eQTL analysis from co-localization of 2739 GWAS loci detects associated genes across 14 human cancers. (English) Zbl 1406.92398
Summary: Genetic variants can predict other “linked” diseases because alterations in one or more genes in vivo may affect relevant phenotype properties. Our study systematically explored the pan-cancer common gene and cancer type-specific genes based on GWAS loci and TCGA data of multiple cancers. It was found that there were 17 SNPs were significantly associated with the expression of 18 genes. Associations between the 18 cis-regulatory genes and the pathologic stage of each cancer showed that MYL2 and PTGFR in HNSC, 4 genes (F8, SATB2, G6PD and UGT1A6) in KIRP, 3 genes (CHMP4C, MAP3K1 and MECP2) in LUAD were all strongly associated with cancer stage levels. Additionally, the survival association analysis showed that SATB2 was correlated with HNSC survival, and MPP1 was strongly associated with the survival of SARC. This study will shed light on the biological pathways involved in cancer-genetic associations, and has the potential to be applied to the predictions of the risk of cancers developing in healthy individuals.
MSC:
| 92D10 | Genetics and epigenetics |
| 62P10 | Applications of statistics to biology and medical sciences; meta analysis |
References:
| [1] | Abbott, K. L.; Nyre, E. T.; Abrahante, J.; Ho, Y. Y.; Isaksson Vogel, R.; Starr, T. K., The candidate cancer gene database: a database of cancer driver genes from forward genetic screens in mice, Nucleic Acids Res., 43, D844-D848 (2015) |
| [2] | Barajas, J. M.; Reyes, R.; Guerrero, M. J.; Jacob, S. T.; Motiwala, T.; Ghoshal, K., The role of miR-122 in the dysregulation of glucose-6-phosphate dehydrogenase (G6PD) expression in hepatocellular cancer, Sci. Rep., 8, 1, 9105 (2018) |
| [3] | Benito, A.; Polat, I. H.; Noé, V.; Ciudad, C. J.; Marin, S.; Cascante, M., Glucose-6-phosphate dehydrogenase and transketolase modulate breast cancer cell metabolic reprogramming and correlate with poor patient outcome, Oncotarget, 8, 63, 106693-106706 (2017) |
| [4] | Bernard, D.; Gil, J.; Dumont, P.; Rizzo, S.; Monté, D.; Quatannens, B.; Hudson, D.; Visakorpi, T.; Fuks, F.; de Launoit, Y., The methyl-CpG-binding protein MECP2 is required for prostate cancer cell growth, Oncogene, 25, 9, 1358-1366 (2006) |
| [5] | Berndt, S. I.; Skibola, C. F.; Joseph, V.; Camp, N. J.; Nieters, A.; Wang, Z., Genome-wide association study identifies multiple risk loci for chronic lymphocytic leukemia, Nat. Genet., 45, 8, 868-876 (2013) |
| [6] | Cao, Z.; Zhang, S., An integrative and comparative study of pan-cancer transcriptomes reveals distinct cancer common and specific signatures, Sci. Rep., 6, 33398 (2016) |
| [7] | Chen, X.; Xu, Z.; Zhu, Z.; Chen, A.; Fu, G.; Wang, Y.; Pan, H.; Jin, B., Modulation of G6PD affects bladder cancer via ROS accumulation and the AKT pathway in vitro, Int. J. Oncol., 53, 4, 1703-1712 (2018) |
| [8] | Chung, J.; Lau, J.; Cheng, L. S., DeltaNp63alpha in head and neck squamous cell carcinoma, EMBO Rep., 11, 10, 777-783 (2010) |
| [9] | Enciso-Mora, V.; Broderick, P.; Ma, Y.; Jarrett, R. F.; Hjalgrim, H.; Hemminki, K., A genome-wide association study of Hodgkin’s lymphoma identifies new susceptibility loci at 2p16.1 (REL), 8q24.21 and 10p14 (GATA3), Nat. Genet., 42, 12, 1126-1130 (2010) |
| [10] | Gabrielsen, I. S.; Viken, M. K.; Amundsen, S. S.; Helgeland, H.; Holm, K.; Flåm, S. T.; Lie, B. A., Autoimmune risk variants in ERAP2 are associated with gene-expression levels in thymus, Genes Immun., 17, 7, 406-411 (2016) |
