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Objectives: This study aims to assess the prognostic implications of gene signature of the tertiary lymphoid structures (TLSs) in head and neck squamous cell carcinoma (HNSCC) and scrutinize the influence of TLS on immune infiltration. Methods: Patients with HNSCC from the Cancer Genome Atlas were categorized into high/low TLS signature groups based on the predetermined TLS signature threshold. The association of the TLS signature with the immune microenvironment, driver gene mutation status, and tumor mutational load was systematically analyzed. Validation was conducted using independent datasets (GSE41613 and GSE102349). Results: Patients with a high TLS signature score exhibited better prognosis compared to those with a low TLS signature score. The group with a high TLS signature score had significantly higher immune cell subpopulations compared to the group with a low TLS signature score. Moreover, the major immune cell subpopulations and immune circulation characteristics in the tumor immune microenvironment were positively correlated with the TLS signature. Mutational differences in driver genes were observed between the TLS signature high/low groups, primarily in the cell cycle and NRF2 signaling pathways. Patients with TP53 mutations and high TLS signature scores demonstrated a better prognosis compared to those with TP53 wild-type. In the independent cohort, the relationship between TLS signatures and patient prognosis and immune infiltration was also confirmed. Additionally, immune-related biological processes and signaling pathways were activated with elevated TLS signature. Conclusion: High TLS signature is a promising independent prognostic factor for HNSCC patients. Immunological analysis indicated a correlation between TLS and immune cell infiltration in HNSCC. These findings provide a theoretical basis for future applications of TLS signature in HNSCC prognosis and immunotherapy.
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Fusion of RET with different partner genes has been detected in papillary thyroid, lung, colorectal, pancreatic, and breast cancer. Approval of selpercatinib for treatment of lung and thyroid cancer with RET gene mutations or fusions calls for studies to explore RET fusion partners and their eligibility for RET-based targeted therapy. In this study, RET fusion patterns in a large group of Chinese cancer patients covering several cancer types were identified using next-generation sequencing. A total of 44 fusion patterns were identified in the study cohort with KIF5B, CCDC6, and ERC1 being the most common RET fusion partners. Notably, 17 novel fusions were first reported in this study. Prevalence of functional RET fusions was 1.05% in lung cancer, 6.03% in thyroid cancer, 0.39% in colorectal cancer, and less than 0.1% in gastric cancer and hepatocellular carcinoma. Analysis showed a preference for fusion partners in different tumor types, with KIF5B being the common type in lung cancer, CCDC6 in thyroid cancer, and NCOA4 in colorectal cancer. Co-occurrence of EGFR mutations and RET fusions with rare partner genes (rather than KIF5B) in lung cancer patients was correlated with epidermal growth factor receptor-tyrosine kinase inhibitor resistance and could predict response to targeted therapies. Findings from this study provide a guide to clinicians in determining tumors with specific fusion patterns as candidates for RET targeted therapies.
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Povo Asiático/genética , Perfilação da Expressão Gênica/métodos , Neoplasias/genética , Proteínas de Fusão Oncogênica/genética , Proteínas Proto-Oncogênicas c-ret/genética , Análise de Sequência de DNA/métodos , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , China , Feminino , Regulação Neoplásica da Expressão Gênica , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , Pessoa de Meia-Idade , Prevalência , Estudos Retrospectivos , Análise de Sequência de RNA , Adulto JovemRESUMO
In non-small cell lung cancer (NSCLC), about 15% of epidermal growth factor receptor (EGFR) mutations are rare. Herein, we report a 39-year-old male with stage IV NSCLC with a rare EGFR M277E mutation and high PD-L1 expression. The patient first underwent gamma-knife treatment for brain metastasis; then, he was started on 40 mg afatinib daily in combination with two cycles of chemotherapy. The clinical effect was stable disease (SD), so the patient underwent intensity-modulated radiation therapy guided by cone beam computed tomography on the lesion in the lower lobe of the right lung. A combination therapy with afatinib and chemotherapy was employed as the first-line therapy. A palliative radiotherapy to the primary pulmonary tumor was added, resulting in a significant response based on the next computerized tomography (CT) scan. To date, this is the first presented case of NSCLC with EGFR p.M277E mutation and its corresponding clinical outcome to combination therapies.
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Adenocarcinoma de Pulmão , Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Adenocarcinoma de Pulmão/tratamento farmacológico , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/radioterapia , Adulto , Afatinib/uso terapêutico , Antígeno B7-H1/genética , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/radioterapia , Receptores ErbB/genética , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/radioterapia , Masculino , MutaçãoRESUMO
Lung cancer is the most common solid tumor in the worldwide. Targeted therapy and immunotherapy are important treatment options in advanced non-small cell lung cancer (NSCLC). The association of PTEN mutation and tumor immunotherapy is less established for patients with NSCLC. We present the case of an Asian woman diagnosed with stage IV lung adenocarcinoma harboring an ERBB2 mutation. She received Nivolumab treatment when her disease progresses after previous chemotherapy and Afatinib treatment. However, the patient did not response to Nivolumab. PTEN mutation was detected by next-generation sequencing (NGS) after treatment with Nivolumab. PTEN, a secondary mutation, may be served as a biomarker of resistance to anti-PD-1 immunotherapy in lung adenocarcinoma. The relationship between PTEN mutation and immunotherapy is complex and needs further study.
