Nasha Zhang1,2, Yan Zheng2, Jie Liu2, Tiansui Lei2, Yeyang Xu1,2, Ming Yang3. 1. Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China. 2. Shandong Provincial Key Laboratory of Radiation Oncology, Cancer Research Center, Shandong Cancer Hospital Affiliated to Shandong University, Shandong Academy of Medical Sciences, Jinan, 250117, Shandong, China. 3. Shandong Provincial Key Laboratory of Radiation Oncology, Cancer Research Center, Shandong Cancer Hospital Affiliated to Shandong University, Shandong Academy of Medical Sciences, Jinan, 250117, Shandong, China. aaryoung@yeah.net.
Abstract
BACKGROUND: Aberrant telomere lengthening is a critical feature of malignant cells. Short leukocyte telomere length (LTL) confers elevated risk of gastric cardia adenocarcinoma (GCA). Multiple genome-wide association studies (GWAS) identified various single-nucleotide polymorphisms (SNPs) associated with LTL in different ethnic populations. However, it remains largely unexplored how these genetic variants are involved in GCA susceptibility. METHODS: We systematically screened GWAS-identified candidate SNPs and tested the impact of 30 polymorphisms in genes associated with interindividual LTL variation on GCA using two-stage case-control comparisons consisting of 1024 GCA patients and 1118 controls. RESULTS: We observed that CXCR4 rs6430612, TERT rs10069690, and rs2853676 as well as VPS34 rs2162440 are significantly associated with GCA development. A 0.64-fold decreased risk of GCA is associated with the CXCR4 rs6430612 CT genotype compared with the CC genotype (P = 0.002). On the contrary, the TERT rs10069690 TT genotype carriers had a 1.83-fold increased risk to develop GCA compared to the CC genotype carriers (P = 5.8×10-6). We also detected a 2.17-fold increased OR for GCA that was associated with the TERT rs2853676 TT genotype (P = 2.6×10-6). In addition, the odds of having the VPS34 rs2162440 GA genotype in GCA patients were 1.35 compared with the GG genotype (P = 0.002). In stratified analyses, the association between TERT rs10069690 polymorphism and GCA was more pronounced in nonsmokers (Pinteraction = 9.7 × 10-5) and nondrinkers (Pinteraction = 4.6 × 10-5). CONCLUSIONS: Our results highlight the importance of both LTL and LTL-related genetic variants to GCA predisposition.
BACKGROUND: Aberrant telomere lengthening is a critical feature of malignant cells. Short leukocyte telomere length (LTL) confers elevated risk of gastric cardia adenocarcinoma (GCA). Multiple genome-wide association studies (GWAS) identified various single-nucleotide polymorphisms (SNPs) associated with LTL in different ethnic populations. However, it remains largely unexplored how these genetic variants are involved in GCA susceptibility. METHODS: We systematically screened GWAS-identified candidate SNPs and tested the impact of 30 polymorphisms in genes associated with interindividual LTL variation on GCA using two-stage case-control comparisons consisting of 1024 GCA patients and 1118 controls. RESULTS: We observed that CXCR4rs6430612, TERTrs10069690, and rs2853676 as well as VPS34rs2162440 are significantly associated with GCA development. A 0.64-fold decreased risk of GCA is associated with the CXCR4rs6430612 CT genotype compared with the CC genotype (P = 0.002). On the contrary, the TERTrs10069690 TT genotype carriers had a 1.83-fold increased risk to develop GCA compared to the CC genotype carriers (P = 5.8×10-6). We also detected a 2.17-fold increased OR for GCA that was associated with the TERTrs2853676 TT genotype (P = 2.6×10-6). In addition, the odds of having the VPS34rs2162440 GA genotype in GCA patients were 1.35 compared with the GG genotype (P = 0.002). In stratified analyses, the association between TERTrs10069690 polymorphism and GCA was more pronounced in nonsmokers (Pinteraction = 9.7 × 10-5) and nondrinkers (Pinteraction = 4.6 × 10-5). CONCLUSIONS: Our results highlight the importance of both LTL and LTL-related genetic variants to GCA predisposition.
Authors: Julius Gudmundsson; Gudmar Thorleifsson; Jon K Sigurdsson; Lilja Stefansdottir; Jon G Jonasson; Sigurjon A Gudjonsson; Daniel F Gudbjartsson; Gisli Masson; Hrefna Johannsdottir; Gisli H Halldorsson; Simon N Stacey; Hannes Helgason; Patrick Sulem; Leigha Senter; Huiling He; Sandya Liyanarachchi; Matthew D Ringel; Esperanza Aguillo; Angeles Panadero; Enrique Prats; Almudena Garcia-Castaño; Ana De Juan; Fernando Rivera; Li Xu; Lambertus A Kiemeney; Gudmundur I Eyjolfsson; Olof Sigurdardottir; Isleifur Olafsson; Hoskuldur Kristvinsson; Romana T Netea-Maier; Thorvaldur Jonsson; Jose I Mayordomo; Theo S Plantinga; Hannes Hjartarson; Jon Hrafnkelsson; Erich M Sturgis; Unnur Thorsteinsdottir; Thorunn Rafnar; Albert de la Chapelle; Kari Stefansson Journal: Nat Commun Date: 2017-02-14 Impact factor: 14.919
Authors: Z Xiang; Z-J Zhou; G-K Xia; X-H Zhang; Z-W Wei; J-T Zhu; J Yu; W Chen; Y He; R E Schwarz; R A Brekken; N Awasthi; C-H Zhang Journal: Oncogene Date: 2017-05-08 Impact factor: 9.867
Authors: Daniel Levy; Susan L Neuhausen; Steven C Hunt; Masayuki Kimura; Shih-Jen Hwang; Wei Chen; Joshua C Bis; Annette L Fitzpatrick; Erin Smith; Andrew D Johnson; Jeffrey P Gardner; Sathanur R Srinivasan; Nicholas Schork; Jerome I Rotter; Utz Herbig; Bruce M Psaty; Malinee Sastrasinh; Sarah S Murray; Ramachandran S Vasan; Michael A Province; Nicole L Glazer; Xiaobin Lu; Xiaojian Cao; Richard Kronmal; Massimo Mangino; Nicole Soranzo; Tim D Spector; Gerald S Berenson; Abraham Aviv Journal: Proc Natl Acad Sci U S A Date: 2010-04-26 Impact factor: 11.205
Authors: Veryan Codd; Massimo Mangino; Pim van der Harst; Peter S Braund; Michael Kaiser; Alan J Beveridge; Suzanne Rafelt; Jasbir Moore; Chris Nelson; Nicole Soranzo; Guangju Zhai; Ana M Valdes; Hannah Blackburn; Irene Mateo Leach; Rudolf A de Boer; Masayuki Kimura; Abraham Aviv; Alison H Goodall; Willem Ouwehand; Dirk J van Veldhuisen; Wiek H van Gilst; Gerjan Navis; Paul R Burton; Martin D Tobin; Alistair S Hall; John R Thompson; Tim Spector; Nilesh J Samani Journal: Nat Genet Date: 2010-02-07 Impact factor: 38.330
Authors: S Volinia; R Dhand; B Vanhaesebroeck; L K MacDougall; R Stein; M J Zvelebil; J Domin; C Panaretou; M D Waterfield Journal: EMBO J Date: 1995-07-17 Impact factor: 11.598
Authors: Ma Lili; Fan Yuxiang; Han Zhongcheng; Su Ying; Chen Ru; Xu Rong; Liu Jiang Journal: Medicine (Baltimore) Date: 2020-06-05 Impact factor: 1.817