| [11] | Giambartolomei, C.; Vukcevic, D.; Schadt, E. E.; Franke, L.; Hingorani, A. D.; Wallace, C.; Plagnol, V., Bayesian test for colocalisation between pairs of genetic association studies using summary statistics, PLoS Genet., 10, 5, Article e1004383 pp. (2014) |
| [12] | Gibbs, J. R.; van der Brug, M. P.; Hernandez, D. G.; Traynor, B. J.; Nalls, M. A.; Lai, S. L., Abundant quantitative trait loci exist for DNA methylation and gene expression in human brain, PLoS Gen., 6, Article e1000952 pp. (2010) |
| [13] | The Genotype-Tissue Expression (GTEx) project, Nat. Genet., 45, 6, 580-585 (2013) |
| [14] | Hong, W.; Cai, P.; Xu, C.; Cao, D.; Yu, W.; Zhao, Z.; Huang, M.; Jin, J., Inhibition of glucose-6-phosphate dehydrogenase reverses cisplatin resistance in lung cancer cells via the redox system, Front Pharmacol., 9, 43 (2018) |
| [15] | Hormozdiari, F.; van de Bunt, M.; Segrè, A. V.; Li, X.; Joo, J. W.; Bilow, M.; Sul, J. H.; Sankararaman, S.; Pasaniuc, B.; Eskin, E., Colocalization of GWAS and eQTL signals detects target genes, Am. J. Hum. Genet., 99, 6, 1245-1260 (2016) |
| [16] | Hsu, M. C.; Lee, K. T.; Hsiao, W. C.; Wu, C. H.; Sun, H. Y.; Lin, I. L.; Young, K. C., The dyslipidemia-associated SNP on the APOA1/C3/A5 gene cluster predicts post-surgery poor outcome in Taiwanese breast cancer patients: a 10-year follow-up study, BMC Cancer, 13, 330 (2013) |
| [17] | Joehanes, R.; Zhang, X.; Huan, T.; Yao, C.; Ying, S. X.; Nguyen, Q. T.; Demirkale, C. Y.; Feolo, M. L.; Sharopova, N. R.; Sturcke, A.; Schäffer, A. A., Integrated genome-wide analysis of expression quantitative trait loci aids interpretation of genomic association studies, Genome Biol., 18, 1, 16 (2017) |
| [18] | Kidd, B. A.; Peters, L. A.; Schadt, E. E.; Dudley, J. T., Unifying immunology with informatics and multiscale biology, Nat. Immunol., 15, 118-127 (2014) |
| [19] | Lappalainen, T.; Sammeth, M.; Friedlander, M. R.; Hoen, P. A.; Monlong, J.; Rivas, M. A., Transcriptome and genome sequencing uncovers functional variation in humans, Nature, 501, 506-511 (2013) |
| [20] | Lawrenson, K.; Li, Q.; Kar, S.; Seo, J. H.; Tyrer, J.; Spindler, T. J., Cis-eQTL analysis and functional validation of candidate susceptibility genes for high-grade serous ovarian cancer, Nat. Commun., 22, 8234 (2015) |
| [21] | Li, Q.; Seo, J. H.; Stranger, B.; McKenna, A.; Pe’er, I.; Laframboise, T.; Brown, M.; Tyekucheva, S.; Freedman, M. L., Integrative eQTL-based analyses reveal the biology of breast cancer risk loci, Cell, 152, 3, 633-641 (2013) |
| [22] | Li, Y.; Sun, Z.; Cunningham, J. M.; Aubry, M. C.; Wampfler, J. A.; Croghan, G. A.; Johnson, C.; Wu, D.; Aakre, J. A.; Molina, J.; Wang, L.; Pankratz, V. S., Genetic variations in multiple drug action pathways and survival in advanced stage non-small cell lung cancer treated with chemotherapy, Clin. Cancer Res., 17, 11, 3830-3840 (2011) |
| [23] | Ma, Y. N.; Zhang, H. Y.; Fei, L. R.; Zhang, M. Y.; Wang, C. C.; Luo, Y.; Han, Y. C., SATB2 suppresses non-small cell lung cancer invasiveness by G9a, Clin. Exp. Med., 18, 1, 37-44 (2018) |
| [24] | Major, J. M.; Yu, K.; Weinstein, S. J.; Berndt, S. I.; Hyland, P. L.; Yeager, M.; Chanock, S.; Albanes, D., Genetic variants reflecting higher vitamin e status in men are associated with reduced risk of prostate cancer, J. Nutr., 144, 5, 729-733 (2014) |
