Functional genetic variants in centrosome-related genes CEP72 and YWHAG confer susceptibility to gastric cancer
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GENOTOXICITY AND CARCINOGENICITY
Functional genetic variants in centrosome‑related genes CEP72 and YWHAG confer susceptibility to gastric cancer Jing Ni1,2 · Jinchen Wang1,2 · Yao Fu3 · Caiwang Yan1,2 · Meng Zhu1,2 · Yue Jiang1,2 · Jiaping Chen1,2 · Yanbing Ding4 · Xiangshan Fan3 · Gang Li5 · Guangfu Jin1,2 Received: 7 December 2019 / Accepted: 7 May 2020 © Springer-Verlag GmbH Germany, part of Springer Nature 2020
Abstract Structural and numeric centrosome aberrations can induce chromosome segregation errors and promote tumor development and progression. We systematically evaluated associations of 19,603 single nucleotide polymorphisms (SNPs) across 136 centrosome-related genes with gastric cancer (GC) risk using four GWAS datasets with a total of 3771 cases and 5426 controls. We identified two loci at 15p13.3 and 7q11.23 significantly associated with GC risk, whose risk alleles were correlated with increased mRNA expression of CEP72 (P = 7.30 × 10–4) and YWHAG (P = 1.60 × 10–3), respectively. Dual-luciferase reporter assays confirmed that the risk T allele of rs924607 at 15p13.3 significantly increased a promoter activity of the reporter gene, leading to a higher CEP72 expression level. At 7q11.23, the risk haplotype of rs2961037 [G]-rs2961038 [G] significantly elevated an enhancer activity and the expression of YWHAG. Both the mRNA and protein levels of CEP72 and YWHAG were overexpressed in GC tumor tissues compared with peritumor tissues and overexpression of either gene showed an unfavorable prognosis of GC patients. Moreover, knockdown of either CEP72 or YWHAG inhibited GC cell proliferation, migration and invasion and promoted GC cell apoptosis. The genes coexpressed with CEP72 or YWHAG in GC tumor tissues were enriched in the Ras signaling pathway, which was confirmed that knockdown of either one decreased the expression of cyclin D1 but increased the expression of p21 and p27. In conclusion, genetic variants at 15p13.3 and 7q11.23 may confer GC risk via modulating the biological functions of CEP72 and YWHAG, respectively, suggesting the importance of centrosome-regulated genes in GC development. Keywords Centrosome · Stomach cancer · Mutation · Gene regulation
Jing Ni and Jinchen Wang contributed equally to this work. Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00204-020-02782-7) contains supplementary material, which is available to authorized users. * Gang Li [email protected] * Guangfu Jin [email protected] 1
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Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing 211166, People’s Republic of China Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Medicine, Nanjing Medical University, Nanjing 211166, People’s Republic of China
Abbreviations GWAS Genome-wide association studies SNP Single nucleotide polymorphism MSigDB The Molecular Signatures Database eQTL Expression quantitative trait locus MAF Minor allele
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