Shared Genetic Etiology of Obesity-Related Traits and Barrett's Esophagus/Adenocarcinoma: Insights from Genome-Wide Association Studies

Abstract Background: Obesity is a major risk factor for esophageal adenocarcinoma (EA) and its precursor Barrett's esophagus (BE). Research suggests that individuals with high genetic risk to obesity have a higher BE/EA risk. To facilitate understanding of biological factors that lead to progression from BE to EA, the present study investigated the shared genetic background of BE/EA and obesity-related traits. Methods: Cross-trait linkage disequilibrium score regression was applied to summary statistics from genome-wide association meta-analyses on BE/EA and on obesity traits. Body mass index (BMI) was used as a proxy for general obesity, and waist-to-hip ratio (WHR) for abdominal obesity. …

Achalasia—an unnecessary long way to diagnosis

Although achalasia presents with typical symptoms such as dysphagia, regurgitation, weight loss, and atypical chest pain, the time until first diagnosis often takes years and is frustrating for patients and nevertheless associated with high costs for the healthcare system. A total of 563 patients were interviewed with confirmed diagnosis of achalasia regarding their symptoms leading to diagnosis along with past clinical examinations and treatments. Included were patients who had undergone their medical investigations in Germany. Overall, 527 study subjects were included (male 46%, female 54%, mean age at time of interview 51 ± 14.8 years). Dysphagia was present in 86.7%, regurgitation in 82…

Analysis of Antiproliferative and Chemosensitizing Effects of Sunitinib on Human Esophagogastric Cancer Cells: Synergistic Interaction With Vandetanib via Inhibition of Multireceptor Tyrosine Kinase Pathways

The receptor tyrosine kinases (RTKs), epidermal growth factor receptor (EGFR) and vascular endothelial growth factor receptor 1-3 (VEGFR1-3), are frequently expressed in gastric cancer and are putative therapeutic targets in this disease. We have investigated the anti-proliferative and chemosensitizing properties of the multitargeted small-molecule RTK inhibitors sunitinib and vandetanib in a panel of 4 human gastric and esophageal cancer cell lines. In the 1st instance, the expression of potential targets of these small-molecule inhibitors was examined by reverse transcriptase-polymerase chain reaction, western blotting, and flow cytometry. EGFR mRNA and protein was detected in all cases, …

The Barrett‐associated variants at GDF 7 and TBX 5 also increase esophageal adenocarcinoma risk

Barrett's esophagus (BE) and esophageal adenocarcinoma (EAC) represent two stages within the esophagitis-metaplasia-dysplasia-adenocarcinoma sequence. Previously genetic risk factors have been identified that confer risk to BE and EAC development. However, to which extent the genetic variants confer risk to different stages of the BE/EAC sequence remains mainly unknown. In this study we analyzed three most recently identified BE variants at the genes GDF7 (rs3072), TBX5 (rs2701108), and ALDH1A2 (rs3784262) separately in BE and EAC samples in order to determine their risk effects during BE/EAC sequence. Our data show that rs3072 at GDF7 and rs2701108 at TBX5 are also associated with EAC and …

Prävalenz von Komorbiditäten bei Patienten mit Barrett Ösophagus-Adenokarzinom

Multidisciplinary management of gastric and gastroesophageal cancers

Carcinomas of the stomach and gastroesophageal junction are among the five top leading cancer types worldwide. In spite of radical surgical R0 resections being the basis of cure of gastric cancer, surgery alone provides long-term survival in only 30% of patients with advanced International Union Against Cancer (UICC) stages in Western countries because of the high risk of recurrence and metachronous metastases. However, recent large phase-III studies improved the diagnostic and therapeutic options in gastric cancers, indicating a more multidisciplinary management of the disease. Multimodal strategies combining different neoadjuvant and/or adjuvant protocols have clearly improved the gastric…

Supportive evidence for FOXP 1 , BARX 1 , and FOXF 1 as genetic risk loci for the development of esophageal adenocarcinoma

