Gastric cancer is a highly heterogeneous disease and the second leading cause of cancer-associated mortality. However, the genomic basis of gastric cancer is not completely understood and the underlying genetic heterogeneity has not been well studied. In the present study, 1,021 genes were sequenced and the somatic mutations of 45 formalin-fixed, paraffin-embedded gastric adenocarcinoma samples were assessed using next-generation sequencing technologies. In the present study, a median sequencing coverage depth of 708-fold was achieved. Somatic genomic alterations were detected in 37/45 patients (82.4%) and the most frequent genetic alterations identified were tumor protein P53 (TP53) gene mutations. Mutations in MLL4, ERBB3, FBXW7, MLL3, MTOR, NOTCH1, PIK3CA, KRAS, ERBB4 and EGFR were also detected. Patients with TP53 mutations had a higher number of somatic mutations, and the total number of somatic mutations was weakly correlated with patient age. These results provided data on the intratumoral heterogeneity of gastric cancer and may be used in order to develop personalized cancer therapy.
Gastric cancer (GC) is one of the leading malignancies around the world. Identification of novel and efficient biomarkers for GC diagnosis and evaluation of therapeutic efficiency could improve the therapeutic strategy in future clinical application. This study aims to evaluate the levels of plasma thioredoxin reductase (TrxR) activity in GC patients to confirm its validity and efficacy in GC diagnosis and evaluation of therapeutic efficiency. 923 cases were enrolled in the current study. In the group of GC patients before clinical intervention, plasma TrxR activity [9.09 (7.96, 10.45) U/mL] was significantly higher than in healthy controls [3.69 (2.38, 5.32) U/mL]. The threshold of TrxR activity for GC diagnosis was set at 7.34 U/mL with a sensitivity of 85.5% and a specificity of 97.9%. In GC patients after chemotherapy, plasma TrxR activity was remarkably higher in patients with progressive disease or uncontrolled condition [10.07 (8.19, 11.02) U/mL] compared with patients with complete or partial response [7.12 (6.08, 8.37) U/mL] in response to chemotherapy. TrxR activity displayed the higher efficiency to distinguish between GC patients with two distinct clinical outcomes than carcinoembryonic antigen (CEA), cancer antigen 72-4 (CA72-4) and cancer antigen 19-9 (CA19-9). Moreover, combination of TrxR, CEA, CA72-4 and CA19-9 was demonstrated to be more effective in both GC diagnosis and evaluation of therapeutic efficiency than was each biomarker individually. Together, plasma TrxR activity was identified as a novel and efficient biomarker of GC, both in diagnosis and monitoring of therapeutic efficiency in response to chemotherapy.
To investigate the clinical value of plasma cell-free DNA (cfDNA) as a potential biomarker for advanced gastric cancer (GC). Patients and Methods: One hundred and six cases of advanced gastric cancer patients receiving chemotherapy were selected as study objects. Another 40 healthy volunteers were included as control groups. Plasma cfDNA concentration was detected by (SuperbDNA TM) hybridization. Changes in cfDNA concentration during chemotherapy in patients with gastric cancer whose efficacy was assessed as partial response (PR), stable disease (SD) and disease progression (PD) were analyzed respectively. The relationship between the level of cfDNA and the efficacy of chemotherapy and clinical characteristics was also explored. In addition, cfDNA and other tumor markers were subjected to specificity and sensitivity analyses using ROC. Results: cfDNA concentration in advanced GC patients was significantly higher than that in healthy controls (P<0.05). The concentration of plasma cfDNA in patients with PD showed an increasing trend over time. The concentration of plasma cfDNA in patients with therapeutic effect of PR decreased over time. In patients with therapeutic effect of SD, the plasma DNA concentration showed a stable trend over time. There was no significant correlation between cfDNA concentration and factors including gender, age, pathological type, CA724, CA125,CA199, AFP and CEA. ROC results showed that the area under the curve of cfDNA was larger than other tumor markers. Conclusion: Plasma cfDNA concentration was significantly increased in patients with gastric cancer, and its diagnostic efficacy was superior to that of traditional tumor markers. It can be used as a tumor biomarker to monitor the efficacy of chemotherapy for gastric cancer.
