Genome-wide association studies of gastric adenocarcinoma and esophageal squamous cell carcinoma identify a shared susceptibility locus in PLCE1 at 10q23

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Abstract

We conducted a genome-wide association study of gastric cancer (GC) and esophageal squamous cell carcinoma (ESCC) in ethnic Chinese subjects in which we genotyped 551,152 single nucleotide polymorphisms (SNPs). We report a combined analysis of 2,240 GC cases, 2,115 ESCC cases, and 3,302 controls drawn from five studies. In logistic regression models adjusted for age, sex, and study, multiple variants at 10q23 had genome-wide significance for GC and ESCC independently. A notable signal was rs2274223, a nonsynonymous SNP located in PLCE1, for GC ( P=8.40×10 ⁻⁹; per allele odds ratio (OR) = 1.31) and ESCC ( P=3.85×10 ⁻⁹; OR = 1.34). The association with GC differed by anatomic subsite. For tumors located in the cardia the association was stronger ( P=4.19 × 10 ⁻¹⁵; OR= 1.57) and for those located in the noncardia stomach it was absent ( P=0.44; OR=1.05). Our findings at 10q23 could provide insight into the high incidence rates of both cancers in China.

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Most cited references 19

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Prospective study of risk factors for esophageal and gastric cancers in the Linxian general population trial cohort in China.

Gina D Tran, Xiu-Di Sun, Christian C Abnet … (2005)

Esophageal cancer incidence and mortality rates in Linxian, China are among the highest in the world. We examined risk factors for esophageal squamous cell carcinoma (ESCC), gastric cardia cancer (GCC), and gastric noncardia cancer (GNCC) in a population-based, prospective study of 29,584 adults who participated in the Linxian General Population Trial. All study participants completed a baseline questionnaire that included questions on demographic characteristics, personal and family history of disease, and lifestyle factors. After 15 years of follow-up, a total of 3,410 incident upper gastrointestinal cancers were identified, including 1,958 ESCC, 1,089 GCC and 363 GNCC. Cox proportional hazard models were used to estimate risks. Increased age and a positive family history of esophageal cancer (including ESCC or GCC) were significantly associated with risk at all 3 cancer sites. Additional risk factors for ESCC included being born in Linxian, increased height, cigarette smoking and pipe smoking; for GCC, male gender, consumption of moldy breads and pipe smoking; and for GNCC, male gender and cigarette smoking. Protective factors for ESCC included formal education, water piped into the home, increased consumption of meat, eggs and fresh fruits and increased BMI; for GCC, formal education, water piped into the home, increased consumption of eggs and fresh fruits and alcohol consumption; and for GNCC, increased weight and BMI. General socioeconomic status (SES) is a common denominator in many of these factors and improving SES is a promising approach for reducing the tremendous burden of upper gastrointestinal cancers in Linxian.

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Genetic variation in PSCA is associated with susceptibility to diffuse-type gastric cancer.

Masataka Ando, Minoru Ohdaira, Hiromi Sakamoto … (2008)

Gastric cancer is classified into intestinal and diffuse types, the latter including a highly malignant form, linitis plastica. A two-stage genome-wide association study (stage 1: 85,576 SNPs on 188 cases and 752 references; stage 2: 2,753 SNPs on 749 cases and 750 controls) in Japan identified a significant association between an intronic SNP (rs2976392) in PSCA (prostate stem cell antigen) and diffuse-type gastric cancer (allele-specific odds ratio (OR) = 1.62, 95% CI = 1.38-1.89, P = 1.11 x 10(-9)). The association was far less significant in intestinal-type gastric cancer. We found that PSCA is expressed in differentiating gastric epithelial cells, has a cell-proliferation inhibition activity in vitro and is frequently silenced in gastric cancer. Substitution of the C allele with the risk allele T at a SNP in the first exon (rs2294008, which has r(2) = 0.995, D' = 0.999 with rs2976392) reduces transcriptional activity of an upstream fragment of the gene. The same risk allele was also significantly associated with diffuse-type gastric cancer in 457 cases and 390 controls in Korea (allele-specific OR = 1.90, 95% CI = 1.56-2.33, P = 8.01 x 10(-11)). The polymorphism of the PSCA gene, which is possibly involved in regulating gastric epithelial-cell proliferation, influences susceptibility to diffuse-type gastric cancer.

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Functional variants in ADH1B and ALDH2 coupled with alcohol and smoking synergistically enhance esophageal cancer risk.

