Decreased expression of claudin-18.2 in alpha-fetoprotein-producing gastric cancer compared to conventional gastric cancer

BackgroundAlpha-fetoprotein-producing gastric cancer (AFPGC) is a subtype of gastric cancer (GC) with more aggressive biological behavior. As a highly specific tight junction component exclusively present in gastric mucosa and gastric adenocarcinomas, claudin-18.2 (CLDN18.2) has become an emerging target in GC. In this study, we aimed to provide insight into AFPGC and investigate the expression and the clinical implications of CLDN18.2 in AFPGC.MethodsWe retrospectively collected 98 cases of AFPGC and reviewed their clinical, morphological, and immunohistochemical features. Another 356 patients with stage-matched conventional GC (cGC) were enrolled as a control group. We further surveyed CLDN18.2 expression by immunohistochemistry (IHC) in 51 AFPGC tissues and explained its association with the clinicopathological parameters of AFPGC.ResultsOur results showed that AFPGC was a unique GC type with elevated serum alpha-fetoprotein (AFP), which was a predictor of a worse prognosis. AFPGC showed typical morphological features and positive staining of at least 1 hepatocytic or enteroblastic marker. The expression rate of CLDN18.2 was low, with a positivity rate of 21.6%, which was much lower than that observed in cGC tissues (38.5%). A significant correlation was found between CLDN18.2 expression and the differentiation of AFPGC. CLDN18.2 expression was negatively correlated with the serum AFP level of AFPGC. We also found that AFPGC with a hepatoid type (HPT) component showed a significantly lower CLDN18.2 expression than those without.ConclusionsThis study demonstrated that CLDN18.2 was significantly decreased in AFPGC and was negatively correlated with the patient’s preoperative serum AFP level. The negative correlation between AFP and CLDN18.2 could be explained by retro-differentiation of AFPGC. Special treatment strategies might be needed for this unique tumor type.     

A multicentre,phase IIa study of zolbetuximab as a single agent in patients with recurrent or refractory advanced adenocarcinoma of the stomach or lower oesophagus: the MONO study

BackgroundClaudin 18.2 (CLDN18.2) is physiologically confined to gastric mucosa tight junctions; however, upon malignant transformation, perturbations in cell polarity lead to CLDN18.2 epitopes being exposed on the cancer cell surface. The first-in-class monoclonal antibody, zolbetuximab (formerly known as IMAB362), binds to CLDN18.2 and can induce immune-mediated lysis of CLDN18.2-positive cells.Patients and methodsPatients with advanced gastric, gastro-oesophageal junction (GEJ) or oesophageal adenocarcinomas with moderate-to-strong CLDN18.2 expression in ≥50% of tumour cells received zolbetuximab intravenously every 2 weeks for five planned infusions. At least three patients were enrolled in two sequential cohorts (cohort 1300 mg/m²; cohort 2600 mg/m²); additional patients were enrolled into a dose-expansion cohort (cohort 3600 mg/m²). The primary end point was the objective response rate [ORR: complete and partial response (PR)]; secondary end points included clinical benefit [ORR+stable disease (SD)], progression-free survival, safety/tolerability, and zolbetuximab pharmacokinetic profile.ResultsFrom September 2010 to September 2012, 54 patients were enrolled (cohort 1, n = 4; cohort 2, n = 6; cohort 3, n = 44). Three patients in cohort 1 and 25 patients in cohorts 2/3 received at least 5 infusions. Antitumour activity data were available for 43 patients, of whom 4 achieved PR (ORR 9%) and 6 (14%) had SD for a clinical benefit rate of 23%. In a subgroup of patients with moderate-to-high CLDN18.2 expression in ≥70% of tumour cells, ORR was 14% (n = 4/29). Treatment-related adverse events occurred in 81.5% (n = 44/54) patients; nausea (61%), vomiting (50%), and fatigue (22%) were the most frequent.ConclusionsZolbetuximab monotherapy was well tolerated and exhibited antitumour activity in patients with CLDN18.2-positive advanced gastric or GEJ adenocarcinomas, with response rates similar to those reported for single-agent targeted agents in gastric/GEJ cancer trials.ClinicalTrials.gov numberNCT01197885.     

