Thrift, Aaron P

INTRODUCTION: The adjunctive use of p53 immunohistochemistry has been proposed as a potential tool to improve risk stratification in Barrett's esophagus (BE) with conflicting results. We performed a systematic review and meta-analysis to evaluate the performance of p53 in predicting progression to advanced neoplasia (high-grade dysplasia [HGD] and esophageal adenocarcinoma [EAC]) among patients with BE. METHODS: We searched multiple databases for studies that evaluated the use of aberrant p53 in esophageal biopsies among patients with BE and reported progression rates to HGD/EAC. The outcomes were p53 test characteristics and incidence and risk ratio (RR) for progression to HGD/EAC in patients with and without aberrant p53 using random effects models. RESULTS: Among the 27 included studies, the proportion of patients with aberrant p53 expression at baseline was 20% (95% CI: 14%, 27%). The rate of progression with and without aberrant p53 was 8 per 100 person-years (95% CI: 6, 11) and 0.3 per 100 person-years (95% CI: 0.1, 0.6), respectively. Compared with patients without aberrant p53 expression, those with aberrant p53 had a higher risk for progression to HGD/EAC in cohort studies (RR = 10.2 [95% CI: 6.9, 15.0]) and case control studies (RR = 3.3 [95% CI: 2.5, 4.4]). The sensitivity for progression for non-dysplastic Barrett's esophagus and low-grade dysplasia/indefinite for dysplasia was 42% and 77% and specificity was 96% and 76%, respectively. DISCUSSION: While aberrant p53 expression has been associated with an increased risk of progression to advanced neoplasia in patients with BE undergoing surveillance, the diagnostic characteristics are suboptimal precluding uniform clinical adoption. Prospective studies with standardized grading protocols are needed to determine whether p53-guided surveillance strategies can meaningfully improve patient outcomes.

Abstract Hepatocellular carcinoma (HCC) mortality is increasing globally, partly due to the growing prevalence of nonviral liver diseases. Genome‐wide association studies (GWAS) have identified genetic variants associated with HCC development. Leveraging GWAS summary statistics and linkage disequilibrium score regression (LDSR), we investigated disease co‐development with hepatitis C virus‐negative (HCV‐negative) HCC to provide unique insights into HCC etiology and prioritize relationships for further causal inquiry. We utilized the LDSR statistical framework to estimate the genetic correlation and heritability between HCV‐negative HCC with 901 epidemiologic, behavioral, and clinical traits from the United Kingdom Biobank (UKBB). First, we set the threshold for observed scale heritability of each trait at 0.02 to ensure reliable inferences with adequate study power. Next, we observed significant positive genetic correlations between HCV‐negative HCC and blood‐based biomarkers of liver injury (ALT, GGT) and allostatic load (including glycated hemoglobin, blood pressure, and total albumin). We also identified a positive genetic correlation between HCV‐negative HCC and diseases associated with metabolic dysfunction‐associated steatotic liver disease (MASLD), including diabetes, hypertension, chronic ischemic heart disease, and others. Taken together, our results help to identify polygenic and pleiotropic signals related to different phenotypic traits associated with HCC and support further exploration of the predictive power of blood‐based biomarkers identified in this study for inferring HCC development among HCV‐negative individuals.