Genomic and clinical characterization of HER2 exon 20 mutations in non-small cell lung cancer: insights from a multicenter study in South China
Abstract Background The objective of this study was to investigate the clinical and genetic characteristics and clinical relevance of HER2 exon 20 oncogenic variants in non-small cell lung cancer (NSCLC) patients. Methods This prospective study analyzed 51 NSCLC patients with HER2 mutations, identif...
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2025-04-01
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| Online Access: | https://doi.org/10.1186/s12885-025-14125-9 |
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| author | Yating Hou Xingyang Xue Zhuoyun Zhang Dahai Mai Wei Luo Mingyu Zhou Zichuan Liu Yisheng Huang |
| author_facet | Yating Hou Xingyang Xue Zhuoyun Zhang Dahai Mai Wei Luo Mingyu Zhou Zichuan Liu Yisheng Huang |
| author_sort | Yating Hou |
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| description | Abstract Background The objective of this study was to investigate the clinical and genetic characteristics and clinical relevance of HER2 exon 20 oncogenic variants in non-small cell lung cancer (NSCLC) patients. Methods This prospective study analyzed 51 NSCLC patients with HER2 mutations, identified via next-generation sequencing (NGS) of tissue, blood, cerebrospinal fluid, or pleural effusion samples. Patients were grouped based on the presence of exon 20 mutations (exon 20 vs. non-exon 20) and further divided based on whether they had received prior anti-tumor treatments (baseline vs. non-baseline). Clinical and genetic data, treatment responses were analyzed. Progression-free survival (PFS) and overall survival (OS) were evaluated using Kaplan-Meier methods and compared with log-rank tests. Gene ontology (GO) analysis was performed to uncover the biological significance of the mutated genes. Results In a cohort of 651 NSCLC patients, 51 (7.83%) harbored HER2 alterations, including 20 (3.08%) with exon 20 mutations. The median age of the HER2-altered subgroup was 58.5 years. Adenocarcinoma was the most prevalent subtype (96.1%), and most patients presented at stage IV (72.5%). The most common metastatic sites were the lungs (68.6%), lymph nodes (52.9%), and brain (43.1%). Among the HER2 mutated patients, 20 (39.3%) had exon 20 mutations. Exon 20 mutations were more prevalent in the non-baseline group (55.0% vs. 29.0%, P = 0.049) and males (75.0%, P = 0.025). These mutations were associated with a higher rate of metastasis to the lungs, lymph nodes (P < 0.001). Patients with exon 20 mutations demonstrated poorer overall survival (OS) outcomes (P = 0.048). No significant differences were observed in age, smoking history, histological subtype, or TNM stage at diagnosis between groups. The majority of exon 20 mutations were in-frame indel mutations (92.0%), with the most common specific mutation being p.Y772_A775dup (70%). Gene Ontology (GO) analysis linked exon 20 mutations to unregulated protein kinase activity and anoikis. Conclusions Our study found that NSCLC patients with HER2 exon 20 oncogenic variants have a higher risk of metastasis and drug resistance, leading to worse outcomes than non-exon 20 mutations. This highlights the urgent need for targeted therapies aimed at exon 20 insertions to improve survival and treatment outcomes in this subgroup. |
| format | Article |
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| spelling | doaj-art-d70c602aa503402c8c09731febc673762025-08-20T02:20:25ZengBMCBMC Cancer1471-24072025-04-0125111010.1186/s12885-025-14125-9Genomic and clinical characterization of HER2 exon 20 mutations in non-small cell lung cancer: insights from a multicenter study in South ChinaYating Hou0Xingyang Xue1Zhuoyun Zhang2Dahai Mai3Wei Luo4Mingyu Zhou5Zichuan Liu6Yisheng Huang7Department of Oncology, Maoming People’s HospitalDepartment of Thoracic Surgery and Oncology, State Key Laboratory of Respiratory Disease, The First Affiliated Hospital of Guangzhou Medical University, National Clinical Research Centre for Respiratory DiseaseDepartment of Oncology, Maoming People’s HospitalDepartment of Oncology, Maoming People’s HospitalDepartment of Oncology, Maoming People’s HospitalDepartment of Oncology, Maoming People’s HospitalInternal Medicine Section 