Claudin 18.2 is a potential therapeutic target for zolbetuximab in pancreatic ductal adenocarcinoma

BACKGROUNDPancreatic ductal adenocarcinoma (PDAC) is frequently diagnosed and treated in advanced tumor stages with poor prognosis. More effective screening programs and novel therapeutic means are urgently needed. Recent studies have regarded tight junction protein claudin 18.2 (CLDN18.2) as a candidate target for cancer treatment, and zolbetuximab (formerly known as IMAB362) has been developed against CLDN18.2. However, there are few data reported thus far related to the clinicopathological characteristics of CLDN18.2 expression for PDAC.AIMTo investigate the expression of CLDN18.2 in PDAC patients and subsequently propose a new target for the treatment of PDAC.METHODSThe Cancer Genome Atlas, Genotype-Tissue Expression, Gene Expression Omnibus, and European Genome-phenome Archive databases were first employed to analyze the CLDN18 gene expression in normal pancreatic tissue compared to that in pancreatic cancer tissue. Second, we analyzed the expression of CLDN18.2 in 93 primary PDACs, 86 para-cancer tissues, and 13 normal pancreatic tissues by immunohistochemistry. Immunostained tissues were assessed applying the histoscore. subsequently, they fell into two groups according to the expression state of CLDN18.2. Furthermore, the correlations between CLDN18.2 expression and diverse clinicopathological characteristics, including survival, were investigated.RESULTSThe gene expression of CLDN18 was statistically higher (P < 0.01) in pancreatic tumors than in normal tissues. However, there was no significant correlation between CLDN18 expression and survival in pancreatic cancer patients. CLDN18.2 was expressed in 88 (94.6%) of the reported PDACs. Among these tumors, 50 (56.8%) cases showed strong immunostaining. The para-cancer tissues were positive in 81 (94.2%) cases, among which 32 (39.5%) of cases were characterized for strong staining intensities. Normal pancreatic tissue was identified solely via weak immunostaining. Finally, CLDN18.2 expression significantly correlated with lymph node metastasis, distant metastasis, nerve invasion, stage, and survival of PDAC patients, while there was no correlation between CLDN18.2 expression and localization, tumor size, patient age and sex, nor any other clinicopathological characteristic. CONCLUSIONCLDN18.2 expression is frequently increased in PDAC patients. Thus, it may act as a potential therapeutic target for zolbetuximab in PDAC.     

Future of targeted therapy for gastrointestinal cancer: Claudin 18.2

The treatment of gastrointestinal cancer has always been a crucial research area, and targeted therapy has been receiving increasing attention. At present, the effect of targeted therapy is unsatisfactory for gastric cancer. Thus, the discovery of new targets is crucial. Claudin 18.2 (CLDN18.2), a member of the claudin family, belongs to the tight junction protein family that controls the flow of molecules between cell layers. CLDN18.2 expression has been discussed in many studies. In recent years, there have been many studies on targeted therapy with CLDN18.2-ideal monoclonal antibody 362. Furthermore, CLDN18.2-specific chimeric antigen receptor T therapy has been used for CLDN18.2-positive tumors, such as gastric and pancreatic cancers. Considerable research has been focused on CLDN18.2. CLDN18.2, a newly discovered marker for precise targeted therapy of gastric cancer, could offer new hope for the treatment of gastric cancer.     

CLDN18.2在胃癌中的研究进展

CLDN18.2是表达于正常胃黏膜的紧密连接蛋白,参与构成细胞间的紧密连接,影响细胞旁离子通透性.CLDN18.2在胃癌中阳性率可达40％左右,其表达特异性使其成为胃癌治疗的潜在靶点.靶向CLDN18.2的抗体药IMAB362联合化疗可显著延长CLDN18.2阳性胃癌患者生存,IMAB362有望进入胃癌一线治疗.然而由...     