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In recent years, immune checkpoint inhibitors (ICIs), represented by PD-1/PD-L1 monoclonal antibodies, have become a research hotspot in the field of oncology treatment. Immunotherapy has shown significant survival advantages in a variety of solid tumors. However, the phenomenon of hyperprogressive disease (HPD) in some patients treated with immunotherapy is gradually getting more attention and focus. An early understanding of the characteristics of HPD is crucial to optimize the treatment strategy. We report a patient with unresectable stage III lung adenocarcinoma who developed HPD with metastasis during consolidation therapy with durvalumab after chemoradiation. To further investigate the potential mechanism of HPD after anti-PD-L1 treatment, primary lung baseline tissue, baseline plasma, post-immunotherapy plasma, and liver metastasis samples of the patient were detected via next-generation sequencing (NGS). Then, multiplex immunohistochemistry (mIHC) was performed on primary lung baseline tissue and liver metastasis samples. KRAS and p.G12C were identified as the major driver mutation genes. With a low tumor mutation burden (TMB) value, the patient presented a very high percentage of CD8+PD-L1+ T cells that infiltrated in the baseline tissue, with 95.5% of all CD8+ cells expressing PD-L1 and a low percentage of CD8+ T cells expressing PD-1. After the emergence of HPD from immunotherapy, liver metastases were similarly infiltrated with an extremely high proportion of CD8+PD-L1+ T cells, with 85.6% of all CD8+ cells expressing PD-L1 and almost no CD8+ T cells expressing PD-1. The extreme infiltration of PD-L1+CD8+ T cells in the tumor microenvironment of baseline tissue might be associated with the aggressive tumor growth observed in anti-PD-L1 treatment for related HPD and could be a potential biomarker for HPD development.
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Growing evidence has highlighted the roles of circular RNAs (circRNAs) in non-small-cell lung cancer (NSCLC), however, their roles in NSCLC glycolysis remains poorly understood. CircRNAs microarray profiles discovered a novel exon-derived circRNA, circSLC25A16 (hsa_circ_0018534), in NSCLC tissue samples. In NSCLC samples, high-expression of circSLC25A16 was associated with unfavorable prognosis. Cellular experiments revealed that circSLC25A16 accelerated the glycolysis and proliferation of NSCLC cells. Besides, circSLC25A16 knockdown repressed the in vivo growth by xenograft assays. RNA-fluorescence in situ hybridization (RNA-FISH) illustrated that circSLC25A16 and miR-488-3p were both located in cytoplasm. Mechanistic experiments demonstrated that circSLC25A16 interacts with miR-488-3p/HIF-1α, which activates lactate dehydrogenase A (LDHA) by facilitating its transcription. Collectively, present research reveals the crucial function of circSLC25A16 on NSCLC glycolysis through miR-488-3p/HIF-1α/LDHA, suggesting the underlying pathogenesis for NSCLC and providing a therapeutic strategy for precise treatment.
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Carcinoma Pulmonar de Células não Pequenas/genética , Epigênese Genética/genética , Glicólise/genética , Neoplasias Pulmonares/genética , RNA Circular/metabolismo , Animais , Carcinoma Pulmonar de Células não Pequenas/patologia , Linhagem Celular Tumoral , Humanos , Neoplasias Pulmonares/patologia , Camundongos , Camundongos Nus , Pessoa de Meia-Idade , Prognóstico , TransfecçãoRESUMO
OBJECTIVE: To make an informed choice of chemotherapy drugs according to the oncogene mRNA expression and to explore whether it could increase the survival rate of patients. PATIENTS AND METHODS: The study retrospectively analyzed 36 cases of nonsurgical esophageal squamous cell carcinoma patients treated at the Center for Oncology of Shandong Provincial Hospital from December 1, 2010, to November 1, 2013. Intensity-modulated radiation therapy was used for the treatment with a conventional radiotherapy dose of 60-66 Gy. Chemotherapy started 1-5 weeks after radiation therapy. The selection of the chemotherapy drug was based on the mRNA expression levels of excision repair cross-complementation 1, thymidylate synthetase, ribonucleotide reductase M1, and ß-tubulin isotype III. The objective response rate, progression-free survival, and overall survival were observed. RESULTS: The reason for poor prognosis of patients with high expression of excision repair cross-complementation 1 was unknown. No correlation was observed between patient survival and expression of thymidylate synthetase, ribonucleotide reductase M1, and ß-tubulin isotype III. Complete response, partial response, stable disease, and progressive disease were observed in 25, five, three, and three patients, respectively. The objective response rate was 83.3%. The 1-year, 2-year, and 3-year progression-free survival rates were 79.8%, 58.9%, and 54.4%, respectively. The 1-year, 2-year, and 3-year overall survival rates were 83.3%, 68.1%, and 58.4%, respectively. CONCLUSION: Selecting the chemotherapy drug according to the oncogene expression, combined with radiation therapy, could increase the 3-year survival rate in nonsurgical esophageal squamous cell carcinoma patients. Such conclusion needs to be further confirmed using a larger sample size.