was set to 2.5. TP53 mutation rate peaked at 59%, which was significantly higher in cases with HER2 amplification (P<0.01). Patients with both HER2 amplification and TP53 mutations exhibited notably shorter survival rates than cases with only TP53 mutations (P<0.05). Furthermore, HER2 amplification did not correlate with PD-L1 expression. A stratified analysis of PD-L1 expression revealed distinct clinical and molecular features. When the CPS threshold is set at 5, 10, and 20, PD-L1 positive patients have a significantly higher proportion of high tumor mutational burden (TMB-H) and high microsatellite instability (MSI-H) status compared to PD-L1 negative patients. Additionally, patients with PD-L1 CPS ≥5 demonstrate an enrichment of mutations in key signaling pathways, such as PI3K, TGFβ, and Wnt/β-catenin.ConclusionOverall, our study highlights the prognostic significance of HER2 amplification and TP53 mutations in patients with advanced GC. Stratified analysis of PD-L1 expression may help to identify candidates for targeted immunotherapy in this patient population.https://www.frontiersin.org/articles/10.3389/fimmu.2025.1567308/fullHER2 amplificationTP53 mutationPD-L1 CPS strataadvanced gastric cancerprognosis |
| spellingShingle | Jun Yao Qiang Sun Han Wu Xiaokai Zhao Pengmin Yang Xiaozhi Wang Xintao Wang Meiping Gu Jieyi Li Yuansi Zheng Ziying Gong Daoyun Zhang Weijun Wang Decoding the molecular landscape: HER2 and PD-L1 in advanced gastric cancer Frontiers in Immunology HER2 amplification TP53 mutation PD-L1 CPS strata advanced gastric cancer prognosis |
| title | Decoding the molecular landscape: HER2 and PD-L1 in advanced gastric cancer |
| title_full | Decoding the molecular landscape: HER2 and PD-L1 in advanced gastric cancer |
| title_fullStr | Decoding the molecular landscape: HER2 and PD-L1 in advanced gastric cancer |
| title_full_unstemmed | Decoding the molecular landscape: HER2 and PD-L1 in advanced gastric cancer |
| title_short | Decoding the molecular landscape: HER2 and PD-L1 in advanced gastric cancer |
| title_sort | decoding the molecular landscape her2 and pd l1 in advanced gastric cancer |
| topic | HER2 amplification TP53 mutation PD-L1 CPS strata advanced gastric cancer prognosis |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2025.1567308/full |
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