Claudin 18.2 is a target for IMAB362 antibody in pancreatic neoplasms

The majority of pancreatic neoplasms are characterized by a generally lethal progress within a short period of time after primary diagnosis and the mortality of patients is expected to increase further. Due to lack of efficient screening programs and moderate response to treatments, novel compounds for treatment are needed. We investigated the CLDN18.2 expression in affected patients as in vitro feasibility study for a potential treatment with the novel antibody IMAB362. Therefore, we analyzed the expression of CLDN18.2 in normal pancreatic tissues (N = 24), primary lesions (N = 202), metastases (N = 84) and intra‐individually matched samples (N = 48) of patients with pancreatic ductal adenocarcinoma (PDAC), neuroendocrine neoplasia (NEN) and acinar cell carcinoma. A standardized method for evaluation by immunohistochemistry was developed. The specific staining was evaluated by two independent raters and analysis of staining intensities (range 0–3+) and relative proportions of tumor cells were performed. One hundred three (59.2%) samples of primary PDAC were found positive. The vast majority of positive samples were characterized to highly express CLDN18.2: 54.6% (N = 95) with staining intensities of ≥2+. NEN were positive in 20% of cases (all ≥2+). Metastases of pancreatic neoplasms were also frequently found positive with comparable high rates (69.4% of lymph node and 65.7% of liver metastases). The rate of CLDN18.2 positivity is high in pancreatic neoplasms whereby the expression is not limited to the primaries but is also maintained upon metastasis. Thus, a considerable number of patients with pancreatic neoplasms would be in principle eligible for a CLDN18.2‐targeting approach.     

Phosphatase activity of nuclear PTEN is required for CDX2-mediated intestinal differentiation of gastric carcinoma

The PTEN tumor suppressor localizes predominantly to the cytoplasm, where it negatively regulates the phosphatidylinositol 3-kinase-AKT signaling pathway; however, the biological significance of nuclear PTEN in gastric carcinoma (GC) remains unknown. In this study, transduction of recombinant PTEN into GC-derived TMK-1 cells promoted PTEN nuclear localization with increased mRNA levels of CDX2 and intestinal claudins (CLDN3 and CLDN4), whereas the G129E phosphatase 'dead' mutant had no effect. In GC tissue samples, tumors with nuclear PTEN expression frequently demonstrated the intestinal-type claudin phenotype. Our results suggested that nuclear localization of PTEN is important for determining intestinal differentiation of GCs.     

CLDN18表达在胃癌进展中的意义

探讨CLDN18表达与胃癌临床病理特征之间的关系。方法:组织芯片免疫组化染色法检测胃癌claudin-18蛋白表达，Real-time PCR法检测胃癌CLDN18 mRNA的表达。结果:胃癌组织claudin-18表达显著降低，并与组织学类型和浸润相关，肠型胃癌和浸润在肌层以内者其黏膜层claudin-18的下调表达率明显高于弥漫型胃癌或浸润程度超过肌层者。从黏膜层进展至侵袭前缘区，claudin-18的下调表达率逐渐升高，黏膜层claudin-18表达水平明显高于侵袭前沿区。进展期胃癌黏膜层癌组织claudin-18表达未下调者34例进展至侵袭前沿区28例转变为表达下调，其中弥漫型胃癌、浸润程度超过肌层者、有淋巴结转移者以及非贲门胃癌者发生率均高于肠型胃癌、浸润程度在肌层内者、无淋巴结转移者以及贲门胃癌者。52例胃癌黏膜层胃癌组织CLDN18 mRNA表达下调者20例，其相对表达量与浸润程度及肿瘤大小有关。结论:胃癌的进展中claudin-18表达降低，组织学类型的维持与其密切相关。      

