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Genome-Wide Association of Genetic Variation in the PSCA Gene with Gastric Cancer Susceptibility in a Korean Population

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Genome-Wide Association of Genetic Variation in the PSCA Gene with Gastric Cancer Susceptibility in a Korean Population pISSN 1598-2998, eISSN 2005-9256 Cancer Res Treat. 2019;51(2):748-757 https://doi.org/10.4143/crt.2018.162 Original Article Open Access Genome-Wide Association of Genetic Variation in the PSCA Gene with Gastric Cancer Susceptibility in a Korean Population Boyoung Park, MD, PhD1,2 Purpose Sarah Yang, PhD3,4 Half of the world’s gastric cancer cases and the highest gastric cancer mortality rates are observed in Eastern Asia. Although several genome-wide association studies (GWASs) have Jeonghee Lee, MS3 revealed susceptibility genes associated with gastric cancer, no GWASs have been con- PhD3 Hae Dong Woo, ducted in the Korean population, which has the highest incidence of gastric cancer. Il Ju Choi, MD, PhD5 Young Woo Kim, MD, PhD5 Materials and Methods Keun Won Ryu, MD, PhD5 We performed genome scanning of 450 gastric cancer cases and 1,134 controls via Affymetrix Axiom Exome 319 arrays, followed by replication of 803 gastric cancer cases and Young-Il Kim, MD, PhD5 3,693 healthy controls. Jeongseon Kim, PhD2,3 Results We showed that the rs2976394 in the prostate stem cell antigen (PSCA) gene is a gastric- 1Department of Medicine, Hanyang cancer-susceptibility gene in a Korean population, with genome-wide significance and an University College of Medicine, Seoul, odds ratio (OR) of 0.70 (95% confidence interval [CI], 0.64 to 0.77). A strong linkage dise- 2 Graduate School of Cancer Science and quilibrium with rs2294008 was also found, indicating an association with susceptibility. Policy, National Cancer Center, Goyang, 3Molecular Epidemiology Branch, Division of Individuals with the CC genotype of the PSCA gene showed an approximately 2-fold lower Cancer Epidemiology and Prevention, risk of gastric cancer compared to those with the TT genotype (OR, 0.47; 95% CI, 0.39 to Research Institute, National Cancer Center, 0.57). The effect of the PSCA gene on gastric cancer was more prominent in the female Goyang, 4Department of Public Health, population and for diffuse type gastric cancer. Graduate School of Public Health, Seoul National University, Seoul, Conclusion 5Center for Gastric Cancer, Our result confirmed that the PSCA gene may be the most important susceptibility gene for National Cancer Center Hospital, gastric cancer risk in a Korean population. National Cancer Center, Goyang, Korea + C +o r+re s+p o+n d+e n+c e +: J e+o n +g s +e o +n K+i m +, P+h D+ + + + + + + + + + + + + + + + + + + + + + + + + Key words + G +r a +d u +a t e+ S +ch o+o l+ o f+ C +an c+e r+ S c+ie n+c e+ a n+d +P o +li c +y , + National Cancer Center, 323 Ilsan-ro, Stomach neoplasms, Genome-wide association study, + + + + + + + + + + + + + + + + + + + + Prostate stem cell antigen gene + I l+s a +n d +o n +g - g+u ,+ G +oy +an g+ 1 +0 4 +08 ,+ K o+r e+a + + + + + + T +e l :+ 8 2+-3 1+- 9 +2 0 +-2 5 +7 0 + + + + + + + + + + + + + F +a x +: 8 2+- 3 +1 - 9+2 0 +-2 5+7 9+ + + + + + + + + + + + + E +-m +a i l+: j s+k i +m @+n c+c . r+e . k+r + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + R +e c +ei v +e d + M +a r+c h + 1 5 +, 2 +01 8+ + + + + + + + + + + A +c c +ep +te d + S +e p +te m+ b +er +4, 2+0 1 +8 + + + + + + + + + P +u b +li s +h e d+ O +n l+in e+ S +e p +te m+ b +er +5, 2+0 1+8 + + + + + + + + + + + + + + + + + + + + + + + + + Introduction tion growth and aging [1]. Half of the world’s gastric cancer cases are in Eastern Asia, and the highest mortality rates are also found in this region [2]. Gastric cancer is the fifth most common type of cancer and Many previous studies have investigated the risk factors the second most common cause of cancer death worldwide for gastric cancer and indicated that Helicobacter pylori infec- [1]. Although the incidence rate has decreased, the absolute tion is one of the most important factors in its etiology [3,4]. number of gastric cancer cases has increased due to popula- However, countries in Eastern Asia, such as Japan and China, 748 Copyright ⓒ 2019 by the Korean Cancer Association │ https://www.e-crt.org │ This is an Open-Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. Boyoung Park, Variation in the PSCA Gene with Gastric Cancer have a high gastric cancer incidence rate despite low H. pylori 86,949 SNPs remained, and SNPs showing (1) call rates < 0.95 infection rates. In contrast, other countries, such as India, in cases or controls (n=0), (2) deviation from the Hardy- Bangladesh, Pakistan, and Thailand, have a high prevalence Weinberg equilibrium (HWE) (p < 110–6) in