Dataset Information

Genetic profiles of Barrett's esophagus and esophageal adenocarcinoma in Japanese patients.

ABSTRACT: The genetic characteristics of Barrett's esophagus (BE) and esophageal adenocarcinoma (EAC) in the Japanese population is unclear. This study aims to investigate the genetic characteristics from nondysplastic BE (NDBE) to early EAC in Japan. Clinical information was collected. Moreover, the genetic profile of NDBE without concurrent dysplasia, early EAC, and surrounding BE were also investigated using endoscopic biopsy samples and formalin-fixed, paraffin-embedded specimens from Japanese patients by targeted next-generation sequencing. Immunohistochemical staining for p53 was also performed for EAC lesions. Targeted NGS was performed for 33 cases with 77 specimens. No significant difference exists in the NDBE group between the number of putative drivers per lesion in the short-segment Barrett's esophagus (SSBE) and long-segment Barrett's esophagus (LSBE) [0 (range, 0-1) vs. 0 (range, 0-1). p = 1.00]. TP53 putative drivers were found in two patients (16.7%) with nondysplastic SSBE. TP53 was the majority of putative drivers in both BE adjacent to EAC and EAC, accounting for 66.7% and 66.7%, respectively. More putative drivers per lesion were found in the EAC than in the NDBE group [1 (range, 0-3) vs. 0 (range, 0-1). p < 0.01]. The genetic variants of TP53 in the Japanese early EAC were similar to those in western countries. However, TP53 putative drivers were detected even in Japanese patients with nondysplastic SSBE. This is significant because such nondysplastic SSBE might have higher risk of progressing to high-grade dysplasia or EAC. The risks of progression may not be underestimated and appropriate follow-ups may be necessary even in patients with SSBE.Trial registration: This study was registered at the University Hospital Medical Information Network (UMIN000034247).

SUBMITTER: Tokunaga M

PROVIDER: S-EPMC8417273 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BACKGROUND:The tissue specificity and robustness of miRNAs may aid risk prediction in individuals diagnosed with Barrett's esophagus. As an initial step, we assessed whether miRNAs can positively distinguish esophageal adenocarcinoma from the precursor metaplasia Barrett's esophagus. METHODS:In a case-control study of 150 esophageal adenocarcinomas frequency matched to 148 Barrett's esophagus cases, we quantitated expression of 800 human miRNAs in formalin-fixed paraffin-embedded tissue RNA using NanoString miRNA v2. We tested differences in detection by case group using the ?(2) test and differences in expression using the Wilcoxon rank-sum test. Bonferroni-corrected statistical significance threshold was set at P < 6.25E-05. Sensitivity and specificity were assessed for the most significant miRNAs using 5-fold cross-validation. RESULTS:We observed 46 distinct miRNAs significantly increased in esophageal adenocarcinoma compared with Barrett's esophagus, 35 of which remained when restricted to T1b and T2 malignancies. Three miRNAs (miR-663b, miR-421, and miR-502-5p) were detected in >80% esophageal adenocarcinoma, but <20% of Barrett's esophagus. Seven miRNAs (miR-4286, miR-630, miR-575, miR-494, miR-320e, miR-4488, and miR-4508) exhibited the most extreme differences in expression with >5-fold increases. Using 5-fold cross-validation, we repeated feature (miR) selection and case-control prediction and computed performance criteria. Each of the five folds selected the same top 10 miRNAs, which, together, provided 98% sensitivity and 95% specificity. CONCLUSION:This study provides evidence that tissue miRNA profiles can discriminate esophageal adenocarcinoma from Barrett's esophagus. This large analysis has identified miRNAs that merit further investigation in relation to pathogenesis and diagnosis of esophageal adenocarcinoma. IMPACT:These candidate miRNAs may provide a means for improved risk stratification and more cost-effective surveillance.

Project description:BACKGROUND & AIMS:Genome-wide association studies (GWAS) have identified more than 20 susceptibility loci for esophageal adenocarcinoma (EA) and Barrett's esophagus (BE). However, variants in these loci account for a small fraction of cases of EA and BE. Genetic factors might interact with environmental factors to affect risk of EA and BE. We aimed to identify single nucleotide polymorphisms (SNPs) that may modify the associations of body mass index (BMI), smoking, and gastroesophageal reflux disease (GERD), with risks of EA and BE. METHODS:We collected data on single BMI measurements, smoking status, and symptoms of GERD from 2284 patients with EA, 3104 patients with BE, and 2182 healthy individuals (controls) participating in the Barrett's and Esophageal Adenocarcinoma Consortium GWAS, the UK Barrett's Esophagus Gene Study, and the UK Stomach and Oesophageal Cancer Study. We analyzed 993,501 SNPs in DNA samples of all study subjects. We used standard case-control logistic regression to test for gene-environment interactions. RESULTS:For EA, rs13429103 at chromosome 2p25.1, near the RNF144A-LOC339788 gene, showed a borderline significant interaction with smoking status (P = 2.18×10-7). Ever smoking was associated with an almost 12-fold increase in risk of EA among individuals with rs13429103-AA genotype (odds ratio=11.82; 95% CI, 4.03-34.67). Three SNPs (rs12465911, rs2341926, rs13396805) at chromosome 2q23.3, near the RND3-RBM43 gene, interacted with GERD symptoms (P = 1.70×10-7, P = 1.83×10-7, and P = 3.58×10-7, respectively) to affect risk of EA. For BE, rs491603 at chromosome 1p34.3, near the EIF2C3 gene, and rs11631094 at chromosome 15q14, at the SLC12A6 gene, interacted with BMI (P = 4.44×10-7) and pack-years of smoking history (P = 2.82×10-7), respectively. CONCLUSION:The associations of BMI, smoking, and GERD symptoms with risks of EA and BE appear to vary with SNPs at chromosomes 1, 2, and 15. Validation of these suggestive interactions is warranted.

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Genetic profiles of Barrett's esophagus and esophageal adenocarcinoma in Japanese patients.

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