A genome wide association study of genetic loci that influence tumour biomarkers cancer antigen 19-9, carcinoembryonic antigen and α fetoprotein and their associations with cancer risk

Objective Tumour biomarkers are used as indicators for cancer screening and as predictors for therapeutic responses and prognoses in cancer patients. We aimed to identify genetic loci that influence concentrations of cancer antigen 19-9 (CA19-9), carcinoembryonic antigen (CEA) and α fetoprotein (AFP), and investigated the associations between the significant single nucleotide polymorphisms (SNPs) with risks of oesophageal squamous cell (OSCC), pancreatic and hepatocellular cancers. Design We carried out a genome wide association study on plasma CA19-9, CEA and AFP concentrations in 3451 healthy Han Chinese and validated the results in 10 326 individuals. Significant SNPs were further investigated in three case control studies (2031 OSCC cases and 2044 controls; 981 pancreatic cancer cases and 1991 controls; and 348 hepatocellular cancer cases and 359 controls). Results The analyses showed association peaks on three genetic loci for CA19-9 (FUT6-FUT3 at 19p13.3, FUT2-CA11 at 19q13.3 and B3GNT3 at 19p13.1; p=1.16×10−13–3.30×10−290); four for CEA (ABO at 9q34.2, FUT6 at 19p13.3, FUT2 at 19q13.3 and FAM3B at 21q22.3; p=3.33×10−22–5.81×10−209); and two for AFP (AFP at 4q11-q13 and HISPPD2A at 15q15.3; p=3.27×10−18 and 1.28×10−14). These explained 17.14% of the variations in CA19-9, 8.95% in CEA and 0.57% in AFP concentrations. Significant ABO variants were also associated with risk of OSCC and pancreatic cancers, and AFP variants with risk of hepatocellular cancer (p<0.05). Conclusions This study identified several loci associated with CA19-9, CEA and AFP concentrations. The ABO variants were associated with risk of OSCC and pancreatic cancers and AFP variants with risk of hepatocellular cancer.

[1]  F. Hu,et al.  Cohort Profile: the Dongfeng-Tongji cohort study of retired workers. , 2013, International journal of epidemiology.

[2]  Yusuke Nakamura,et al.  A genome-wide association study identifies two susceptibility loci for duodenal ulcer in the Japanese population , 2012, Nature Genetics.

[3]  M. Guo,et al.  ABO blood type, diabetes and risk of gastrointestinal cancer in northern China. , 2012, World journal of gastroenterology.

[4]  Wen Tan,et al.  Genome-wide association study identifies five loci associated with susceptibility to pancreatic cancer in Chinese populations , 2011, Nature Genetics.

[5]  Z. Mo,et al.  Low serum osteocalcin level is a potential marker for metabolic syndrome: results from a Chinese male population survey. , 2011, Metabolism: clinical and experimental.

[6]  Jinn Shiun Chen,et al.  Preoperative carcinoembryonic antigen elevation in colorectal cancer. , 2011, Hepato-gastroenterology.

[7]  Hongbing Shen,et al.  Genome-wide association study identifies three new susceptibility loci for esophageal squamous-cell carcinoma in Chinese populations , 2011, Nature Genetics.

[8]  K. Matsuo,et al.  ABO Genotype and the Risk of Gastric Cancer, Atrophic Gastritis, and Helicobacter pylori Infection , 2011, Cancer Epidemiology, Biomarkers & Prevention.

[9]  Qiwen Ben,et al.  Pancreatic cancer incidence and outcome in relation to ABO blood groups among Han Chinese patients: A case–control study , 2011, International journal of cancer.

[10]  Fuchu He,et al.  Genome-wide association study identifies 1p36.22 as a new susceptibility locus for hepatocellular carcinoma in chronic hepatitis B virus carriers , 2010, Nature Genetics.

[11]  Yun Li,et al.  METAL: fast and efficient meta-analysis of genomewide association scans , 2010, Bioinform..

[12]  Yurii S. Aulchenko,et al.  ProbABEL package for genome-wide association analysis of imputed data , 2010, BMC Bioinformatics.

[13]  K. Miyazaki,et al.  Clinical Significance of CEA and CA19-9 in Postoperative Follow-up of Colorectal Cancer , 2010, Annals of Surgical Oncology.

[14]  Geoffrey S. Tobias,et al.  Pancreatic cancer risk and ABO blood group alleles: results from the pancreatic cancer cohort consortium. , 2010, Cancer research.

[15]  B. Lu,et al.  Diagnosis value of serum B7-H3 expression in non-small cell lung cancer. , 2009, Lung cancer.

[16]  J. Bertranpetit,et al.  A natural history of FUT2 polymorphism in humans. , 2009, Molecular biology and evolution.

[17]  Timothy J. Yeatman,et al.  Predictive biomarkers: identification and verification. , 2009, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[18]  S. Chanock,et al.  ABO blood group and the risk of pancreatic cancer. , 2009, Journal of the National Cancer Institute.

[19]  R. Abrams,et al.  Postresection CA 19-9 predicts overall survival in patients with pancreatic cancer treated with adjuvant chemoradiation: a prospective validation by RTOG 9704. , 2008, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[20]  Y. Goto,et al.  Smoking and serum CA19‐9 levels according to Lewis and secretor genotypes , 2008, International Journal of Cancer.

[21]  Andrew D. Johnson,et al.  SNAP: a web-based tool for identification and annotation of proxy SNPs using HapMap , 2008, Bioinform..

[22]  P. Ridker,et al.  Novel Association of ABO Histo-Blood Group Antigen with Soluble ICAM-1: Results of a Genome-Wide Association Study of 6,578 Women , 2008, PLoS genetics.

