Abstract
Genetic variations in microRNAs (miRNA) that affect control of their target genes may alter individual susceptibilities to cancer. In this study, we took an in silico approach to identify single-nucleotide polymorphisms (SNP) within the 3'-untranslated region (UTR) of miRNA genes deregulated in human small-cell lung cancer (SCLC), and then investigated their associations with SCLC susceptibility in 666 SCLC patients and 758 controls. Odds ratios (OR) were estimated by multivariate logistic regression, and biochemical assays were conducted to investigate SNP functions. We identified 2 SNPs, rs3134615 and rs2291854, which were located in the 3'-UTR of the L-MYC gene MYCL1 and the neuronal development Achaete-Scute Complex homolog ASCL1. Case-control analyses showed that the rs3134615T allele was associated with a significantly increased risk of SCLC, with the OR for carrying the GT or TT genotype being 2.08 (95% confidence interval, 1.39-3.21; P = 0.0004) compared with the GG genotype. In support of the likelihood that these 3'-UTR SNPs may directly affect miRNA-binding sites, reporter gene assays indicated MYCL1 as the target of hsa-miR-1827 and the rs3134615 G>T change resulted in altered regulation of MYCL1 expression. Our findings define a 3'-UTR SNP in the human L-MYC oncogene that may increase susceptibility to SCLC, possibly resulting from attenuated interaction with the miRNA hsa-miR-1827.
Highlights
Lung cancer is the leading cause of cancer-related deaths worldwide [1]
We found that H446 cells transfected with vectors containing the rs3134615 G allele of the MYCL1 30-untranslated region (UTR) yielded a 22% reduced luciferase activity compared with cells transfected with vectors containing the
We have examined 2 single-nucleotide polymorphisms (SNP), rs3134615 and rs2291854, located respectively in the 30-untranslated region (30-UTR) of the MYCL1 and ASCL1 genes that are deregulated in Small-cell lung cancer (SCLC), and identified rs3134615 SNP in the hsa-miR-1827 complementary site of MYCL1 30-UTR associated with increased risk for developing SCLC in a Chinese population
Summary
Lung cancer is the leading cause of cancer-related deaths worldwide [1]. Small-cell lung cancer (SCLC) is the most aggressive subtype of lung cancer, characterized by rapid doubling time, high growth fraction, and early development of widespread metastases [2]. SCLC is a complex trait caused by both genetic and environmental factors. Smoking is a well-known environmental risk factor for SCLC; little has been known about the genetic factors associated with the development of SCLC. It has been reported previously that the CYP3A4*1B variant and MPO promoter À463G variant are associated with increased risk of developing SCLC [3, 4]. Several genome-wide association studies have been conducted to explore the common genetic variations associated with susceptibility to lung
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