Comprehensive analyses using next-generation sequencing and immunohistochemistry enable precise treatment in advanced gastric cancer

BackgroundIn advanced gastric cancer (AGC), most clinical trials are designed on the basis of protein expression or gene amplification of specific genes. Recently, next-generation sequencing (NGS) allowed us to comprehensively profile the tumor gene status. This study aimed to elucidate the profiling between gene alterations and protein expression in AGC to aid in future clinical trials on AGC.Patients and methodsFormalin-fixed, paraffin-embedded tumor samples from 121 stage III/IV gastric cancer patients were examined for protein expression of tyrosine kinase receptors (RTKs; ERBB2, EGFR, c-MET, and FGFR2) using immunohistochemistry (IHC). Furthermore, 409 cancer-related genes were sequenced to detect mutations and copy number variations using NGS.ResultsMost ERBB2 overexpression (IHC 3+) cases (80.0%) had ERBB2 amplification and did not have other RTK amplification or oncogene mutations. However, one-fourth of MET overexpression cases (25.0%) had ERBB2 alterations. EGFR and FGFR2 overexpression cases had ERBB2 alterations or other gene alterations such as KRAS or PIK3CA. On the other hand, most of the four RTK amplification cases (88.2%) were mutually exclusive with each amplification. However, RTK amplification did not simply correlate with protein overexpression, whereas cases with RTK high-level amplification had protein overexpression and rarely showed other co-existing gene alterations.ConclusionAGC involves a complicated arrangement of protein expression and gene alterations. Comprehensive analyses of NGS and IHC will be necessary to design the optimal therapy for treating the appropriate population of patients in future clinical trials.     

Impact of genomic alterations on lapatinib treatment outcome and cell-free genomic landscape during HER2 therapy in HER2+ gastric cancer patients

BackgroundTo identify predictive markers for responders in lapatinib-treated patients and to demonstrate molecular changes during lapatinib treatment via cell-free genomics.Patients and methodsWe prospectively evaluated the efficacy of combining lapatinib with capecitabine and oxaliplatin as first line neoadjuvant therapy in patients with previously untreated, HER2-overexpressing advanced gastric cancer. A parallel biomarker study was conducted by simultaneously performing immunohistochemistry and next-generation sequencing (NGS) with tumor and blood samples.ResultsComplete response was confirmed in 7/32 patients (21.8%), 2 of whom received radical surgery with pathologic-confirmed complete response. Fifteen partial responses (46.8%) were observed, resulting in a 68.6% overall response rate. NGS of the 16 tumor specimens demonstrated that the most common co-occurring copy number alteration was CCNE1 amplification, which was present in 40% of HER2+ tumors. The relationship between CCNE1 amplification and lack of response to HER2-targeted therapy trended toward statistical significance (66.7% of non-responders versus 22.2% of responders harbored CCNE1 amplification; P = 0.08). Patients with high level ERBB2 amplification by NGS were more likely to respond to therapy, compared with patients with low level ERBB2 amplification (P = 0.02). Analysis of cfDNA showed that detectable ERBB2 copy number amplification in plasma was predictive to the response (100%, response rate) and changes in plasma-detected genomic alterations were associated with lapatinib sensitivity and/or resistance. The follow-up cfDNA genomics at disease progression demonstrated that there are emergences of other genomic aberrations such as MYC, EGFR, FGFR2 and MET amplifications.ConclusionsThe present study showed that HER2+ GC patients respond differently according to concomitant genomic aberrations beyond ERBB2, high ERBB2 amplification by NGS or cfDNA can be a positive predictor for patient selection, and tumor genomic alterations change significantly during targeted agent therapy.     

