Hepatocellular carcinoma (HCC) accounts for approximately 85%-90% of all liver cancer cases and has poor relapse-free survival. There are many gene expression studies that have been performed to elucidate the genetic landscape and driver pathways leading to HCC. However, existing studies have been limited by the sample size and thus the pathogenesis of HCC is still unclear. In this study, we performed an integrated characterization using four independent datasets including 320 HCC samples and 270 normal liver tissues to identify the candidate genes and pathways in the progression of HCC. A total of 89 consistent differentially expression genes (DEGs) were identified. Gene-set enrichment analysis revealed that these genes were significantly enriched for cellular response to zinc ion in biological progress group, collagen trimer in the cellular component group, extracellular matrix structural (ECM) constituent conferring tensile strength in the molecular function group, protein digestion and absorption, mineral absorption and ECM-receptor interaction. Network system biology
Abstract Small-cell lung cancer (SCLC) is speculated to harbor complex genomic intratumor heterogeneity (ITH) associated with high recurrence rate and suboptimal response to immunotherapy. Here, we revealed a rather homogeneous mutational landscape but extremely suppressed and heterogeneous T cell receptor (TCR) repertoire in SCLCs. Higher mutational burden, lower chromosomal copy number aberration (CNA) burden, less CNA ITH and less TCR ITH were associated with longer overall survival of SCLC patients. Compared to non-small cell lung cancers (NSCLCs), SCLCs had similar predicted neoantigen burden and mutational ITH, but significantly more suppressed and heterogeneous TCR repertoire that may be associated with higher CNA burden and CNA ITH in SCLC. Novel therapeutic strategies targeting CNA could potentially improve the tumor immune microenvironment and response to immunotherapy in SCLC.
e14555 Background: The optimal systemic treatment for pulmonary large-cell neuroendocrine carcinoma (LCNEC) is still under debate. Previous studies showed that LCNEC with different genomic characteristics might respond differently to different chemotherapy regimens suggesting the potential role of genomic profiling in therapeutic decision-making. Tumor biopsies are often inadequate for genomic profiling, while cell-free DNA (cfDNA) analysis has demonstrated great potential in genomic profiling. Methods: A total of 63 patients with LCNEC treated with different chemotherapy regimens (etoposide-platinum doublets, pemetrexed with platinum and gemcitabine, docetaxel, or paclitaxel with platinum, hereafter referred to as SCLC-PE, NSCLC-PEM and NSCLC-GEM/TAX) were enrolled in this study. Samples were collected and included tumor DNA only from 22 patients, cfDNA only from 18 patients and paired tumor DNA and plasma cfDNA from 23 patients. Tumor DNA and cfDNA were sequenced by target-captured 179 genes from Geneplus-Beijing or Oncomine Cancer Panel v3 or 70 genes panel from Guardant 360. Survival and response analyses were only applied to 54 patients who received first line chemotherapy. Results: The mutation landscape of frequently mutated cancer genes in LCNEC from cfDNA closely resembled that from tumor DNA, which led to a 90% concordance in genomic subtyping. We classified LCNEC harboring any of these alterations: RB1 mutation/loss, PTEN mutation/loss, FGFR1/FGFR4 mutation/amplification, TP53 loss, as “SCLC-like” tumors, otherwise as NSCLC-like. Overall, patients with SCLC-like LCNEC had a shorter overall survival (OS) than those with NSCLC-like LCNEC (10.3 vs 14.4 months, p = 0.32) despite higher response rate (RR) (41% vs 22%) to chemotherapy. Furthermore, treatment with SCLC-PE was associated with longer PFS in SCLC-like LCNEC compared to NSCLC-PEM and NSCLC-GEM/TAX (median 8.3 vs 2.3 months, p = 0.0002; median 8.3 vs 5.9 months, p = 0.05), while treatment with NSCLC-GEM/TAX led to a shorter survival compared to SCLC-PE (median 1.9 vs 4.1 months, p = 0.03) or NSCLC-PEM in NSCLC-like LCNEC patients (median 1.9 vs 4 months, p = 0.07). Conclusions: Genomic subtyping has potentials in prognostication and therapeutic decision-making for patients with LCNEC and cfDNA analysis is a reliable alternative for genomic profiling of LCNEC.
