Efforts to address the poor prognosis associated with esophageal adenocarcinoma (EAC) have been hampered by a lack of biomarkers to identify early disease and therapeutic targets. Despite extensive efforts to understand the somatic mutations associated with EAC over the past decade, a gap remains in understanding how the atlas of genomic aberrations in this cancer impacts the proteome and which somatic variants are of importance for the disease phenotype. We performed a quantitative proteomic analysis of 23 EACs and matched adjacent normal esophageal and gastric tissues. We explored the correlation of transcript and protein abundance using tissue-matched RNA-seq and proteomic data from seven patients and further integrated these data with a cohort of EAC RNA-seq data (n = 264 patients), EAC whole-genome sequencing (n = 454 patients), and external published datasets. We quantified protein expression from 5879 genes in EAC and patient-matched normal tissues. Several biomarker candidates with EAC-selective expression were identified, including the transmembrane protein GPA33. We further verified the EAC-enriched expression of GPA33 in an external cohort of 115 patients and confirm this as an attractive diagnostic and therapeutic target. To further extend the insights gained from our proteomic data, an integrated analysis of protein and RNA expression in EAC and normal tissues revealed several genes with poorly correlated protein and RNA abundance, suggesting posttranscriptional regulation of protein expression. These outlier genes, including SLC25A30, TAOK2, and AGMAT, only rarely demonstrated somatic mutation, suggesting post-transcriptional drivers for this EAC-specific phenotype. AGMAT was demonstrated to be overexpressed at the protein level in EAC compared to adjacent normal tissues with an EAC-selective, post-transcriptional mechanism of regulation of protein abundance proposed. Integrated analysis of proteome, transcriptome, and genome in EAC has revealed several genes with tumor-selective, posttranscriptional regulation of protein expression, which may be an exploitable vulnerability.

• MeSH
• adenokarcinom * genetika   metabolismus   patologie   MeSH
• lidé MeSH
• multiomika MeSH
• nádorové biomarkery * metabolismus   genetika   MeSH
• nádory jícnu * genetika   metabolismus   patologie   MeSH
• posttranskripční úpravy RNA MeSH
• proteom metabolismus   MeSH
• proteomika * metody   MeSH
• regulace genové exprese u nádorů * MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

• MeSH
• klinická studie jako téma MeSH
• lidé MeSH
• nádory jícnu * genetika   MeSH
• nádory žaludku genetika   MeSH
• sekvenční analýza DNA metody   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• komentáře MeSH
• souhrny MeSH

• MeSH
• gastroezofageální junkce MeSH
• lidé MeSH
• nádory jícnu * farmakoterapie   genetika   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• komentáře MeSH
• práce podpořená grantem MeSH

The Cdx2 homeobox gene is important in assigning positional identity during the finely orchestrated process of embryogenesis. In adults, regenerative responses to tissues damage can require a replay of these same developmental pathways. Errors in reassigning positional identity during regeneration can cause metaplasias-normal tissue arising in an abnormal location-and this in turn, is a well-recognized cancer risk factor. In animal models, a gain of Cdx2 function can elicit a posterior shift in tissue identity, modeling intestinal-type metaplasias of the esophagus (Barrett's esophagus) and stomach. Conversely, loss of Cdx2 function can elicit an anterior shift in tissue identity, inducing serrated-type lesions expressing gastric markers in the colon. These metaplasias are major risk factors for the later development of esophageal, stomach and colon cancer. Leukemia, another cancer in which Cdx2 is ectopically expressed, may have mechanistic parallels with epithelial cancers in terms of stress-induced reprogramming. This review will address how animal models have refined our understanding of the role of Cdx2 in these common human cancers.