| [25] | McCarthy, M. I.; Abecasis, G. R.; Cardon, L. R.; Goldstein, D. B.; Little, J.; Ioannidis, P. A., Genome-wide association studies for complex traits: consensus, uncertainty and challenges, Nat. Rev. Genet., 9, 5, 356-369 (2008) |
| [26] | Montgomery, S. B.; Sammeth, M.; Gutierrez-Arcelus, M.; Lach, R. P.; Ingle, C.; Nisbett, J., Transcriptome genetics using second generation sequencing in a Caucasian population, Nature, 464, 773-777 (2010) |
| [27] | Naranbhai, V.; Fairfax, B. P.; Makino, S.; Humburg, P.; Wong, D.; Ng, E., Genomic modulators of gene expression in human neutrophils, Nat. Commun., 6, 7545 (2015) |
| [28] | Nicolae, D. L.; Gamazon, E.; Zhang, W.; Duan, S.; Dolan, M. E.; Cox, N. J., Trait-associated SNPs are more likely to be eQTLs: annotation to enhance discovery from GWAS, PLoS Genet., 6, Article e1000888 pp. (2010) |
| [29] | Pitre, A.; Ge, Y.; Lin, W.; Wang, Y.; Fukuda, Y.; Temirov, J.; Phillips, A. H.; Peters, J. L.; Fan, Y.; Ma, J.; Nourse, A.; Sinha, C.; Lin, H., An unexpected protein interaction promotes drug resistance in leukemia, Nat. Commun., 8, 1, 1547 (2017) |
| [30] | Podkalicka, J.; Biernatowska, A.; Olszewska, P.; Tabaczar, S.; Sikorski, A. F., The microdomain-organizing protein MPP1 is required for insulin-stimulated activation of H-Ras, Oncotarget, 9, 26, 18410-18421 (2018) |
| [31] | Pomerantz, M. M.; Shrestha, Y.; Flavin, R. J.; Regan, M. M.; Penney, K. L.; Mucci, L. A., Analysis of the 10q11 cancer risk locus implicates MSMB and NCOA4 in human prostate tumorigenesis, PLoS Genet., 6, Article e1001204 pp. (2010) |
| [32] | Purcell, S.; Neale, B.; Todd-Brown, K.; Thomas, L.; Ferreira, M. A.; Bender, D., PLINK: a tool set for whole-genome association and population-based linkage analyses, Am. J. Hum. Genet., 81, 559-575 (2007) |
| [33] | Rada-Iglesias, A.; Bajpai, R.; Swigut, T.; Brugmann, S. A.; Flynn, R. A.; Wysocka, J., A unique chromatin signature uncovers early developmental enhancers in humans, Nature, 470, 279-283 (2011) |
| [34] | Schadt, E. E.; Molony, C.; Chudin, E.; Hao, K.; Yang, X.; Lum, P. Y., Mapping the genetic architecture of gene expression in human liver, PLoS Biol., 6, e107 (2008) |
| [35] | Soufi, M.; Sattler, A. M.; Kurt, B.; Schaefer, J. R., Mutation screening of the APOA5 gene in subjects with coronary artery disease, J. Investig. Med., 60, 7, 1015-1019 (2012) |
| [36] | Stranger, B. E.; Nica, A. C.; Forrest, M. S.; Dimas, A.; Bird, C. P.; Beazley, C., Population genomics of human gene expression, Nat. Genetics, 39, 1217-1224 (2007) |
| [37] | Sur, I.; Taipale, J., The role of enhancers in cancer, Nat. Rev. Cancer, 16, 483-493 (2016) |
| [38] | Ungewitter, E.; Scrable, H., Antagonistic pleiotropy and p53, Mech. Ageing Dev., 130, 1-2, 10-17 (2009) |
| [39] | Visscher, P. M.; Yang, J., A plethora of pleiotropy across complex traits, Nat. Genet., 48, 7, 707-708 (2016) |
| [40] | Wang, S.; Zhou, J.; Wang, X. Y.; Hao, J. M.; Chen, J. Z.; Zhang, X. M.; Jin, H.; Liu, L.; Zhang, Y. F.; Liu, J.; Ding, Y. Q.; Li, J. M., Down-regulated expression of SATB2 is associated with metastasis and poor prognosis in colorectal cancer, J. Pathol., 219, 1, 114-122 (2009) |
| [41] | Ward, L. D.; Kellis, M., HaploReg: a resource for exploring chromatin states, conservation, and regulatory motif alterations within sets of genetically linked variants, Nucleic Acids Res., 40, D930-D934 (2012) |
| [42] | Wei, R.; Zhao, M.; Zheng, C. H.; Zhao, M.; Xia, J., Concordance between somatic copy number loss and down-regulated expression: A pan-cancer study of cancer predisposition genes, Sci. Rep., 6, 37358 (2016) |