Prognostic value and clinicopathological correlation of the tumor regression grade in neoadjuvant chemotherapy for gastric adenocarcinoma: a retrospective cohort study

BackgroundNeoadjuvant chemotherapy (NACT) and radical gastrectomy are the gold standard treatments for resectable advanced gastric cancer (GC). However, the prognostic value of the pathological tumor regression grade (TRG) of NACT remains controversial. This retrospective study aimed to investigate the correlation between the TRG after NACT and clinicopathological features as well as its prognostic value in advanced GC.MethodsIn total, 551 patients with GC who received NACT combined with surgical resection at the Zhejiang Cancer Hospital from April 2004 to December 2019 were included. The demographic characteristics, treatment response, tumor characteristics, treatment regimens, and survival data were reviewed from the medical records of all patients. The Chi-square test was used to analyze the correlation between TRG and clinicopathological factors. Kaplan-Meier univariate analysis and Cox regression multivariate analysis were used to determine the independent risk factors affecting the prognosis of GC patients.ResultsAmong the 551 patients with advanced GC who accepted NACT treatment, 14 were determined to be in TRG 0, 98 in TRG 1, 257 in TRG 2, and 182 in TRG 3. Also, TRG was significantly correlated with the cT stage (P=0.015), ypT stage (P<0.001), ypN stage (P<0.001), ypTNM stage (P<0.001), vascular tumor thrombus (P<0.001), Borrmann classification (P=0.042), and lymph node ratio (LNR) (P<0.001). Furthermore, patients who had a good pathological response to NACT had a better prognosis, with a 3-year overall survival (OS) of 70.9% versus 48.8% in patients who had a poor pathological response. We also found that TRG (P=0.042, HR =1.65) was an independent prognostic factor affecting the OS of GC patients.ConclusionsTRG plays a significant role in the prognostic value in neoadjuvant chemotherapy for gastric adenocarcinoma. Patients with higher cT stage, higher levels of pre-CA199 and pre-CA125 may have worse pathological response.     

The prognostic relevance of histologic subtype in appendiceal adenocarcinoma

BackgroundThe aim of this population-based study was to determine the prognostic value of the histologic subtypes mucinous (MAC), non-mucinous (AC) and signet ring cell (SRCC) adenocarcinoma among patients with appendiceal cancer.Methods and materialsData from the Netherlands Cancer Registry (NCR) of patients with primary appendiceal adenocarcinomas with MAC, AC and SRCC histologic subtype, diagnosed between 2001 and 2015 were used (n = 675). To categorize patients according to the recent histopathological classification, the NCR was linked with the Dutch Pathology Registry (PALGA). Log-rank tests and Kaplan-Meier analyses were performed to estimate overall survival (OS), and the cox proportional hazards model was run to identify prognostic factors.ResultsAC was the most frequently encountered histologic subtype (50.9%), followed by MAC (35.8%) and SRCC (13.3%). In locoregional disease, histologic subtype was not a prognostic factor for OS with 5-year survival rates for patients with AC, MAC and SRCC of 60.0%, 60.5% and 69.6% respectively (p = 0.68). Metastatic disease was more common in SRCC (53.8%) than in MAC (38.8%) and AC (23.4%) (p < 0.0001). Median OS for patients with metastatic disease was 12.6, 27.7 and 18.2 months in AC, MAC and SRCC respectively (p < 0.005). MAC was associated with higher survival compared to AC (HR 0.48, 95%CI 0.34–0.69). In subanalyses, MAC was only a positive prognostic factor compared to AC in patients with peritoneal metastases (HR 0.42, 95%CI 0.28–0.62).ConclusionHistologic subtype had no prognostic relevance in locoregional or systemic metastatic disease in appendiceal adenocarcinoma. In peritoneal metastases, mucinous histologic subtype was a favorable prognostic factor, compared to non-mucinous and signet ring cell subtype.     

