title: Discovery and validation of vascular endothelial growth factor (VEGF) pathway polymorphisms in esophageal adenocarcinoma outcome.
abstract: Polymorphisms in the vascular endothelial growth factor (VEGF)/angiogenesis pathway have been implicated previously in cancer risk, prognosis and response to therapy including in esophageal adenocarcinoma. Prior esophageal adenocarcinoma studies focused on using candidate polymorphisms, limiting the discovery of novel polymorphisms. Here, we applied the tagSNP (single nucleotide polymorphism) approach to identify new VEGF pathway polymorphisms associated with esophageal adenocarcinoma prognosis and validated them in an independent cohort of esophageal adenocarcinoma patients. In 231 esophageal adenocarcinoma patients of all stages/treatment plans, 58 genetic polymorphisms (18 KDR, 7 VEGFA and 33 FLT1) selected through tagging and assessment of predicted function were genotyped. Cox-proportional hazard models adjusted for important socio-demographic and clinico-pathological factors were applied to assess the association of genetic polymorphisms with overall survival (OS) and progression-free survival (PFS). Significantly associated polymorphisms were then validated in an independent cohort of 137 esophageal adenocarcinoma patients. Among the 231 discovery cohort patients, 86% were male, median diagnosis age was 64 years, 34% were metastatic at diagnosis and median OS and PFS were 20 and 12 months, respectively. KDR rs17709898 was found significantly associated with PFS (adjusted hazard ratio, aHR = 0.69, 95% confidence interval (CI): 0.53-0.90; P = 5.9E-3). FLT1 rs3794405 and rs678714 were significantly associated with OS (aHR = 1.44, 95% CI: 1.04-1.99; P = 0.03 and aHR = 1.50, 95% CI: 1.01-2.24; P = 0.045, respectively). No VEGFA polymorphisms were found significantly associated with either outcome. Upon validation, FLT1 rs3794405 remained strongly associated with OS (aHR = 1.59, 95% CI: 1.04-2.44; P = 0.03). FLT1 rs3794405 is significantly associated with OS in esophageal adenocarcinoma, whereby each variant allele confers a 45-60% increased risk of mortality. Validation and evaluation of this association in other cancer sites are warranted.
authors.affiliation: Division of Medical Oncology and Hematology, Department of Medicine, Princess Margaret Cancer Centre and University of Toronto, 610 University Ave, Toronto, Ontario M5G 2M9, Canada, Division of Applied Molecular Oncology, Ontario Cancer Institute-Princess Margaret Cancer Centre and University of Toronto, 610 University Ave, Toronto, Ontario M5G 2M9, Canada.
authors.forename: Lawson
authors.initials: L
authors.lastname: Eng
authors.affiliation: Division of Applied Molecular Oncology, Ontario Cancer Institute-Princess Margaret Cancer Centre and University of Toronto, 610 University Ave, Toronto, Ontario M5G 2M9, Canada.
authors.forename: Abul Kalam
authors.initials: AK
authors.lastname: Azad
authors.affiliation: Division of Applied Molecular Oncology, Ontario Cancer Institute-Princess Margaret Cancer Centre and University of Toronto, 610 University Ave, Toronto, Ontario M5G 2M9, Canada, Department of Biostatistics, Princess Margaret Cancer Centre, 610 University Ave, Toronto, Ontario M5G 2M9, Canada.
authors.forename: Xin
authors.initials: X
authors.lastname: Qiu
authors.affiliation: Division of Applied Molecular Oncology, Ontario Cancer Institute-Princess Margaret Cancer Centre and University of Toronto, 610 University Ave, Toronto, Ontario M5G 2M9, Canada, Department of Biostatistics, Princess Margaret Cancer Centre, 610 University Ave, Toronto, Ontario M5G 2M9, Canada.
authors.forename: Qin Quinn
authors.initials: QQ
authors.lastname: Kong
authors.affiliation: Division of Applied Molecular Oncology, Ontario Cancer Institute-Princess Margaret Cancer Centre and University of Toronto, 610 University Ave, Toronto, Ontario M5G 2M9, Canada.
authors.forename: Dangxiao
authors.initials: D
authors.lastname: Cheng
authors.affiliation: Division of Applied Molecular Oncology, Ontario Cancer Institute-Princess Margaret Cancer Centre and University of Toronto, 610 University Ave, Toronto, Ontario M5G 2M9, Canada, Institute of Biomedical Engineering, Hangzhou Dianzi University Xiasha, Hangzhou 310018, Zhejiang, P. R. China.
authors.forename: Nanjiao
authors.initials: N
authors.lastname: Ying
authors.affiliation: Division of Applied Molecular Oncology, Ontario Cancer Institute-Princess Margaret Cancer Centre and University of Toronto, 610 University Ave, Toronto, Ontario M5G 2M9, Canada.
