Citations

Abstract Purpose: Current endoscopy-based screening and surveillance programs have not been proven effective at decreasing esophageal adenocarcinoma (EAC) mortality, creating an unmet need for effective molecular tests for early detection of this highly lethal cancer. We conducted a genome-wide methylation screen to identify novel methylation markers that distinguish EAC and high-grade dysplasia (HGD) from normal squamous epithelium (SQ) or nondysplastic Barrett's esophagus (NDBE). Experimental Design: DNA methylation profiling of samples from SQ, NDBE, HGD, and EAC was performed using HM450 methylation arrays (Illumina) and reduced-representation bisulfate sequencing. Ultrasensitive methylation-specific droplet digital PCR and next-generation sequencing (NGS)-based bisulfite-sequencing assays were developed to detect the methylation level of candidate CpGs in independent esophageal biopsy and endoscopic brushing samples. Results: Five candidate methylation markers were significantly hypermethylated in HGD/EAC samples compared with SQ or NDBE (P < 0.01) in both esophageal biopsy and endoscopic brushing samples. In an independent set of brushing samples used to construct biomarker panels, a four-marker panel (model 1) demonstrated sensitivity of 85.0% and 90.8% for HGD and EACs respectively, with 84.2% and 97.9% specificity for NDBE and SQ respectively. In a validation set of brushing samples, the panel achieved sensitivity of 80% and 82.5% for HGD and EAC respectively, at specificity of 67.6% and 96.3% for NDBE and SQ samples. Conclusions: A novel DNA methylation marker panel differentiates HGD/EAC from SQ/NDBE. DNA-methylation–based molecular assays hold promise for the detection of HGD/EAC using esophageal brushing samples.

Objectives To examine associations between adiposity and adiposity change (loss, stable, gain) and subsequent longitudinal cognitive performance in African Americans in mid and late life. Design Cohort study using linear mixed models. Setting Genetic Epidemiology Network of Arteriopathy. Participants African‐American sibships with hypertension in Jackson, Mississippi (N = 1,108). Measurements Waist circumference and body mass index ( BMI ) were measured at two examinations 5 years apart. Stable adiposity was defined as values within 5% of the first measure. A composite cognitive Z ‐score was derived from individual cognitive test Z ‐scores at two study visits 6 years apart. Results Larger waist circumference was associated with greater rate of cognitive decline during follow‐up (beta = −0.0009 per year, P = .001); BMI , change in waist circumference, and change in BMI were not associated with rate of decline. Loss of adiposity in midlife was associated with higher cognitive Z ‐scores in middle‐aged individuals, and loss of adiposity in late life was associated with lower Z ‐scores in older adults ( P = .01 for interaction between waist circumference and age; P = .04 for interaction between BMI and age). Simultaneous inclusion of waist circumference and BMI in the cross‐sectional model suggested an association between larger waist circumference and poorer cognitive performance (beta = −0.009, P = .006) and between higher BMI and better cognitive performance (beta = 0.014, P = .06). Conclusion The results suggested a differential pattern of the relationship between adiposity and cognition according to age (mid‐ or late life) and regional distribution of adiposity.