ABSTRACT

Genome-wide association studies (GWAS) have identified SNPs linked with lung cancer risk. Our aim was to discover the genes, non-coding RNAs, and regulatory elements within GWAS-identified risk regions that are deregulated in non-small cell lung carcinoma (NSCLC) to identify novel, clinically targetable genes and mechanisms in carcinogenesis. A targeted bisulphite-sequencing approach was used to comprehensively investigate DNA methylation changes occurring within lung cancer risk regions in 17 NSCLC and adjacent normal tissue pairs. We report differences in differentially methylated regions between adenocarcinoma and squamous cell carcinoma. Among the minimal regions found to be differentially methylated in at least 50% of the patients, 7 candidates were replicated in 2 independent cohorts (n = 27 and n = 87) and the potential of 6 as methylation-dependent regulatory elements was confirmed by functional assays. This study contributes to understanding the pathways implicated in lung cancer initiation and progression, and provides new potential targets for cancer treatment.

摘要

全基因组关联研究 (GWAS) 已经确定了与肺癌风险相关的 SNP。我们的目标是在 GWAS 识别的风险区域内发现在非小细胞肺癌 (NSCLC) 中失调的基因、非编码 RNA 和调控元件，以识别新的、临床可靶向的基因和致癌机制。使用靶向亚硫酸氢盐测序方法全面研究了 17 个 NSCLC 和相邻正常组织对中肺癌风险区域内发生的 DNA 甲基化变化。我们报告了腺癌和鳞状细胞癌之间差异甲基化区域的差异。在至少 50% 的患者中发现差异甲基化的最小区域中，7 个候选者在 2 个独立的队列（n = 27 和 n = 87）中重复，并且通过功能测定证实了 6 个作为甲基化依赖性调节元件的潜力。该研究有助于了解与肺癌发生和进展有关的途径，并为癌症治疗提供新的潜在靶点。