controls (n=36), of H. pylori infection but low gastric cancer incidence rates, or (3) minor allele frequencies < 0.01 (n=36,781) in cases and suggesting that individual genetic characteristics may influ- controls were excluded. There were 40,659 markers remain- ence the risk of gastric carcinogenesis [5]. ing, the mean success rate of individuals was 0.998 after fil- In this context, the effects of genetic susceptibility factors tering, and 450 cases and 1,134 controls were included in the for gastric cancer have been explored in several candidate discovery stage. variation approaches, and several recent genome-wide asso- For replication, 803 gastric cancer cases and 3,693 healthy ciation studies (GWASs) have yielded suggestive variations. controls who were recruited as part of the Korean Genome Most of the GWASs were conducted in Asian countries, Epidemiology Study (KoGES) from an urban community including China and Japan, and the variants associated with were used. The genotyping was performed using an Affy- gastric cancer were located at the PSCA [6], PLCE1 [7], PTG- metrix Genome-wide Human SNP Array 6.0 (Affymetrix ER4-PKKAA1, ZBTB20 [8], LRFN2, DNAH11 [9], PRKAA1, Inc.), and 569,930 variants were available for further analysis MUC1, and UNC5CL genes [10]. In addition, a study in a after the same quality control criteria were applied. European population showed that loss-of-function variants in the ATM gene increased gastric cancer risk [11]. Although 3. Imputation of genotypes the incidence of gastric cancer is high in Korea [12], GWASs targeting the Korean population are limited, and replication Genotypes were phased using SHAPEIT (v2. r837), and phases with a Korean population have been conducted in genotype imputation was performed using IMPUTE2 (2.3.2). only a few studies [6,10]. The 1000 Genome Project phase 3 East Asian Ancestry sam- Therefore, we investigated genetic polymorphisms associ- ple (n=504) was used for a reference panel. The variants with ated with gastric cancer development in a Korean population INFO scores above 0.6 were retained for an NCC sample using a genome-wide scanning approach based on gastric (n=2,073,558), and for KoGES, variants with INFO 0.9 cancer patients and healthy controls and large replication (n=6,699,176) were selected. After controlling for the miss- sets from a Korean population cohort. ingness rate, HWE, and minor allele frequency, 713,348 SNPs for NCC and 4,470,730 SNPs for KoGES were available for further analysis. Materials and Methods 4. Statistical analysis For the discovery stage, logistic regression analysis based 1. Study population on an additive genetic model was performed to identify the association between each SNP and gastric cancer status with For GWAS analysis, subjects were recruited from the adjustments for age and sex. In addition, we performed strat- National Cancer Center (NCC) in Korea. A total of 450 pati- ified analysis by sex. The SNPs with a p-value of < 5105 in ents with histologically confirmed gastric cancer at the Cen- the total population or either the male or female subgroup ter for Gastric Cancer between April 2011 and December were selected for replication in the KoGES samples. A total 2014 and 1,135 controls who participated in a cancer screen- of 51 SNPs for the total population, 36 SNPs for males, and ing program between April 2011 and December 2014 were 52 SNPs for females were replicated in the KoGES samples. enrolled in this study. The genomic DNA samples of the par- In the replication stage, logistic regression analysis based on ticipants were extracted from peripheral blood leukocytes. an additive genetic model was also applied with adjustment for age and sex. For the replicated SNPs showing statistical 2. Genome-wide scanning and quality controls significance (p < 0.05 in the replication phase), a codominant model with the homozygote of the major allele as a reference Genome-wide scanning was performed using Axiom was applied to calculate frequencies and odds ratios (ORs). Exome 319 (Affymetrix Inc., Santa Clara, CA) containing In addition, the effect of the PSCA gene was adjusted, and 318,983 polymorphisms to 450 gastric cancer cases and 1,135 the SNPs with p-value of < 5105 for the total population controls. None of the subjects had a call rate < 90%. Geno- and males and SNPs with p-value of < 1105 for females in typing revealed that 68.1% of the single-nucleotide polymor- the discovery stage were selected for replication. phisms (SNPs) in the array plate were monomorphic in the To combine the association results for the discovery and Korean population. After excluding monomorphic variants, replication stages, a meta-analysis with a fixed-effect model VOLUME 51 NUMBER 2 APRIL 2019 749 Cancer Res Treat.
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