Approximately half of the world's 500,000 new oesophageal squamous-cell carcinoma (ESCC) cases each year occur in China. Here, we show whole-genome sequencing of DNA and RNA in 94 Chinese individuals with ESCC. We identify six mutational signatures (E1–E6), and Signature E4 is unique in ESCC linked to alcohol intake and genetic variants in alcohol-metabolizing enzymes. We discover significantly recurrent mutations in 20 protein-coding genes, 4 long non-coding RNAs and 10 untranslational regions. Functional analyses show six genes that have recurrent copy-number variants in three squamous-cell carcinomas (oesophageal, head and neck and lung) significantly promote cancer cell proliferation, migration and invasion. The most frequently affected genes by structural variation are LRP1B and TTC28. The aberrant cell cycle and PI3K-AKT pathways seem critical in ESCC. These results establish a comprehensive genomic landscape of ESCC and provide potential targets for precision treatment and prevention of the cancer.
Background: Esophageal squamous cell carcinoma (ESCC) is a gastrointestinal malignancy with a poor prognosis. Although studies have shown metabolic reprogramming to be linked to ESCC development, no prognostic metabolic biomarkers or potential therapeutic metabolic targets have been identified. Method: The present study investigated some circulating metabolites associated with overall survival in 276 curatively resected ESCC patients using liquid chromatography/mass spectrometry metabolomics and Kaplan-Meier analysis. Tissue metabolomic analysis of 23-paired ESCC tissue samples was performed to discover metabolic dysregulation in ESCC cancerous tissue. A method consisting of support vector machine recursive feature elimination and LIMMA differential expression analysis was utilized to select promising feature genes within transcriptomic data from 179-paired ESCC tissue samples. Joint pathway analysis with genes and metabolites identified relevant metabolic pathways and targets for ESCC. Results: Four metabolites, kynurenine, 1-myristoyl-glycero-3-phosphocholine (LPC(14:0)sn-1), 2-piperidinone, and hippuric acid, were identified as prognostic factors in the preoperative plasma from ESCC patients. A risk score consisting of kynurenine and LPC(14:0)sn-1 significantly improved the prognostic performance of the tumor-node-metastasis staging system and was able to stratify risk for ESCC. Combined tissue metabolomic analysis and support vector machine recursive feature elimination gene selection revealed dysregulated kynurenine pathway as an important metabolic feature of ESCC, including accumulation of tryptophan, formylkynurenine, and kynurenine, as well as up-regulated indoleamine 2,3-dioxygenase 1 in ESCC cancerous tissue. Chen et al. Metabolic Features of ESCC Conclusions: This work identified for the first time four potential prognostic circulating metabolites. In addition, kynurenine pathway metabolism was shown to be up-regulated tryptophan-kynurenine metabolism in ESCC. Results not only provide a metabolite-based risk score system for prognosis, but also improve the understanding of the molecular basis of ESCC onset and progression, and as well as novel potential therapeutic targets for ESCC.
BackgroundInvasive mucinous adenocarcinoma (IMA) of the lung is a distinct histological subtype with unique clinical and pathological features. Despite previous genomic studies on lung IMA, the genetic characteristics and the prognosis-related biomarkers in Chinese surgically resected lung IMA remain unclear.MethodsWe collected 76 surgically resected primary tumors of invasive lung adenocarcinoma, including 51 IMA and 25 non-mucinous adenocarcinomas (non-IMA). IMA was further divided into pure-IMA (mucinous features≥90%) and mixed-IMA subgroups. Comprehensive genomic profiling based on targeted next-generation sequencing (NGS) of 425 genes was explored and genomic characteristics were evaluated for the correlation with postoperative disease-free survival (DFS).ResultsIMA had a unique genetic profile, with more diverse driver mutations and more tumor drivers/suppressors co-occurrence than that of non-IMA. The frequency of EGFR (72.0% vs. 40.0% vs. 23.1%, p=0.002) and ALK (undetected vs. 20.0% vs. 26.9%, p=0.015) alterations showed a trend of gradual decrease and increase from non-IMA to mixed-IMA to pure-IMA, respectively. The frequency of KRAS mutations in pure-IMA was higher than that in mixed-IMA, albeit