Diagnostic and prognostic value of MATN3 expression in gastric carcinoma: TCGA database mining

BackgroundsGlobally, the high morbidity and mortality of gastric carcinoma (GC) have been one of the great challenges facing humanity. However, the early diagnosis of GC is still unknown. Matrilin-3 (MATN3) is a member of the extracellular matrix (ECM) protein family. Previous studies have reported a correlation between the expression of MATN3 and bone disease. However, the role of MATN3 in GC has not been reported in depth, which can have a possible far-reaching implication for GC.MethodsWe explored the diagnostic and prognostic value and pathway enrichment of MATN3 expression in GC. Limma package conducted by R was used to analysis the difference expression data of MATN3 from The Cancer Genome Atlas (TCGA). The receiver operating characteristic (ROC) curve analysis was used to estimate the diagnostic value of MATN3 expression. univariate and multivariate analysis were used to assess the prognostic value of MATN3, and gene set enrichment analysis (GSEA) to identify the enriched signaling pathways.ResultsMATN3 was found to be significantly higher in GC tissue samples. GC patients with high MATN3 expression had poor prognosis. Then, GSEA showed that the gene sets were correlated with signaling pathways including ECM receptor interaction, hypertrophic cardiomyopathy (HCM), and glycosaminoglycan biosynthesis chondroitin sulfate, among others.ConclusionsThe study suggests that MATN3 can serve as a potential diagnostic and prognostic biomarker for GC.     

Prediction and prognostic significance of ALOX12B and PACSIN1 expression in gastric cancer by genome-wide RNA expression and methylation analysis

BackgroundStomach adenocarcinoma (STAD) is one of the common gastrointestinal cancers, characterized by late discovery and metastasis. However, research of gene methylation and expression in gastric cancer (GC) metastasis has been quite limited. This study aimed to investigate the altered gene expression patterns between metastasis and non-metastasis samples using high-throughput RNA and methylation profiles from a large number of patients. Another aim was to identify a specific potential metastasis biomarker, with the ability to predict the metastasis possibility and prognosis of patients with STAD.MethodsIn this study, we integrated The Cancer Genome Atlas (TCGA) program STAD datasets, analyzed the RNA expression and DNA methylation data between non-metastasis (M0) and distant metastasis (M1) samples, and evaluated the candidate biomarker in survival and prognosis of GC.ResultsAmong all patients enrolled, 329 with M0 and M1 information were positive for RNA analysis, and 353 with M0 and M1 information were positive for methylation analysis. We found 29 upregulated and 200 downregulated genes in RNA level, and 5,046 hypermethylated and 8,563 hypomethylated probes in methylation level. Among these genes, we found high RNA expression level and low DNA methylation level of ALOX12B and PACSIN1 in GC metastasis samples. Patients with high expression of these 2 genes had poor overall survival (OS), progression-free survival (PFS), and post-progression survival (PPS).ConclusionsThe expression levels of ALOX12B and PACSIN1 were higher in the metastasis than non-metastasis group, and participants with high expression of these 2 genes were found to have poor survival. The genes ALOX12B and PACSIN1 are potential biomarkers of metastasis and poor prognosis, especially in early stage GC, and provide additional information for subsequent comprehensive treatment of GC.     

KRAS gene status in gastric signet-ring cell carcinoma patients and acts as biomarker of MEK inhibitor

BackgroundSignet-ring cell carcinoma (SRCC) is a specific subtype of stomach cancer with unique epidemiology. Here, we sought to explore the role of KRAS in SRCC.MethodsKRAS status was studied both in The Cancer Genome Atlas (TCGA) and internal cohorts. Immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) were performed in formalin-fixed and paraffin-embedded (FFPE) samples. We explored patients’ survival and clinicopathological characteristics in terms of KRAS mutation and expression. We also explored KRAS status and drug response curve of MEK/mTOR inhibitors in SRCC cell lines.ResultsPatients with KRAS mutations and copy number variation (CNV) showed higher mRNA level compared to non-mutant cases (P=0.003 and P<0.001). In internal cohort, 15 samples harbored KRAS mutations. Survival analysis showed that these patients had significantly lower overall survival (OS) (P=0.048). We further analyzed 75 patients with sufficient FFPE samples. Eight patients showed KRAS mutations and one patient showed KRAS amplification. The median OS was 12.5 months for patients with KRAS mutation, and 19.5 months for patients without KRAS mutation (P=0.005). Positive expression of KRAS as shown by IHC was detected in majority of SRCC samples, which was higher than our intestinal cohort (28% vs. 12.6%, P=0.033). We further explored the correlation between KRAS status and drug sensitivity in 4 SRCC cell lines. SNU601 and SNU668, which harbored KRAS mutation, were hypersensitive to MEK and mTOR inhibitors than KRAS wide type cell lines KATO-III and NUGC-4.ConclusionsOur findings demonstrate that KRAS gene plays an important role in SRCC and reveals therapeutic potential of targeting tumors by inhibiting MEK and mTOR pathways.     

