Vanderbilt Genetics Institute, Vanderbilt University School of Medicine, Nashville, TN, USA.
Department of Biomedical Informatics, Vanderbilt University Medical Center, Nashville, TN, USA.
Genome Med. 2018 Feb 27;10(1):16. doi: 10.1186/s13073-018-0522-9.
There are two main types of lung cancer: small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC). NSCLC has many subtypes, but the two most common are lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC). These subtypes are mainly classified by physiological and pathological characteristics, although there is increasing evidence of genetic and molecular differences as well. Although some work has been done at the somatic level to explore the genetic and biological differences among subtypes, little work has been done that interrogates these differences at the germline level to characterize the unique and shared susceptibility genes for each subtype.
We used single-nucleotide polymorphisms (SNPs) from a genome-wide association study (GWAS) of European samples to interrogate the similarity of the subtypes at the SNP, gene, pathway, and regulatory levels. We expanded these genotyped SNPs to include all SNPs in linkage disequilibrium (LD) using data from the 1000 Genomes Project. We mapped these SNPs to several lung tissue expression quantitative trait loci (eQTL) and enhancer datasets to identify regulatory SNPs and their target genes. We used these genes to perform a biological pathway analysis for each subtype.
We identified 8295, 8734, and 8361 SNPs with moderate association signals for LUAD, LUSC, and SCLC, respectively. Those SNPs had p < 1 × 10 in the original GWAS or were within LD (r > 0.8, Europeans) to the genotyped SNPs. We identified 215, 320, and 172 disease-associated genes for LUAD, LUSC, and SCLC, respectively. Only five genes (CHRNA5, IDH3A, PSMA4, RP11-650 L12.2, and TBC1D2B) overlapped all subtypes. Furthermore, we observed only two pathways from the Kyoto Encyclopedia of Genes and Genomes shared by all subtypes. At the regulatory level, only three eQTL target genes and two enhancer target genes overlapped between all subtypes.
Our results suggest that the three lung cancer subtypes do not share much genetic signal at the SNP, gene, pathway, or regulatory level, which differs from the common subtype classification based upon histology. However, three (CHRNA5, IDH3A, and PSMA4) of the five genes shared between the subtypes are well-known lung cancer genes that may act as general lung cancer genes regardless of subtype.
肺癌主要有两种类型：小细胞肺癌（SCLC）和非小细胞肺癌（NSCLC）。NSCLC 有许多亚型，但最常见的两种是肺腺癌（LUAD）和肺鳞状细胞癌（LUSC）。这些亚型主要根据生理和病理特征进行分类，但也有越来越多的证据表明存在遗传和分子差异。尽管已经在体细胞水平上进行了一些工作来探索亚型之间的遗传和生物学差异，但很少有研究在种系水平上探讨这些差异，以描述每个亚型特有的和共同的易感性基因。
我们使用全基因组关联研究（GWAS）的欧洲样本中的单核苷酸多态性（SNP）来探究亚型在 SNP、基因、途径和调控水平上的相似性。我们使用来自 1000 基因组计划的数据扩展了这些已分型的 SNP，以包括所有连锁不平衡（LD）的 SNP。我们将这些 SNP 映射到几个肺组织表达数量性状基因座（eQTL）和增强子数据集，以识别调控 SNP 和其靶基因。我们使用这些基因对每个亚型进行了生物学途径分析。
我们分别为 LUAD、LUSC 和 SCLC 鉴定了 8295、8734 和 8361 个具有中度关联信号的 SNP。这些 SNP 在原始 GWAS 中的 p 值<1×10-8，或与已分型 SNP 的 LD（欧洲人 r > 0.8）相关。我们分别为 LUAD、LUSC 和 SCLC 鉴定了 215、320 和 172 个疾病相关基因。只有五个基因（CHRNA5、IDH3A、PSMA4、RP11-650L12.2 和 TBC1D2B）在所有亚型中都有重叠。此外，我们仅观察到两个来自京都基因与基因组百科全书的途径在所有亚型中共享。在调控水平上，只有三个 eQTL 靶基因和两个增强子靶基因在所有亚型中重叠。
我们的结果表明，三种肺癌亚型在 SNP、基因、途径或调控水平上没有共享太多的遗传信号，这与基于组织学的常见亚型分类不同。然而，在这三个亚型中，有三个（CHRNA5、IDH3A 和 PSMA4）是众所周知的肺癌基因，它们可能作为一般的肺癌基因存在，而与亚型无关。