statistically insignificant (23.1% vs. 4.0%, p=0.10). TP53 mutation was significantly less in pure-IMA compared to mixed-IMA and non-IMA (23.1% vs. 52.0% vs. 56.0%, p=0.03). Besides, IMA exhibited less arm-level amplifications (p=0.04) and more arm-level deletions (p=0.004) than non-IMA, and the frequency of amplification and deletion also showed a trend of gradual decrease and increase from non-IMA to mixed-IMA to pure-IMA, respectively. Furthermore, prognosis analysis in stage III IMA patients showed that patients harboring alterations in EGFR (mDFS=30.3 vs. 16.0 months, HR=0.19, P=0.027) and PI3K pathway (mDFS=36.0 vs. 16.0 months, HR=0.12, P=0.023) achieved prolonged DFS, while patients with poorly differentiated tumors (mDFS=14.1 vs. 28.0 months, HR=3.75, p=0.037) or with KRAS mutations (mDFS=13.0 vs. 20.0 months, HR=6.95, p=0.027) had shorter DFS. Multivariate analysis showed that KRAS mutations, PI3K pathway alterations, and tumor differentiation status were independent factors that have statistically significant influences on clinical outcomes of IMA patients.ConclusionOur study provided genomic insights into Chinese surgically resected lung IMA. We also identified several genomic features that may serve as potential biomarkers on postoperative recurrence in IMA patients with stage III disease.
Circulating tumor cells (CTCs) have been implicated in tumor progression and prognosis. Techniques detecting CTCs in the peripheral blood of patients with non-small cell lung carcinoma (NSCLC) may help to identify individuals likely to benefit from early systemic treatment. However, the detection of CTCs with a single marker is challenging, owing to low specificity and sensitivity and due to the heterogeneity and rareness of CTCs. Herein, the probability of cell-free RNA content in the peripheral blood as a potential biomarker for detecting CTCs in cancer patients was investigated. An immunomagnetic enrichment of real-time reverse-transcription PCR (RT-PCR) technology for analysis of CTCs in NSCLC patients was also developed. The mRNA levels of four candidate genes, cytokeratin 7 (CK7), E74-like factor 3 (ELF3), epidermal growth factor receptor (EGFR), and erythropoietin-producing hepatocellular carcinoma receptor B4 (EphB4) that were significantly elevated in tumor tissues and peripheral blood mononuclear cells (PBMCs) were determined. The expression of CK7 and ELF3 in tumor tissues and EGFR in PBMCs was associated with lymph node metastasis (all p < 0.05). The expression of CK7 in PBMCs was correlated with age and EphB4 in PBMCs correlated with histopathological type, respectively (all p < 0.05). The expression of all four genes in tumor tissues and PBMCs was significantly correlated with the clinical stage (all p < 0.01). Survival analysis showed that the patients with enhanced expression of CK7, ELF3, EGFR, and EphB4 mRNA in PBMCs had poorer disease-free survival (DFS) and overall survival (OS) than those without (all p < 0.0001). The present study showed that this alteration of cell-free RNA content in peripheral blood might have clinical ramifications in the diagnosis and treatment of NSCLC patients.
Introduction Sublobar resection has been widely accepted for treating pure ground-glass opacities (GGOs). As GGOs have good prognosis, preserving postoperative pulmonary function is the major concern in surgery. No studies have yet compared the success rates of pulmonary function reservation between segmentectomy and wedge resection. Method The three-dimensional rebuild of computed tomography (CT) images was performed, the segmentectomy and wedge resection of the GGO in the target segment were simulated, and the area of cut surface was measured, which was important data for successful postoperative pulmonary recruitment maneuvers. Result With equal volumes of tissue removed, segmentectomy and wedge resection showed similar surface area loss for RS4 and RS5, followed by LS7 + 8, LS6 and LS1 + 2 segments. Compared with other segments, wedge resection performed in RS10, LS3, LS10, RS9 and RS7 may lead to a loss of lot more surface area than segmentectomy. Conclusion Wedge resection is suggested for segments RS4, RS5, LS1 + 2 and LS7 + 8, whereas segmentectomy is advised for segments RS1, LS4 + 5 and RS2. Meanwhile, deep wedge resection should be avoided for segments RS8, RS7, RS10, LS3, LS10. RS9 and LS9, in order to preserve a larger lung surface area.
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