| [43] | Wen, X.; Pique-Regi, R.; Luca, F., Integrating molecular QTL data into genome-wide genetic association analysis: probabilistic assessment of enrichment and colocalization, PLoS Genet., 13, 3, Article e1006646 pp. (2017) |
| [44] | Westra, H. J.; Peters, M. J.; Esko, T.; Yaghootkar, H.; Schurmann, C.; Kettunen, J., Systematic identification of trans eQTLs as putative drivers of known disease associations, Nat. Genet., 45, 1238-1243 (2013) |
| [45] | Wittig, R.; Nessling, M.; Will, R. D.; Mollenhauer, J.; Salowsky, R.; Münstermann, E.; Schick, M.; Helmbach, H.; Gschwendt, B.; Korn, B., Candidate genes for cross-resistance against DNA-damaging drugs, Cancer Res., 62, 22, 6698-6705 (2002) |
| [46] | Wu, C.; Hu, Z.; He, Z.; Jia, W.; Wang, F.; Zhou, Y.; Liu, Z.; Zhan, Q.; Liu, Y.; Yu, D.; Zhai, K.; Chang, J.; Qiao, Y.; Jin, G.; Liu, Z.; Shen, Y.; Guo, C., Genome-wide association study identifies three new susceptibility loci for esophageal squamous-cell carcinoma in Chinese populations, Nat. Genet., 43, 7, 679-684 (2011) |
| [47] | Wu, L.; Chen, J.; Qin, Y.; Mo, X.; Huang, M.; Ru, H.; Yang, Y.; Liu, J.; Lin, Y., SATB2 suppresses gastric cancer cell proliferation and migration, Tumour Biol., 37, 4, 4597-4602 (2016) |
| [48] | Yang, J.; Lee, S. H.; Goddard, M. E.; Visscher, P. M., GCTA: a tool for genome-wide complex trait analysis, Am. J. Med. Genet., 88, 76-82 (2011) |
| [49] | Yokota, J.; Shiraishi, K.; Kohno, T., Genetic basis for susceptibility to lung cancer: recent progress and future directions, Adv. Cancer Res., 109, 51-72 (2010) |
| [50] | Yu, W.; Ma, Y.; Shankar, S.; Srivastava, R. K., Role of SATB2 in human pancreatic cancer: Implications in transformation and a promising biomarker, Oncotarget, 7, 36, 57783-57797 (2016) |
| [51] | Zhang, G.; Gu, D.; Zhao, Q.; Chu, H.; Xu, Z.; Wang, M.; Tang, C.; Wu, D.; Tong, N.; Gong, W.; Zhou, J.; Xu, Y.; Zhang, Z.; Chen, J., Genetic variation in C12orf51 is associated with prognosis of intestinal-type gastric cancer in a Chinese population, Biomed. Pharmacother., 69, 133-138 (2015) |
| [52] | Zhang, J.; Zhao, J.; Gao, N.; Wang, Y.; Chen, Y.; Han, J., MECP2 expression in gastric cancer and its correlation with clinical pathological parameters, Medicine (Baltimore), 96, 31, e7691 (2017) |
| [53] | Zhu, F.; Wu, Q.; Ni, Z.; Lei, C.; Li, T.; Shi, Y., miR-19a/b and MeCP2 repress reciprocally to regulate multidrug resistance in gastric cancer cells, Int. J. Mol. Med., 42, 1, 228-236 (2018) |
| [54] | Zhu, Z.; Zhang, F.; Hu, H.; Bakshi, A.; Robinson, M. R.; Powell, J. E.; Montgomery, G. W.; Goddard, M. E.; Wray, N. R.; Visscher, P. M.; Yang, J., Integration of summary data from GWAS and eQTL studies predicts complex trait gene targets, Nat. Genet., 48, 5, 481-487 (2016) |
| [55] | Zhu, Z.; Zhang, F.; Hu, H.; Bakshi, A.; Robinson, M. R.; Powell, J. E.; Montgomery, G. W., Integration of summary data from GWAS and eQTL studies predicts complex trait gene targets, Nat. Genet., 48, 5, 481-487 (2016) |
This reference list is based on information provided by the publisher or from digital mathematics libraries. Its items are heuristically matched to zbMATH identifiers and may contain data conversion errors. In some cases that data have been complemented/enhanced by data from zbMATH Open. This attempts to reflect the references listed in the original paper as accurately as possible without claiming completeness or a perfect matching.