Naoyuki Kamatani, Yoichiro Kamatani, Tatsuhiko Tsunoda … (2009)

Esophageal squamous cell carcinoma (ESCC) is prevalent among Asian populations, with marked regional variations in incidence and mortality. Patients with ESCC have a very poor prognosis, but detection of ESCC at earlier stages could improve clinical outcome. Therefore, identification of epidemiologic factors that influence the development of ESCC would facilitate prevention and/or early detection of the disease. We performed a 2-step genome-wide association study with subsequent replication analysis using a total of 1070 Japanese ESCC cases and 2836 controls. We also used logistic regression analysis to estimate the effect of gene-gene and gene-environmental interactions. We identified the significant associations of ESCC with 4q21-23 and 12q24 regions, which include nonsynonymous single nucleotide polymorphisms (SNP) in ADH1B (rs1229984, P = 6.76 x 10(-35)) and ALDH2 (rs671, P = 3.68 x 10(-68)) that were previously shown to be associated with ESCC susceptibility. Multiple logistic regression analysis revealed SNP rs671, rs1229984, alcohol drinking, and smoking as the independent risk factors for ESCC (odds ratios of 1.66, 1.85, 1.92, and 1.79, respectively). Moreover, individuals who had both genetic and lifestyle-related risk factors had a nearly 190 times higher risk of ESCC than those who had neither of these. We found 2 known functional variants involved in the metabolism of alcohol and tobacco by-products as the most significant risk factors for the development of ESCC in a Japanese population. The individuals carrying both risk genotypes have a higher baseline risk of ESCC that is substantially increased by 2 lifestyle risk factors.

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Author and article information

Journal

Journal ID (nlm-journal-id): 9216904

Journal ID (pubmed-jr-id): 2419

Journal ID (nlm-ta): Nat Genet

Title: Nature genetics

ISSN (Print): 1061-4036

ISSN (Electronic): 1546-1718

Publication date Nihms-submitted: 28 July 2010

Publication date (Electronic): 22 August 2010

Publication date (Print): September 2010

Publication date PMC-release: 1 March 2011

Volume: 42

Issue: 9

Pages: 764-767

Affiliations

[1 ]Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA

[2 ]Core Genotyping Facility, NCI-Frederick, SAIC-Frederick Inc., Frederick, Maryland, USA

[3 ]Department of Medicine and Vanderbilt-Ingram Cancer Center, Vanderbilt University, Nashville, Tennessee, USA

[4 ]Division of Epidemiology and Community Health, School of Public Health, University of Minnesota, Minneapolis, Minnesota, USA

[5 ]Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA

[6 ]Shanxi Cancer Hospital, Taiyuan, Shanxi, People's Republic of China

[7 ]Department of Epidemiology, Cancer Institute (Hospital), Chinese Academy of Medical Sciences, Beijing, People's Republic of China

[8 ]Shanghai Cancer Institute, Shanghai, People's Republic of China

[9 ]Department of Epidemiology and Public Health, Yong Loo Lin School of Medicine, National University of Singapore, Singapore

[10 ]Information Management Services Inc., Silver Spring, Maryland, USA

Author notes

[11]

These authors contributed equally to this work.

AUTHOR CONTRIBUTIONS C.C.A., N.D.F., N.H., Z.W., K.Y., X.-O.S., J-M.Y., W.Z., L.M.D., W.-H.C., A.M.G., S.J.C. and P.R.T. organized and designed the study and served as the study steering committee. M.Y., J.Y., A.H., K.B.J., L.B., M.A.T. and S.J.C. supervised genotyping of samples. C.C.A., N.D.F., Z.W., K.Y., W.W., M.H.G., W.-H.C., A.M.G., S.J.C. and P.R.T. contributed to the design and execution of statistical analysis. C.C.A., Z.W. and S.J.C. wrote the first draft of the manuscript. C.C.A., N.H., X.-O.S., J-M.Y., W.Z., S.M.D., M.P.L., T.D., Y.-L.Q., Y.-T. G., W.-P.K., Y.-B.X., Z.-Z.T., J.-H.F., C.W., C.A.G., J.F.F., W.-H.C., A.M.G. and P.R.T. conducted the epidemiologic studies and contributed samples to the GWAS and/or second phase. All authors contributed to writing the manuscript.

Correspondence should be addressed to: Christian Abnet, PhD, MPH Investigator, Nutritional Epidemiology Branch, DCEG, NCI EPS 320 Bethesda, MD 20892-7236 abnetc@ 123456mail.nih.gov Phone (301) 594-1511 Fax (301) 496-6829

Article

Manuscript ID: nihpa224275

DOI: 10.1038/ng.649

PMC ID: 2947317

PubMed ID: 20729852

SO-VID: 9b14d190-c92b-4193-a657-df3c51c6a8d7

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