{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,1]],"date-time":"2026-07-01T23:59:22Z","timestamp":1782950362324,"version":"3.54.5"},"reference-count":40,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,5,30]],"date-time":"2025-05-30T00:00:00Z","timestamp":1748563200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec><jats:title>Introduction<\/jats:title><jats:p>Epidermal growth factor receptor 2 (<jats:italic>HER2<\/jats:italic>) 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.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>In 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. <jats:italic>HER2<\/jats:italic> amplification was further validated using FISH in 254 patients. We analyzed the clinical and molecular characteristics of the subgroups based on <jats:italic>HER2<\/jats:italic> amplification and PD-L1 CPS scores.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results and discussion<\/jats:title><jats:p>The highest consistency with FISH for <jats:italic>HER2<\/jats:italic> amplification was observed when the positive threshold for NGS detection was set to 2.5. <jats:italic>TP53<\/jats:italic> mutation rate peaked at 59%, which was significantly higher in cases with <jats:italic>HER2<\/jats:italic> amplification (P&amp;lt;0.01). Patients with both <jats:italic>HER2<\/jats:italic> amplification and <jats:italic>TP53<\/jats:italic> mutations exhibited notably shorter survival rates than cases with only <jats:italic>TP53<\/jats:italic> mutations (P&amp;lt;0.05). Furthermore, <jats:italic>HER2<\/jats:italic> 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 \u22655 demonstrate an enrichment of mutations in key signaling pathways, such as PI3K, TGF\u03b2, and Wnt\/\u03b2-catenin.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Overall, our study highlights the prognostic significance of <jats:italic>HER2<\/jats:italic> 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.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fimmu.2025.1567308","type":"journal-article","created":{"date-parts":[[2025,5,30]],"date-time":"2025-05-30T05:47:40Z","timestamp":1748584060000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":7,"title":["Decoding the molecular landscape: HER2 and PD-L1 in advanced gastric cancer"],"prefix":"10.3389","volume":"16","author":[{"given":"Jun","family":"Yao","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiang","family":"Sun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Han","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaokai","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pengmin","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaozhi","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xintao","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meiping","family":"Gu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jieyi","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuansi","family":"Zheng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ziying","family":"Gong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daoyun","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weijun","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,5,30]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"12","DOI":"10.3322\/caac.21820","article-title":"Cancer statistics, 2024","volume":"74","author":"Siegel","year":"2024","journal-title":"CA: A Cancer J clinicians"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1038\/nature13480","article-title":"Comprehensive molecular characterization of gastric adenocarcinoma","volume":"513","year":"2014","journal-title":"Nature"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(10)61121-X","article-title":"Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial","volume":"376","author":"Bang","year":"2010","journal-title":"Lancet (London England)"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-021-04161-3","article-title":"The KEYNOTE-811 trial of dual PD-1 and HER2 blockade in HER2-positive gastric cancer","volume":"600","author":"Janjigian","year":"2021","journal-title":"Nature"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1016\/j.annonc.2022.07.004","article-title":"Gastric cancer: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up","volume":"33","author":"Lordick","year":"2022","journal-title":"Ann oncology: Off J Eur Soc Med Oncology"},{"key":"B6","doi-asserted-by":"publisher","first-page":"102226","DOI":"10.1016\/j.esmoop.2023.102226","article-title":"Pan-Asian adapted ESMO Clinical Practice Guidelines for the diagnosis, treatment and follow-up of patients with gastric cancer","volume":"9","author":"Shitara","year":"2024","journal-title":"ESMO Open"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2015.62.6598","article-title":"Lapatinib in combination with capecitabine plus oxaliplatin in human epidermal growth factor receptor 2-positive advanced or metastatic gastric, esophageal, or gastroesophageal adenocarcinoma: TRIO-013\/LOGiC\u2013a randomized phase III trial","volume":"34","author":"Hecht","year":"2016","journal-title":"J Clin oncology: Off J Am Soc Clin Oncology"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2013.53.6136","article-title":"Lapatinib plus paclitaxel