The Barrett's and Esophageal Adenocarcinoma Consortium (BEACON) recently performed a genome-wide association study (GWAS) on esophageal adenocarcinoma (EAC) and Barrett's esophagus. They identified genome-wide significant association for variants at three genes, namely CRTC1, FOXP1, and BARX1. Furthermore, they replicated an association at the FOXF1 gene that has been previously found in a GWAS on Barrett's esophagus. We aimed at further replicating the association at these and other loci that showed suggestive association with P < 10(-4) in the BEACON sample. In total, we tested 88 SNPs in an independent sample consisting of 1065 EAC cases and 1019 controls of German descent. We could repl…

Dissection of lymph node metastases in esophageal cancer.

There has been much recent debate regarding the best surgical procedure to treat esophageal cancer, in particular with regard to the optimum extent of lymphadenectomy to improve survival while minimizing morbidity. No results obtained by prospective, randomized studies on the comparison of radical esophagectomy and extended lymphadenectomy with limited or less invasive resections following neoadjuvant therapy with regard to perioperative morbidity and prognosis are available to date. Until now, there has been no evidence suggesting the usefulness of sentinel lymph node navigation in esophageal cancers, regardless of the cell type. Furthermore, the question as to the benefits and risks of tw…

Detection of lymph node metastases in esophageal cancer.

Lymph node status is the most important single prognostic factor in esophageal cancer. The detection of involved lymph nodes is therefore the key to cure. This article will provide a meta-analysis and metaregression analysis on the diagnostic performances of current lymph node-detection devices; discuss the recent status of the sentinel lymph node concept in esophageal cancer by the two sentinel node-mapping procedures (the radio-guided and the blue dye techniques) and the developing computed tomography (CT) lymphography; discuss the detection of micrometastases; and the potential clinical application of molecular-based patients' profiles. Combined use of endoscopic ultrasonography fine-nee…

Risk of lymph node metastasis in submucosal esophageal cancer: a review of surgically resected patients

Endoscopic local procedures are increasingly applied in patients with superficial esophageal cancer as an alternative to radical oncologic resection. The objective of this article is to determine the risk of nodal metastases in submucosal (sm) esophageal cancer, comparing the two predominating histologic tumor types, squamous cell cancer (SCC) and adenocarcinoma (ADC).A query of PubMed, MEDLINE, Embase and Cochrane Library (1980-2009) using predetermined search terms revealed 675 abstracts, of which 485 full-text articles were reviewed. A total of 105 articles met the selection criteria. A review of article references and consultation with experts revealed additional articles for inclusion.…

Identification of loci of functional relevance to Barrett's esophagus and esophageal adenocarcinoma: Cross-referencing of expression quantitative trait loci data from disease-relevant tissues with genetic association data.

Esophageal adenocarcinoma (EA) and its precancerous condition Barrett's esophagus (BE) are multifactorial diseases with rising prevalence rates in Western populations. A recent meta-analysis of genome-wide association studies (GWAS) data identified 14 BE/EA risk loci located in non-coding genomic regions. Knowledge about the impact of non-coding variation on disease pathology is incomplete and needs further investigation. The aim of the present study was (i) to identify candidate genes of functional relevance to BE/EA at known risk loci and (ii) to find novel risk loci among the suggestively associated variants through the integration of expression quantitative trait loci (eQTL) and genetic…

The use of neural networks in identifying risk factors for lymph node metastasis and recommending management of t1b esophageal cancer.

The objective of this study was to establish a prediction model of lymph node status in T1b esophageal carcinoma and define the best squamous and adenocarcinoma predictors. The literature lacks a satisfactory level of evidence of T1b esophageal cancer management. We performed an analysis pooling the effects of outcomes of 2098 patients enrolled into 37 retrospective studies using “neural networks” as data mining techniques. The percentages for lymph node, lymphatic (L1), and vascular (V1) invasion in Sm1 esophageal cancers were 24, 46, and 20 per cent, respectively. The same parameters apply to Sm2 with 34, 63, and 38 per cent as opposed to Sm3 with 51, 69, and 47 per cent. The respective …