2, Affiliated Cancer Hospital & Institute of Guangzhou Medical UniversityDepartment of Oncology, Maoming People’s HospitalAbstract Background The objective of this study was to investigate the clinical and genetic characteristics and clinical relevance of HER2 exon 20 oncogenic variants in non-small cell lung cancer (NSCLC) patients. Methods This prospective study analyzed 51 NSCLC patients with HER2 mutations, identified via next-generation sequencing (NGS) of tissue, blood, cerebrospinal fluid, or pleural effusion samples. Patients were grouped based on the presence of exon 20 mutations (exon 20 vs. non-exon 20) and further divided based on whether they had received prior anti-tumor treatments (baseline vs. non-baseline). Clinical and genetic data, treatment responses were analyzed. Progression-free survival (PFS) and overall survival (OS) were evaluated using Kaplan-Meier methods and compared with log-rank tests. Gene ontology (GO) analysis was performed to uncover the biological significance of the mutated genes. Results In a cohort of 651 NSCLC patients, 51 (7.83%) harbored HER2 alterations, including 20 (3.08%) with exon 20 mutations. The median age of the HER2-altered subgroup was 58.5 years. Adenocarcinoma was the most prevalent subtype (96.1%), and most patients presented at stage IV (72.5%). The most common metastatic sites were the lungs (68.6%), lymph nodes (52.9%), and brain (43.1%). Among the HER2 mutated patients, 20 (39.3%) had exon 20 mutations. Exon 20 mutations were more prevalent in the non-baseline group (55.0% vs. 29.0%, P = 0.049) and males (75.0%, P = 0.025). These mutations were associated with a higher rate of metastasis to the lungs, lymph nodes (P < 0.001). Patients with exon 20 mutations demonstrated poorer overall survival (OS) outcomes (P = 0.048). No significant differences were observed in age, smoking history, histological subtype, or TNM stage at diagnosis between groups. The majority of exon 20 mutations were in-frame indel mutations (92.0%), with the most common specific mutation being p.Y772_A775dup (70%). Gene Ontology (GO) analysis linked exon 20 mutations to unregulated protein kinase activity and anoikis. Conclusions Our study found that NSCLC patients with HER2 exon 20 oncogenic variants have a higher risk of metastasis and drug resistance, leading to worse outcomes than non-exon 20 mutations. This highlights the urgent need for targeted therapies aimed at exon 20 insertions to improve survival and treatment outcomes in this subgroup.https://doi.org/10.1186/s12885-025-14125-9HER2 oncogenic variantsNon-small cell lung cancer (NSCLC)Exon 20 mutationsMetastasisTargeted therapiesGene ontology (GO) analysis |
| spellingShingle | Yating Hou Xingyang Xue Zhuoyun Zhang Dahai Mai Wei Luo Mingyu Zhou Zichuan Liu Yisheng Huang Genomic and clinical characterization of HER2 exon 20 mutations in non-small cell lung cancer: insights from a multicenter study in South China BMC Cancer HER2 oncogenic variants Non-small cell lung cancer (NSCLC) Exon 20 mutations Metastasis Targeted therapies Gene ontology (GO) analysis |
| title | Genomic and clinical characterization of HER2 exon 20 mutations in non-small cell lung cancer: insights from a multicenter study in South China |
| title_full | Genomic and clinical characterization of HER2 exon 20 mutations in non-small cell lung cancer: insights from a multicenter study in South China |
| title_fullStr | Genomic and clinical characterization of HER2 exon 20 mutations in non-small cell lung cancer: insights from a multicenter study in South China |
| title_full_unstemmed | Genomic and clinical characterization of HER2 exon 20 mutations in non-small cell lung cancer: insights from a multicenter study in South China |
| title_short | Genomic and clinical characterization of HER2 exon 20 mutations in non-small cell lung cancer: insights from a multicenter study in South China |
| title_sort | genomic and clinical characterization of her2 exon 20 mutations in non small cell lung cancer insights from a multicenter study in south china |
| topic | HER2 oncogenic variants Non-small cell lung cancer (NSCLC) Exon 20 mutations Metastasis Targeted therapies Gene ontology (GO) analysis |
| url | https://doi.org/10.1186/s12885-025-14125-9 |
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