Next-generation sequencing (NGS) of cell-free circulating tumor DNA and tumor tissue in patients with advanced urothelial cancer: a pilot assessment of concordance

BackgroundAdvances in cancer genome sequencing have led to the development of various next-generation sequencing (NGS) platforms. There is paucity of data regarding concordance of different NGS tests carried out in the same patient.MethodsHere, we report a pilot analysis of 22 patients with metastatic urinary tract cancer and available NGS data from paired tumor tissue [FoundationOne (F1)] and cell-free circulating tumor DNA (ctDNA) [Guardant360 (G360)].ResultsThe median time between the diagnosis of stage IV disease and the first genomic test was 23.5 days (0–767), after a median number of 0 (0–3) prior systemic lines of treatment of advanced disease. Most frequent genomic alterations (GA) were found in the genesTP53 (50.0%),TERT promoter (36.3%);ARID1 (29.5%);FGFR2/3 (20.5%), PIK3CA (20.5%) andERBB2 (18.2%). While we identified GA in both tests, the overall concordance between the two platforms was only 16.4% (0%–50%), and 17.1% (0%–50%) for those patients (n =6) with both tests conducted around the same time (median difference = 36 days). On the contrary, in the subgroup of patients (n =5) with repeated NGS in ctDNA after a median of 1 systemic therapy between the two tests, average concordance was 55.5% (12.1%–100.0%). Tumor tissue mutational burden was significantly associated with number of GA in G360 report (P<0.001), number of known GA (P =0.009) and number of variants of unknown significance (VUS) in F1 report (P<0.001), and with total number of GA (non-VUS and VUS) in F1 report (P<0.001).ConclusionsThis study suggests a significant discordance between clinically available NGS panels in advanced urothelial cancer, even when collected around the same time. There is a need for better understanding of these two possibly complementary NGS platforms for better integration into clinical practice.     

Expression and prognostic significance of thrombospondin gene family in gastric cancer

BackgroundThrombospondins (THBSs) are glycoproteins expressed in the extracellular matrix (ECM) and have critical roles in tumor development and metastasis. However, the diverse expression patterns and prognostic roles of distinct THBS genes in gastric cancer have not been fully elucidated. In the current study, we aimed to investigate the expression patterns of THBSs in gastric cancer (GC) and determine whether they are prognostic markers for this malignancy.MethodsmRNA expression status and genetic mutations of THBS family members were performed by using ONCOMINE, UCSC Xena browser, GEPIA, and cBioPortal databases. Prognostic values and function enrichment analysis of the members were assessed via Kaplan-Meier plotter and Metascape.Resultswe found that the mRNA expression of THBS1, THBS2, THBS4, and COMP were higher in patients with GC tissues than those in normal gastric mucosa and there was no difference in the mRNA expression of THBS3 between GC and normal tissue. Survival analysis revealed that mRNA levels of THBSs were strongly related to worse OS in GC patients (P<0.05). Overexpression of THBSs indicated poor OS in stage III/IV GC and high expression of THBS1, THBS3, THBS4, and COMP were related to worse OS in stage II GC.ConclusionsBioinformatics analysis revealed a better understanding the value of THBS family members in GC and suggest that THBSs might serve as potential prognostic biomarkers for GC.