[23]  Manuel A. R. Ferreira,et al.  PLINK: a tool set for whole-genome association and population-based linkage analyses. , 2007, American journal of human genetics.

[24]  P. Correa,et al.  Carcinogenesis of Helicobacter pylori. , 2007, Gastroenterology.

[25]  P. Donnelly,et al.  A new multipoint method for genome-wide association studies by imputation of genotypes , 2007, Nature Genetics.

[26]  L. Butterfield,et al.  AFP-specific CD4+ Helper T-cell Responses in Healthy Donors and HCC Patients , 2007, Journal of immunotherapy.

[27]  D. Reich,et al.  Principal components analysis corrects for stratification in genome-wide association studies , 2006, Nature Genetics.

[28]  N. Anderson,et al.  A List of Candidate Cancer Biomarkers for Targeted Proteomics , 2006, Biomarker insights.

[29]  Mengsen Li,et al.  Effects of alpha fetoprotein on escape of Bel 7402 cells from attack of lymphocytes , 2005, BMC Cancer.

[30]  Mark Daly,et al.  Haploview: analysis and visualization of LD and haplotype maps , 2005, Bioinform..

[31]  Roger Williams,et al.  α-Fetoprotein Impairs APC Function and Induces Their Apoptosis1 , 2004, The Journal of Immunology.

[32]  Michael A. Briggs,et al.  Cloning, expression, and initial characterization of a novel cytokine-like gene family. , 2002, Genomics.

[33]  Y. Kodera,et al.  Polymorphisms of two fucosyltransferase genes (Lewis and Secretor genes) involving type I Lewis antigens are associated with the presence of anti-Helicobacter pylori IgG antibody. , 2001, Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology.

[34]  P. Johnson,et al.  The role of serum alpha-fetoprotein estimation in the diagnosis and management of hepatocellular carcinoma. , 2001, Clinics in liver disease.

[35]  S. Hakomori Antigen structure and genetic basis of histo-blood groups A, B and O: their changes associated with human cancer. , 1999, Biochimica et biophysica acta.

[36]  J. Cancelas,et al.  Enhanced Expression of α(1,3)-Fucosyltransferase Genes Correlates with E-selectin-mediated Adhesion and Metastatic Potential of Human Lung Adenocarcinoma Cells , 1998 .

[37]  S. Hirohashi,et al.  Lewis and secretor gene dosages affect CA19-9 and DU-PAN-2 serum levels in normal individuals and colorectal cancer patients. , 1998, Cancer research.

[38]  G. Lennon,et al.  Sequence and expression of a candidate for the human Secretor blood group alpha(1,2)fucosyltransferase gene (FUT2). Homozygosity for an enzyme-inactivating nonsense mutation commonly correlates with the non-secretor phenotype. , 1995, The Journal of biological chemistry.

[39]  G. Lennon,et al.  Sequence and Expression of a Candidate for the Human Secretor Blood Group α(1,2)Fucosyltransferase Gene (FUT2) , 1995, The Journal of Biological Chemistry.

[40]  T. Ando,et al.  Molecular Genetic Analysis of the Human Lewis Histo-blood Group System , 1994, The Journal of Biological Chemistry.

[41]  E. Rose,et al.  Alpha-fetoprotein levels in normal adults. , 1992, The American journal of the medical sciences.

[42]  D. Pleskow,et al.  Evaluation of a serologic marker, CA19-9, in the diagnosis of pancreatic cancer. , 1989, Annals of internal medicine.

[43]  M. Kuroki,et al.  Structural studies of the carbohydrate moieties of carcinoembryonic antigens. , 1987, Cancer research.

[44]  M. Brockhaus,et al.  A monoclonal antibody-defined antigen associated with gastrointestinal cancer is a ganglioside containing sialylated lacto-N-fucopentaose II. , 1982, The Journal of biological chemistry.

[45]  J. Mach,et al.  Long‐term follow‐up of colorectal carcinoma patients by repeated CEA radioimmunoassay , 1978, Cancer.

[46]  A. Holburn,et al.  Studies of the association of the A, B and Lewis Blood group antigens with carcinoembryonic antigen (CEA). , 1974, Immunology.

[47]  Phil Gold,et al.  DEMONSTRATION OF TUMOR-SPECIFIC ANTIGENS IN HUMAN COLONIC CARCINOMATA BY IMMUNOLOGICAL TOLERANCE AND ABSORPTION TECHNIQUES , 1965, The Journal of experimental medicine.

[48]  A. Haddow,et al.  BLOOD-GROUP AND DISEASE. , 1964, Lancet.

[49]  W. G. Cochran The combination of estimates from different experiments. , 1954 .

[50]  K. Yamashita,et al.  Liver metastasis of colorectal cancer by protein-tyrosine phosphatase type 4A, 3 (PRL-3) is mediated through lymph node metastasis and elevated serum tumor markers such as CEA and CA19-9. , 2008, Oncology reports.

[51]  M. Zoli,et al.  Diagnostic and prognostic role of alpha-fetoprotein in hepatocellular carcinoma: both or neither? , 2006, The American journal of gastroenterology.

[52]  Y. Yamada,et al.  Identification and characterization of three novel beta 1,3-N-acetylglucosaminyltransferases structurally related to the beta 1,3-galactosyltransferase family. , 2001, The Journal of biological chemistry.

[53]  J. Cancelas,et al.  Enhanced expression of alpha(1,3)-fucosyltransferase genes correlates with E-selectin-mediated adhesion and metastatic potential of human lung adenocarcinoma cells. , 1998, Cancer research.