8035 Background: Multiple myeloma (MM) is one of the most common primary tumors of the bone marrow that accounts for approximately 10% of all hematological cancer. Gambogenic acid (GNA) is one of the natural compound isolated from gamboge and has demonstrated advantages such as a more potent anticancer effect and less systemic toxicity according to early investigations. In this study, we hypothesized that GNA could synergistically potentiate BTZ-induced apoptosis of MM cells and that combining BTZ and GNA may provide a more effective approach to treat MM. Methods: CCK-8 assay, CI isobologram, flow cytometry, western blot, xenograft tumour models, TUNEL and immunochemistry were used in this study to detect to possible mechanisms of apoptosis led by GNA and BTZ in vitro and in vivo. Results: The percentage of MM.1S in G2/M phase after 48h of 4.0nM BTZ, 0.90μM GNA and combination treatment were 31.09±2.16%, 26.68±1.96% and 19.88±1.89% respectively. The percentage of MM.1S in G2/M phase of control group was 17.23±1.65%. The apoptosis rates of MM.1S cells for 48h were 6.57±0.15% in control group, 89.67±5.15% after treatment with 4.0nM BTZ, 97.80±0.81% after treatment with 0.90μM GNA, and 98.9±3.86% after treatment with 4.0nM BTZ plus 0.9μM GNA respectively. All the treatment groups showed a more significant apoptosis rate compared to that of the control group ( p<0.01). MM.1S tumors were implanted in BALB/Ca nu/nu male mice. The tumor weights of GNA and BTZ plus GNA groups decreased significantly when compared with those of control group (p<0.01 and p<0.001, respectively) and the tumor weight of combination group was significantly less than that of BTZ or GNA group (p<0.001). When mice were treated with BTZ combined with GNA, the tumor inhibition rate was 41.94%, whereas those of mice treated with BTZ or GNA alone were 9.68% and 19.35%, respectively. We also found that the combined treatment could induce more markedly increased apoptosis of MM.1S cells via the activation of PARP cleavage, P53, Caspase-3 cleavage and Bax and inhibition of Bcl-2 expression. Conclusions: Our data support that a synergistic antitumor activity exists between BTZ and GNA, and provide a rationale for successful utilization of dual BTZ and GNA in MM chemotherapy in the future.
Background: Serum tumor markers carcinoembryonic antigen (CEA), cancer antigen 125 (CA125), cytokeratin 19 fragment (CYFRA21-1) and squamous-cell carcinoma-related antigen (SCC-Ag) are routinely used for monitoring the response to chemotherapy or targeted therapy in advanced-stage non-small cell lung cancer (NSCLC), however their role in immunotherapy remains unclear. The aim of this study was to investigate whether dynamics of these serum markers could predict prognosis of patients with late-stage NSCLC treated by programmed cell death-1/programmed cell death ligand-1 (PD-1/PD-L1) inhibitors. Methods: We initiated a longitudinal study on advanced NSCLC patients treated by PD-1/PD-L1 inhibitors. Blood samples of baseline and after 6 weeks' treatment were collected. At least 20% decreases of the biomarkers from baseline were considered as meaningful improvements after 6 weeks of treatment. Optimization-based method was used to balance baseline covariates between different groups. Results: A total of 308 patients with advanced NSCLC were enrolled in the study. After balancing the baseline covariates between different groups, patients with meaningful improvements in less than 2 out of 4 biomarkers was ended up with lower ORR (0.08 vs 0.35, p < 0.001), shorten PFS (5.4 vs 12.5 months, p < 0.001) and OS (11.7 vs 25.6 months, p < 0.001) in the total population. Subgroup analysis of patients with adenocarcinoma (ADC) revealed that patients with meaningful improvements in less than 2 out of 4 biomarkers had significant lower ORR (0.06 vs 0.36, p < 0.001), shorten PFS (4.1 vs 11.9 months, p < 0.001) and OS (11.9 vs 24.2 months, p < 0.001). So as in patients with squamous cell carcinoma (SCC), meaningful improvements in at least 2 out of 4 biomarkers were linked to better ORR (0.42 vs 0.08, p = 0.014), longer PFS (13.1 vs 5.6 months, p = 0.001) and OS (25.6 vs 10.9 months, p = 0.06). Conclusions: The dynamic change of CEA, CA125, CYFRA21-1 and SCC-Ag from baseline could predict efficacy of PD-1/PD-L1 inhibitors in late-stage NSCLC patients. Decrease of associated biomarkers serum levels were associated with favorable clinical outcomes.
Background: A better understanding of the tumor-immune system interactions in gastric cancer (GC) may provide promising diagnostic, prognostic, and therapeutic biomarkers for patients with this disease. We aimed to identify a prognostic signature of GC through a comprehensive bioinformatics analysis on the tumor-immune interactions as well as the molecular characteristics. Methods: We employed the single sample Gene Sets Enrichment Analysis (ssGSEA) to define immune-related subtypes and investigated the complicated biological functions and regulatory networks of these subtypes. We then developed a risk model using Lasso Cox regression and verified it via the external validation set and correlated the immune signature with GC clinicopathologic features and genomic characteristics. Findings: We observed two immune subgroups depending on the activity and level of immune cell in GC patients. We also identified a six-immune-gene signature as a promising independent prognostic biomarker for GC. A nomogram was constructed based on the immune signature and clinical characteristics and showed high potential for GC prognosis prediction. The receiver operating characteristic (ROC) curve analysis distinguishing patients with distinct prognosis yielded an area under the curve (AUC) of 0.779 for 5 years. Interpretation: Our work supports the clinical significance of this immune gene-associated signature for predicting the prognosis of GC patients. This study also shed light on the treatment strategies for GC patients from the perspective of immunology. Funding: This study was supported by Natural Science Foundation of Zhejiang Province (LY18H290006), National Natural Science Foundation of China (81903842, 81973634), and Program of Zhejiang Provincial TCM Sci-tech Plan (2018ZY006, 2020ZZ005).Declaration of Interests: The authors declare that they have no competing interests.Ethics Approval Statement: The patient data in this work were acquired from the publicly available datasets whose informed consent of patients were complete.
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