• MeSH
• ezofágus patologie   MeSH
• homeoboxové geny genetika   MeSH
• kolon patologie   MeSH
• lidé MeSH
• metaplazie genetika   patologie   MeSH
• modely nemocí na zvířatech MeSH
• nádory jícnu genetika   patologie   MeSH
• nádory tračníku genetika   patologie   MeSH
• nádory žaludku genetika   patologie   MeSH
• progrese nemoci MeSH
• regulace genové exprese u nádorů * MeSH
• transkripční faktor CDX2 genetika   metabolismus   MeSH
• žaludek patologie   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH

Esophageal and gastric cancers represent tumors with poor prognosis. Unfortunately, radiotherapy, chemotherapy, and targeted therapy have made only limited progress in recent years in improving the generally disappointing outcome. Immunotherapy with checkpoint inhibitors is a novel treatment approach that quickly entered clinical practice in malignant melanoma and renal cell cancer, but the role in esophageal and gastric cancer is still poorly defined. The principal prognostic/predictive biomarkers for immunotherapy efficacy currently considered are PD-L1 expression along with defects in mismatch repair genes resulting in microsatellite instability (MSI-H) phenotype. The new molecular classification of gastric cancer also takes these factors into consideration. Available reports regarding PD-1, PD-L1, PD-L2 expression and MSI status in gastric and esophageal cancer are reviewed to summarize the clinical prognostic and predictive role together with potential clinical implications. The most important recently published clinical trials evaluating checkpoint inhibitor efficacy in these tumors are also summarized.

• MeSH
• antigeny CD273 metabolismus   MeSH
• antigeny CD274 metabolismus   MeSH
• antigeny CD279 metabolismus   MeSH
• epitelo-mezenchymální tranzice MeSH
• exprese genu MeSH
• fenotyp MeSH
• imunita * MeSH
• imunoterapie * metody   MeSH
• kombinovaná terapie MeSH
• lidé MeSH
• mikrosatelitní nestabilita MeSH
• mikrosatelitní repetice MeSH
• nádory jícnu diagnóza   genetika   imunologie   terapie   MeSH
• nádory žaludku diagnóza   genetika   imunologie   terapie   MeSH
• únik nádoru z imunitní kontroly imunologie   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

• MeSH
• antigeny CD274 antagonisté a inhibitory   MeSH
• geny erbB genetika   účinky léků   MeSH
• imunohistochemie metody   MeSH
• lidé MeSH
• mikrosatelitní nestabilita MeSH
• nádorové biomarkery MeSH
• nádory jícnu * genetika   klasifikace   patologie   MeSH
• nádory žaludku * genetika   klasifikace   patologie   MeSH
• oprava chybného párování bází DNA genetika   MeSH
• Check Tag
• lidé MeSH

The prognosis of esophageal cancer (EC) is poor, despite considerable effort of both experimental scientists and clinicians. The tri-modality treatment consisting of neoadjuvant chemoradiation followed by surgery has remained the gold standard over decades, unfortunately, without significant progress in recent years. Suitable prognostic factors indicating which patients will benefit from this tri-modality treatment are missing. Some patients rapidly progress on the neoadjuvant chemoradiotherapy, which is thus useless and sometimes even harmful. At the same time, other patients achieve complete remission on neoadjuvant chemoradiotherapy and subsequent surgery may increase their risk of morbidity and mortality. The prognosis of patients ranges from excellent to extremely poor. Considering these differences, the role of drug metabolizing enzymes and transporters, among other factors, in the EC response to chemotherapy may be more important compared, for example, with pancreatic cancer where all patients progress on chemotherapy regardless of the treatment or disease stage. This review surveys published literature describing the potential role of ATP-binding cassette transporters, the genetic polymorphisms, epigenetic regulations, and phenotypic changes in the prognosis and therapy of EC. The review provides knowledge base for further research of potential predictive biomarkers that will allow the stratification of patients into defined groups for optimal therapeutic outcome.

• MeSH
• ABC transportéry genetika   metabolismus   MeSH
• epigeneze genetická MeSH
• lidé MeSH
• nádorové biomarkery genetika   metabolismus   MeSH
• nádory jícnu genetika   metabolismus   terapie   MeSH
• neoadjuvantní terapie metody   MeSH
• polymorfismus genetický MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