versus paclitaxel alone in the second-line treatment of HER2-amplified advanced gastric cancer in Asian populations: TyTAN\u2013a randomized, phase III study","volume":"32","author":"Satoh","year":"2014","journal-title":"J Clin oncology: Off J Am Soc Clin Oncology"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1016\/S1470-2045(17)30111-0","article-title":"Trastuzumab emtansine versus taxane use for previously treated HER2-positive locally advanced or metastatic gastric or gastro-oesophageal junction adenocarcinoma (GATSBY): an international randomised, open-label, adaptive, phase 2\/3 study","volume":"18","author":"Thuss-Patience","year":"2017","journal-title":"Lancet Oncology"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1016\/j.annonc.2024.08.1466","article-title":"1400O Final overall survival for the phase III, KEYNOTE-811 study of pembrolizumab plus trastuzumab and chemotherapy for HER2+ advanced, unresectable or metastatic G\/GEJ adenocarcinoma","volume":"35","author":"Janjigian","year":"2024","journal-title":"Ann Oncology"},{"key":"B11","doi-asserted-by":"publisher","first-page":"27","DOI":"10.1016\/S0140-6736(21)00797-2","article-title":"First-line nivolumab plus chemotherapy versus chemotherapy alone for advanced gastric, gastro-oesophageal junction, and oesophageal adenocarcinoma (CheckMate 649): a randomised, open-label, phase 3 trial","volume":"398","author":"Janjigian","year":"2021","journal-title":"Lancet (London England)"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1016\/S1470-2045(23)00515-6","article-title":"Pembrolizumab plus chemotherapy versus placebo plus chemotherapy for HER2-negative advanced gastric cancer (KEYNOTE-859): a multicentre, randomised, double-blind, phase 3 trial","volume":"24","author":"Rha","year":"2023","journal-title":"Lancet Oncology"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(21)01234-4","article-title":"Pembrolizumab plus chemotherapy versus chemotherapy alone for first-line treatment of advanced oesophageal cancer (KEYNOTE-590): a randomised, placebo-controlled, phase 3 study","volume":"398","author":"Sun","year":"2021","journal-title":"Lancet (London England)"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1136\/bmj-2023-078876","article-title":"Tislelizumab plus chemotherapy versus placebo plus chemotherapy as first line treatment for advanced gastric or gastro-oesophageal junction adenocarcinoma: RATIONALE-305 randomised, double blind, phase 3 trial","volume":"385","author":"Qiu","year":"2024","journal-title":"BMJ (Clinical Res ed)"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1093\/bib\/bbaa402","article-title":"MSIsensor-ct: microsatellite instability detection using cfDNA sequencing data","volume":"22","author":"Han","year":"2021","journal-title":"Briefings Bioinf"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btu436","article-title":"Multi-factor data normalization enables the detection of copy number aberrations in amplicon sequencing data","volume":"30","author":"Boeva","year":"2014","journal-title":"Bioinformatics"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1016\/j.dld.2022.01.128","article-title":"PD-L1 and HER2 expression in gastric adenocarcinoma and their prognostic significance","volume":"54","author":"Lian","year":"2022","journal-title":"Digestive liver disease: Off J Ital Soc Gastroenterology Ital Assoc Study Liver"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1097\/PAI.0000000000000408","article-title":"Development of a companion diagnostic PD-L1 immunohistochemistry assay for pembrolizumab therapy in non-small-cell lung cancer","volume":"24","author":"Roach","year":"2016","journal-title":"Appl immunohistochemistry Mol morphology: AIMM"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1002\/imt2.v1.3","article-title":"Sangerbox: A comprehensive, interaction-friendly clinical bioinformatics analysis platform","volume":"1","author":"Shen","year":"2022","journal-title":"iMeta"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1101\/gr.239244.118","article-title":"Maftools: efficient and comprehensive analysis of somatic variants in cancer","volume":"28","author":"Mayakonda","year":"2018","journal-title":"Genome Res"},{"key":"B21","doi-asserted-by":"publisher","first-page":"371","DOI":"10.1016\/j.cell.2018.02.060","article-title":"Comprehensive characterization of cancer driver genes and mutations","volume":"173","author":"Bailey","year":"2018","journal-title":"Cell"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.3748\/wjg.v22.i19.4619","article-title":"HER2 testing in gastric cancer: An update","volume":"22","author":"Abrahao-MaChado","year":"2016","journal-title":"World J gastroenterology"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1016\/j.jmoldx.2016.09.010","article-title":"Next-generation assessment of human epidermal growth factor receptor 2 (ERBB2) amplification status: Clinical validation in the context of a hybrid capture-based, comprehensive solid tumor genomic profiling assay","volume":"19","author":"Ross","year":"2017","journal-title":"J Mol diagnostics: JMD"},{"key":"B24","doi-asserted-by":"publisher","first-page":"498","DOI":"10.1111\/his.14241","article-title":"Next-generation assessment of