Background: Tumor mutation burden (TMB) assessed by tumor-related gene panels (CRGP), microsatellite instability (MSI), and mismatch repair (MMR) has been proven to be associated with prognosis, and these factors are prognostic indicators in predicting the benefits of immune checkpoint blockade (ICB) in solid tumors. However, whether the TMB calculated by CRGPs, MSI, and MMR is associated with overall survival (OS) in patients with colorectal cancer (CRC) remains to be explored. Methods:The prognostic threshold of the panel-TMB was explored by a panel of 645 genes (GP645) from 41 CRC patients in Jiangsu Cancer Hospital (JCH dataset). The results were further validated using 531 CRC patients from The Cancer Genome Atlas (TCGA) database.Results: Mutations of the GP645 genes were distributed on 21 chromosomes. Spearman correlation analysis showed that the panel-TMB was positively correlated with TMB measured by whole-exome sequencing (WES) (wTMB) in the TCGA dataset (R=0.75, P<0.001). Kaplan-Meier survival analysis demonstrated that higher panel-TMB in CRC patients was significantly associated with a poor OS (P=0.0062).MSI and MMR status were determined using the GP645 by next-generation sequencing (NGS). The proportions of MSI-H and dMMR accounted for less than 10% in CRC, the vast majority of MSI-H/dMMR samples also had high TMB [positive predictive value (PPV) =66.6%], and only 13.3% of samples with high TMB were classified as MSI-high/dMMR. In addition, patients with low-TMB were associated with MSS/ pMMR (96.2%), and these results are consistent with earlier studies.Conclusions: GP645 was constructed to evaluate OS in Chinese CRC patients. Panel-TMB and MSI/ MMR might be potential prognostic predictors of CRC patients using the GP645.
Introduction: Gastric cancer is highly heterogeneous both clinically and pathologically and is one of the leading causes of cancer-related deaths worldwide. Genomic coverage variations, also known as copy number variations (CNVs), play a critical role in the carcinogenesis of gastric cancer. Many studies have demonstrated that DNA CNVs are important factors affecting the expression of protein-encoding genes in the gastric cancer genome. Methods: Thirty gastric cancer patients from a Chinese population were enrolled. Genomic DNA was extracted from gastric cancer tissue and matched adjacent non-cancerous tissue from each patient. A panel of 1,021 genes including 3300 exons was designed and subjected to next-generation sequencing. Copy numbers of each gene and exon were calculated for each tissue. Coverage variations between gastric cancer tissue and matched adjacent noncancerous tissue were also calculated, and we examined the correlation between overall survival of patients and coverage variation type for each exon. Results: DNA from cancerous tissue and corresponding adjacent non-cancerous tissue were significantly different with respect to the pattern of gene copy number. Exon copy numbers were highly consistent among non-cancerous samples and confirmed that non-cancerous tissue contain diploid genomes. In contrast, the gene coverage pattern among cancerous tissue showed significant differences and confirmed that gastric cancer is a genetically heterogeneous disease. Numerous exon coverage variations were identified in gastric cancer tissue compared with matched, adjacent non-cancerous tissue. Overall survival between patients with and without coverage variations in regions of NOTCH2, NTRK3, ERBB2 and RERE exons exhibited significant differences. This is consistent with previous reports and indicates that these findings may have prognostic value. Conclusion: Our results confirm that gastric cancer is a genetically heterogeneous disease. Exon coverage variations between cancer tissue and their adjacent non-cancerous tissue were shown to be associated with prognosis in gastric cancer.
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Objective To explore the efficacy and safety of neoadjuvant chemotherapy in the doublet and triplet regimens of locally advanced gastric cancer. Patients and Methods A retrospective analysis was conducted on 162 patients with gastric cancer who received neoadjuvant chemotherapy, including 74 patients receiving doublet regimen (fluorouracil/platinum) and 88 patients receiving triplet regimen (fluorouracil/platinum/Taxol). Patients in both groups received neoadjuvant chemotherapy for two cycles, and underwent surgical resection 4 weeks after the end of chemotherapy. Results The total clinical remission rate was 68.6% (105/153), the phase-down rate was 46.4% (71/153), and the pathological response rate was 59.9% (97/162). In the doublet and triplet regimen, the clinical remission rate was 65.7% (44/67) and 70.9% (61/86) (P = 0.708), the descending period rate was 41.8% (28/67) and 50.0% (43/86) (P = 0.485), and the pathological response rate was 51.4% (38/74) and 67.0% (59/88) (P = 0.190). The median disease-free survival (DFS) and overall survival (OS) of 162 patients were 36.0 and 58.5 months. In the doublet and triplet regimen, the median DFS was 38.0 and 34.0 months (P = 0.377), and the median OS was 59.0 and 56.5 months (P = 0.256). The side effects of the doublet group were significantly lower than those of the triplet group, with leucopenia rate of 45.9% (34/74) and 62.5% (55/88) (P = 0.035); thrombocytopenia rate of 18.9% (14/74) and 35.2% (31/88) (P = 0.021); nausea rate of 45.9% (34/74) and 64.8% (57/88) (P = 0.016), and diarrhea rate of 1.4% (1/74) and 9.1% (8/88) (P = 0.032). Conclusion Neoadjuvant chemotherapy is safe and effective for locally advanced gastric cancer. The clinical efficacy of neoadjuvant chemotherapy in the doublet group and the triplet group is equivalent, and the doublet group has better safety and tolerance.
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