The incidence of adenocarcinoma of oesophagus or gastro-oesophageal junction is increasing in Europe and other regions of the Western world. Research of possible causes has shifted to the molecular level. This study evaluated human papillomavirus (HPV) using real-time PCR and mutational status of selected genes using the multiparallel sequencing method (NGS) in DNA extracted from paraffin-embedded tumour tissue of 56 patients with oesophageal or gastro-oesophageal junction adenocarcinoma. The genetic material was in sufficient quality for the analysis in 37 cases (66 %). No HPV-positive sample was found. NGS revealed higher frequency of mutations in TP53, ARID1A, PIK3CA, SMAD4, ERBB2, MSH6, BRCA2, and RET genes. Association between gene mutations and histological grade, subtype according to Lauren, or primary tumour site was not statistically significant. In conclusion, the study did not confirm any HPV-positive sample of oesophageal and gastro-oesophageal junction adenocarcinoma. The study confirmed the usefulness of NGS analysis of paraffin-embedded tissue of these tumours, and it could be used in clinical studies to evaluate the prognostic and/or predictive value of the tested mutations. The association between gene mutations and histological features should be tested in larger patient cohorts.

• MeSH
• adenokarcinom genetika   virologie   MeSH
• dospělí MeSH
• frekvence genu genetika   MeSH
• gastroezofageální junkce patologie   virologie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• mutace genetika   MeSH
• mutační analýza DNA * MeSH
• nádory jícnu genetika   virologie   MeSH
• Papillomaviridae genetika   MeSH
• senioři MeSH
• vysoce účinné nukleotidové sekvenování * MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

Background: Esophageal squamous cell carcinoma (ESCC) is considered as the seventh most common cancer worldwide, and the second prevalent malignancy in the north of Iran. A subfamily group of tumor-specific antigens, commonly specified as cancer/testis antigens (CTAs), are expressed restrictedly in testis, ovary, and placenta. Melanoma-associated antigen A4 (MAGEA4) as a CTA is overexpressed in a variety of cancers. Expressional analysis of MAGEA4 protein in ESCC may be useful to investigate its clinical relevance leading to effective improvements in ESCC diagnosis and treatment. Materials and Methods: Fifty-six ESCC patients with no preoperative therapeutic circumstance such as radiotherapy or chemotherapy were analyzed to explore the protein expression level of MAGEA4 using immunohistochemistry assay. Results: MAGEA4 overexpression was detected in 66% of ESCC samples showing strong nuclear and cytoplasmic staining compared to the normal epithelium. There were significant correlations between MAGEA4 protein expression and depth of tumor invasion (P = 0.019), and the number of involved lymph nodes (P = 0.045). Conclusion: Because of the significant correlation of MAGEA4 and indices of poor prognosis, the role of this CTA may be confirmed in ESCC aggressiveness and metastasis. Therefore, MAGEA4 may be a promising therapeutic candidate for suppressing ESCC aggressiveness.

• MeSH
• antigeny nádorové genetika   MeSH
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• lymfatické metastázy genetika   patologie   MeSH
• nádorové biomarkery genetika   MeSH
• nádorové proteiny genetika   MeSH
• nádory jícnu genetika   patologie   MeSH
• přežití po terapii bez příznaků nemoci MeSH
• prognóza * MeSH
• regulace genové exprese u nádorů genetika   MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• skvamózní karcinom jícnu MeSH
• spinocelulární karcinom genetika   patologie   MeSH
• staging nádorů MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

Esophageal cancer is a disease with disappointing prognosis. Currently, there are no predictive factors that can identify patients who on the one hand would likely benefit from tri-modality management and, on the other hand, would not be significantly affected by the morbidity accompanying the treatment. MicroRNAs are short non-coding RNAs responsible for post-transcriptional modification of gene expression by binding to 3'-UTR of messenger RNA and represent emerging potential predictive biomarkers of treatment (chemotherapy and radiotherapy) efficacy and toxicity. We reviewed the current literature, addressing the potential predictive role of microRNAs for efficacy of chemotherapy (specifically cisplatin, 5-fluorouracil, doxorubicin and paclitaxel) and radiotherapy, including predicted targets in the cell. Altogether 82 articles were identified and included in this review. This may be the first review on this topic specifically focusing on neoadjuvant treatment of esophageal cancer.

• MeSH
• adjuvantní chemoradioterapie MeSH
• lidé MeSH
• mikro RNA biosyntéza   genetika   MeSH
• nádory jícnu genetika   terapie   MeSH
• neoadjuvantní terapie MeSH
• prediktivní hodnota testů MeSH
• prognóza MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH