Format

Send to

Choose Destination
Genome Med. 2018 Feb 27;10(1):16. doi: 10.1186/s13073-018-0522-9.

Weak sharing of genetic association signals in three lung cancer subtypes: evidence at the SNP, gene, regulation, and pathway levels.

Author information

1
Vanderbilt Genetics Institute, Vanderbilt University School of Medicine, Nashville, TN, USA.
2
Department of Biomedical Informatics, Vanderbilt University Medical Center, Nashville, TN, USA.
3
Center for Precision Health, School of Biomedical Informatics, The University of Texas Health Science Center at Houston, 7000 Fannin St. Suite 820, Houston, TX, 77030, USA.
4
Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA.
5
Vanderbilt Genetics Institute, Vanderbilt University School of Medicine, Nashville, TN, USA. zhongming.zhao@uth.tmc.edu.
6
Department of Biomedical Informatics, Vanderbilt University Medical Center, Nashville, TN, USA. zhongming.zhao@uth.tmc.edu.
7
Center for Precision Health, School of Biomedical Informatics, The University of Texas Health Science Center at Houston, 7000 Fannin St. Suite 820, Houston, TX, 77030, USA. zhongming.zhao@uth.tmc.edu.
8
Human Genetics Center, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX, USA. zhongming.zhao@uth.tmc.edu.

Abstract

BACKGROUND:

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.

METHODS:

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.

RESULTS:

We identified 8295, 8734, and 8361 SNPs with moderate association signals for LUAD, LUSC, and SCLC, respectively. Those SNPs had p < 1 × 10- 3 in the original GWAS or were within LD (r2 > 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.

CONCLUSIONS:

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.

KEYWORDS:

Enhancer; Functional genomics; GWAS; Lung cancer subtype; Pathway analysis; eQTL

PMID:
29486777
PMCID:
PMC5828003
DOI:
10.1186/s13073-018-0522-9
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for BioMed Central Icon for PubMed Central
Loading ...
Support Center