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Distinct esophageal adenocarcinoma molecular subtype has subtype-specific gene expression and mutation patterns.

ABSTRACT: BACKGROUND:Esophageal carcinoma (EC), consists of two histological types, esophageal squamous carcinoma (ESCC) and esophageal adenocarcinoma (EAC). EAC accounted for 10% of EC for centuries; however, the prevalence of EAC has alarmingly risen 6 times and increased to about 50% of EC in recent 30 years in the western countries, while treatment options for EAC patients are still limited. Stratification of molecular subtypes by gene expression profiling methods had offered opportunities for targeted therapies. However, the molecular subtype in EAC has not been defined. Hence, Identification of EAC molecular subtypes is needed and will provide important insights for future new therapies. RESULTS:We performed meta-analysis of gene expression profiling data on three independent EAC cohorts and showed that there are two common molecular subtypes in EAC. Each of the two EAC molecular subtypes has subtype specific expression patterns and mutation signatures. Genes which were over-expressed in subtype I EACs rather than subtype II EAC cases, were enriched in biological processes including epithelial cell differentiation, keratinocyte differentiation, and KEGG pathways including basal cell carcinoma. TP53 and CDKN2A are significantly mutated in both EAC subtypes. 24 genes including SMAD4 were found to be only significantly mutated in subtype I EAC cases, while 30 genes including ARID1A are only significantly mutated in subtype II EACs. CONCLUSION:Two EAC molecular subtypes were defined and validated. This finding may offer new opportunities for targeted therapies.

SUBMITTER: Guo X

PROVIDER: S-EPMC6201634 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature

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Distinct esophageal adenocarcinoma molecular subtype has subtype-specific gene expression and mutation patterns.

Guo Xiangqian X Tang Yitai Y Zhu Wan W

BMC genomics 20181024 1

<h4>Background</h4>Esophageal carcinoma (EC), consists of two histological types, esophageal squamous carcinoma (ESCC) and esophageal adenocarcinoma (EAC). EAC accounted for 10% of EC for centuries; however, the prevalence of EAC has alarmingly risen 6 times and increased to about 50% of EC in recent 30 years in the western countries, while treatment options for EAC patients are still limited. Stratification of molecular subtypes by gene expression profiling methods had offered opportunities for ...[more]

PMID: 30355311

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Project description:Background Sepsis causes a high rate of mortality and long-term morbidity, associated with an imbalance of innate immunity against infections and inflammation. Obesity and diabetes increase the risk for disease severity. Monocyte dysfunction plays a major role and justify further investigations. Objective To investigate the distribution and inflammatory phenotypes in circulating monocyte subsets in patients manifesting with sepsis including septic shock with and without obesity and diabetes. Methods A total of 235 blood samples were tested from critically ill adult patients registered at the intensive care unit (ICU). The cohorts were divided into non-diabetic groups with or without obesity and diabetic groups with or without obesity, suffering from sepsis or septic shock. We determined frequencies of total monocytes and of monocyte subsets in the circulation and density expression levels of functional markers, including CD14, CD16, HLA-DR, CD33, CD163, CD206, and arginase-1 by flow cytometric analysis. Results When progressing to septic shock in non-diabetic and diabetic patients, the percentages of total monocytes among the leukocyte population and of CD33+ and CD14+ monocytes among the monocyte population were consistently down-regulated compared to non-sepsis in non-diabetic and diabetic patients, respectively. Non-diabetic sepsis patients further presented with decreased CD33 and up-regulated CD163 expression density, which was absent in diabetic patients. We subsequently addressed obesity-related changes of monocytes in non-diabetic and diabetic septic patients. Obese septic patients with diabetes were unique in displaying increased monocytic CD16 and CD163 expression. However, obese septic patients without diabetes solely presented with lower amounts of non-classical monocytes. Body mass index (BMI) dependent changes were restricted to diabetic septic patients, with a significantly higher diminution of the classical monocyte subset and concomitantly increased CD16 expression densities. Conclusion Distribution and phenotypes of monocyte subsets were differentially modulated in critically ill patients with and without metabolic disease when progressing to sepsis or septic shock. Only diabetic septic patients displayed decline of classical monocytes and increase of CD16 expression densities. Therefore, diabetes but not obesity appears to promote the inflammatory phenotype of circulating monocytes in critically ill patients.

Project description:Esophageal adenocarcinoma (EAC) is strongly associated with Barrett's esophagus (BE), a pre-malignant condition resulting from gastric reflux. Esophageal squamous cell carcinoma (ESCC), the other major subtype of esophageal cancer, shows strong association with smoking and alcohol intake and no association with gastric reflux. In this study, we constructed and validated gene expression signatures of EAC vs. ESCC tumors using publicly available datasets, and subsequently assessed the enrichment levels of these signatures in commonly used EAC and ESCC cell lines, normal esophageal tissues and normal esophageal cell lines, and primary BE tissues and BE cell lines. We found that unlike ESCC cell lines which were quite similar to primary ESCC tumors, EAC cell lines were considerably different from primary EAC tumors but still more similar to EAC tumors than ESCC tumors, as the genes up in EAC vs. ESCC (EAChi) had considerably lower expression in EAC cell lines than EAC tumors. However, more surprisingly, unlike various normal cell lines (EPC2, Het-1A) which were very similar to various tissues from normal esophagus, BE cell lines (BAR-T, CP-A) were extremely different from primary BE tissues, as BE cell lines had substantially lower levels of EAChi and substantially higher levels of ESCChi gene expression. This ESCC-like profile of the BAR-T remained unaltered even after prolonged exposure to an acidic bile mixture in vitro resulting in malignant transformation of this cell line. However, primary BE tissues had EAC-like gene expression profiles as expected. Only one EAC case from the Cancer Genome Atlas resembled BE cell lines, and while it had the clinical profile and some mutational features of EAC, it had some mutational features, the copy number alteration profile, and the gene expression profile of ESCC instead. These incomprehensible changes in gene expression patterns may result in ambiguous changes in the phenotype and warrants careful evaluation to inform selection of appropriate in vitro tools for future studies on esophageal adenocarcinoma.

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Distinct esophageal adenocarcinoma molecular subtype has subtype-specific gene expression and mutation patterns.

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Distinct esophageal adenocarcinoma molecular subtype has subtype-specific gene expression and mutation patterns.

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