human epidermal growth factor receptor 2 gene (ERBB2) amplification status in invasive breast carcinoma: a focus on Group 4 by use of the 2018 American Society of Clinical Oncology\/College of American Pathologists HER2 testing guideline","volume":"78","author":"Hoda","year":"2021","journal-title":"Histopathology"},{"key":"B25","doi-asserted-by":"publisher","first-page":"439","DOI":"10.1038\/s41419-018-0463-7","article-title":"APR-246 reactivates mutant p53 by targeting cysteines 124 and 277","volume":"9","author":"Zhang","year":"2018","journal-title":"Cell Death disease"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1136\/gutjnl-2015-309770","article-title":"APR-246 potently inhibits tumour growth and overcomes chemoresistance in preclinical models of oesophageal adenocarcinoma","volume":"64","author":"Liu","year":"2015","journal-title":"Gut"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1038\/nature13480","article-title":"Comprehensive molecular characterization of gastric adenocarcinoma","volume":"513","year":"2014","journal-title":"Nature"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1002\/cam4.2018.7.issue-6","article-title":"Programmed death-ligand 1 expression in gastric cancer: correlation with mismatch repair deficiency and HER2-negative status","volume":"7","author":"Wang","year":"2018","journal-title":"Cancer medicine"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.3390\/cancers16061227","article-title":"HER2 and PD-L1 expression in gastric and gastroesophageal junction cancer: insights for combinatorial targeting approaches","volume":"16","author":"Freitas","year":"2024","journal-title":"Cancers"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1002\/cam4.v12.24","article-title":"The genomic and immune landscapes of gastric cancer and their correlations with HER2 amplification and PD-L1 expression","volume":"12","author":"Jing","year":"2023","journal-title":"Cancer medicine"},{"key":"B31","doi-asserted-by":"publisher","first-page":"169","DOI":"10.1186\/s12943-024-02085-w","article-title":"Implications of PD-L1 expression on the immune microenvironment in HER2-positive gastric cancer","volume":"23","author":"Chen","year":"2024","journal-title":"Mol cancer"},{"key":"B32","doi-asserted-by":"publisher","first-page":"101420","DOI":"10.1016\/j.jbc.2021.101420","article-title":"A bispecific antibody targeting HER2 and PD-L1 inhibits tumor growth with superior efficacy","volume":"297","author":"Chen","year":"2021","journal-title":"J Biol Chem"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1002\/jbt.v37.10","article-title":"Cbl induced ubiquitination of HER2 mediate immune escape from HER2-targeted CAR-T","volume":"37","author":"Yang","year":"2023","journal-title":"J Biochem Mol toxicology"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1007\/s13577-023-00990-8","article-title":"Tracking circulating PD-L1-positive cells to monitor the outcome of patients with gastric cancer receiving anti-HER2 plus anti-PD-1 therapy","volume":"37","author":"Chong","year":"2024","journal-title":"Hum Cell"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1002\/ijc.v131.2","article-title":"Microsatellite instability in sporadic gastric cancer: its prognostic role and guidance for 5-FU based chemotherapy after R0 resection","volume":"131","author":"An","year":"2012","journal-title":"Int J cancer"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-cancerbio-070620-103554","article-title":"TGF\u03b2: signaling blockade for cancer immunotherapy","volume":"6","author":"Chen","year":"2022","journal-title":"Annu Rev Cancer Biol"},{"key":"B37","doi-asserted-by":"publisher","first-page":"1956173","DOI":"10.1080\/2162402X.2021.1956173","article-title":"Association of PIK3CA mutation and PTEN loss with expression of CD274 (PD-L1) in colorectal carcinoma","volume":"10","author":"Ugai","year":"2021","journal-title":"Oncoimmunology"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1038\/nm1517","article-title":"Loss of tumor suppressor PTEN function increases B7-H1 expression and immunoresistance in glioma","volume":"13","author":"Parsa","year":"2007","journal-title":"Nat Medicine"},{"key":"B39","article-title":"PTEN\/PI3K\/mTOR\/B7-H1 signaling pathway regulates cell progression and immuno-resistance in pancreatic cancer","volume":"60","author":"Zhang","year":"2013","journal-title":"Hepatogastroenterology"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1038\/s41423-020-00549-9","article-title":"The innate immune effector ISG12a promotes cancer immunity by suppressing the canonical Wnt\/\u03b2-catenin signaling pathway","volume":"17","author":"Deng","year":"2020","journal-title":"Cell Mol Immunol"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2025.1567308\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,5,30]],"date-time":"2025-05-30T05:47:41Z","timestamp":1748584061000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2025.1567308\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,5,30]]},"references-count":40,"alternative-id":["10.3389\/fimmu.2025.1567308"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2025.1567308","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,5,30]]},"article-number":"1567308"}}