J Cancer 2020; 11(5):1075-1081. doi:10.7150/jca.35127 This issue

Research Paper

Systematic analyses of genetic variants in chromatin interaction regions identified four novel lung cancer susceptibility loci

Pei Ji1*, Dongsheng Ding1*, Na Qin1*, Cheng Wang1,2,3, Meng Zhu1,3, Yuancheng Li1, Juncheng Dai1,3, Guangfu Jin1,3, Zhibin Hu1,3, Hongbing Shen1,3, Liang Chen4✉, Hongxia Ma1,3✉

1. Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, China.
2. Department of Bioinformatics, School of Basic Medical Sciences, Nanjing Medical University, Nanjing, China.
3. Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Medicine, Nanjing Medical University, Nanjing, China.
4. Department of Thoracic Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
*These authors contributed equally to this work.

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Citation:
Ji P, Ding D, Qin N, Wang C, Zhu M, Li Y, Dai J, Jin G, Hu Z, Shen H, Chen L, Ma H. Systematic analyses of genetic variants in chromatin interaction regions identified four novel lung cancer susceptibility loci. J Cancer 2020; 11(5):1075-1081. doi:10.7150/jca.35127. Available from https://www.jcancer.org/v11p1075.htm

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Abstract

Genome-wide association studies (GWAS) have reported 45 single-nucleotide polymorphisms (SNPs) that may contribute to the susceptibility of lung cancer, with the majority in non-coding regions. However, no study has ever systematically evaluated the association between SNPs in physical chromatin interaction regions and lung cancer risk. In this study, we integrated the chromatin interaction information (Hi-C data) of lung cancer cell line and conducted a meta-analysis with two Asian GWASs (7,127 cases and 6,818 controls) to evaluate the association of potentially functional SNPs in chromatin interaction regions with lung cancer risk. We identified four novel lung cancer susceptibility loci located at 1q21.1 (rs17160062, P=4.00×10-6), 2p23.3 (rs670343, P=4.87×10-7), 2p15 (rs9309336, P=3.24×10-6) and 17q21.2 (rs9252, P=1.51×10-5) that were significantly associated with lung cancer risk after correction for multiple tests. Functional annotation result indicated that these SNPs may contribute to the development of lung cancer by affecting the availability of transcription factor binding sites. The HaploReg analysis suggested that rs9309336 may affect binding motif of transcription factor Foxp1. Expression quantitative trait loci analysis revealed that rs9309336 and rs17160062 could regulate the expressions of cancer-related genes (PUS10 and CHD1L). Our results revealed that variants in chromatin interaction regions could contribute to the development of lung cancer by regulating the expression of target genes, which providing novel implications for the understanding of functional variants in the development of lung cancer.

Keywords: lung cancer, single-nucleotide polymorphisms (SNPs), chromatin interactions, Genome-wide association studies (GWAS), expression quantitative trait loci.