authors.forename: Alvina
authors.initials: A
authors.lastname: Tse
authors.affiliation: Division of Applied Molecular Oncology, Ontario Cancer Institute-Princess Margaret Cancer Centre and University of Toronto, 610 University Ave, Toronto, Ontario M5G 2M9, Canada.
authors.forename: Qin
authors.initials: Q
authors.lastname: Kuang
authors.affiliation: Division of Applied Molecular Oncology, Ontario Cancer Institute-Princess Margaret Cancer Centre and University of Toronto, 610 University Ave, Toronto, Ontario M5G 2M9, Canada.
authors.forename: Lorin
authors.initials: L
authors.lastname: Dodbiba
authors.affiliation: British Columbia Cancer Agency, Department of Medical Oncology, University of British Columbia, 600 West 10th Avenue, Vancouver, BC V5Z 4E6, Canada.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Renouf
authors.affiliation: Faculty of Pharmacy and Pharmaceutical Sciences, 3142F, Katz Group Centre for Pharmacy & Health Research, University of Alberta, 11361-87 Ave, Edmonton, Alberta T6G 2E1, Canada.
authors.forename: Sharon
authors.initials: S
authors.lastname: Marsh
authors.affiliation: Discipline of Genetics, Faculty of Medicine, H4333C, Memorial University of Newfoundland, St. John's, Newfoundland A1B 3V6, Canada.
authors.forename: Sevtap
authors.initials: S
authors.lastname: Savas
authors.affiliation: Division of Medical Oncology and Hematology, Department of Medicine, Princess Margaret Cancer Centre and University of Toronto, 610 University Ave, Toronto, Ontario M5G 2M9, Canada.
authors.forename: Helen J
authors.initials: HJ
authors.lastname: Mackay
authors.affiliation: Division of Medical Oncology and Hematology, Department of Medicine, Princess Margaret Cancer Centre and University of Toronto, 610 University Ave, Toronto, Ontario M5G 2M9, Canada.
authors.forename: Jennifer J
authors.initials: JJ
authors.lastname: Knox
authors.affiliation: Division of Thoracic Surgery, Department of Surgery, Toronto General Hospital, 200 Elizabeth Street, 9N-955, Toronto, Ontario M5G 2C4, Canada.
authors.forename: Gail E
authors.initials: GE
authors.lastname: Darling
authors.affiliation: Department of Radiation Oncology, Princess Margaret Cancer Centre, 610 University Ave, Toronto, Ontario M5G 2M9, Canada and.
authors.forename: Rebecca K S
authors.initials: RK
authors.lastname: Wong
authors.affiliation: Division of Applied Molecular Oncology, Ontario Cancer Institute-Princess Margaret Cancer Centre and University of Toronto, 610 University Ave, Toronto, Ontario M5G 2M9, Canada, Department of Biostatistics, Princess Margaret Cancer Centre, 610 University Ave, Toronto, Ontario M5G 2M9, Canada, Dalla Lana School of Public Health, University of Toronto, 155 College Street, 6th Floor, Toronto, Ontario M5T 3M7, Canada.
authors.forename: Wei
authors.initials: W
authors.lastname: Xu
authors.affiliation: Division of Medical Oncology and Hematology, Department of Medicine, Princess Margaret Cancer Centre and University of Toronto, 610 University Ave, Toronto, Ontario M5G 2M9, Canada, Division of Applied Molecular Oncology, Ontario Cancer Institute-Princess Margaret Cancer Centre and University of Toronto, 610 University Ave, Toronto, Ontario M5G 2M9, Canada, Dalla Lana School of Public Health, University of Toronto, 155 College Street, 6th Floor, Toronto, Ontario M5T 3M7, Canada geoffrey.liu@uhn.ca.
authors.forename: Geoffrey
authors.initials: G
authors.lastname: Liu
authors.affiliation: Division of Medical Oncology and Hematology, Department of Medicine, Princess Margaret Cancer Centre and University of Toronto, 610 University Ave, Toronto, Ontario M5G 2M9, Canada.
authors.forename: Olusola O
authors.initials: OO
authors.lastname: Faluyi
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics* / Q000401:mortality; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018572:Disease-Free Survival; D004938:Esophageal Neoplasms / Q000235:genetics* / Q000401:mortality; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009389:Neovascularization, Pathologic / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011446:Prospective Studies; D011795:Surveys and Questionnaires; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics*; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000235:genetics*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000235:genetics*
chemical_list: C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; C501162:FLT1 protein, human; D040281:Vascular Endothelial Growth Factor Receptor-1; D040301:Vascular Endothelial Growth Factor Receptor-2