Abstract
Simple SummaryGallbladder cancer (GBC) is an aggressive disease with poor prognosis that urgently needs risk biomarkers for prevention. Long noncoding RNAs (lncRNAs) have been linked to various types of cancer and have good potential as circulating biomarkers. Prediction of lncRNA expression based on genotype data may contribute to quantify individual GBC risk even without direct lncRNA expression measurement. In this study, we investigate the relationship between GBC risk and genotype-based expression of circulating lncRNAs.Long noncoding RNAs (lncRNAs) play key roles in cell processes and are good candidates for cancer risk prediction. Few studies have investigated the association between individual genotypes and lncRNA expression. Here we integrate three separate datasets with information on lncRNA expression only, both lncRNA expression and genotype, and genotype information only to identify circulating lncRNAs associated with the risk of gallbladder cancer (GBC) using robust linear and logistic regression techniques. In the first dataset, we preselect lncRNAs based on expression changes along the sequence “gallstones → dysplasia → GBC”. In the second dataset, we validate associations between genetic variants and serum expression levels of the preselected lncRNAs (cis-lncRNA-eQTLs) and build lncRNA expression prediction models. In the third dataset, we predict serum lncRNA expression based on individual genotypes and assess the association between genotype-based expression and GBC risk. AC084082.3 and LINC00662 showed increasing expression levels (p-value = 0.009), while C22orf34 expression decreased in the sequence from gallstones to GBC (p-value = 0.04). We identified and validated two cis-LINC00662-eQTLs (r2 = 0.26) and three cis-C22orf34-eQTLs (r2 = 0.24). Only LINC00662 showed a genotyped-based serum expression associated with GBC risk (OR = 1.25 per log2 expression unit, 95% CI 1.04–1.52, p-value = 0.02). Our results suggest that preselection of lncRNAs based on tissue samples and exploitation of cis-lncRNA-eQTLs may facilitate the identification of circulating noncoding RNAs linked to cancer risk.
Highlights
Gallbladder cancer (GBC; International Classification of Diseases, 10th Revision, diagnosis code C23) is an aggressive malignancy responsible for around 85,000 deaths each year worldwide [1]
The final goal of this study was the identification of circulating Long noncoding RNAs (lncRNAs) that may serve as biomarkers for gallbladder cancer (GBC) risk prediction
Genetic studies on molecular phenotypes are mostly based on individuals of European descent, and lncRNA and genotype data from Latin Americans are still limited
Summary
Gallbladder cancer (GBC; International Classification of Diseases, 10th Revision, diagnosis code C23) is an aggressive malignancy responsible for around 85,000 deaths each year worldwide [1]. GBC early symptoms are unspecific, and less than 20% of patients are candidates for curative surgery at diagnosis. This translates into 5-year survival rates of 5% to 30%, depending on the country at diagnosis [2,3,4,5]. GBC incidence and mortality vary widely around the world, with about 65% of cases occurring in less developed countries [6]. As GBC develops over 10–20 years, generally following
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