title: Validation of microRNA pathway polymorphisms in esophageal adenocarcinoma survival.
abstract: Polymorphisms in miRNA and miRNA pathway genes have been previously associated with cancer risk and outcome, but have not been studied in esophageal adenocarcinoma outcomes. Here, we evaluate candidate miRNA pathway polymorphisms in esophageal adenocarcinoma prognosis and attempt to validate them in an independent cohort of esophageal adenocarcinoma patients. Among 231 esophageal adenocarcinoma patients of all stages/treatment plans, 38 candidate genetic polymorphisms (17 biogenesis, 9 miRNA targets, 5 pri-miRNA, 7 pre-miRNA) were genotyped and analyzed. Cox proportional hazard models adjusted for sociodemographic and clinicopathological covariates helped assess the association of genetic polymorphisms with overall survival (OS) and progression-free survival (PFS). Significantly associated polymorphisms were then evaluated 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. GEMIN3 rs197412 (aHR = 1.37, 95%CI: [1.04-1.80]; P = 0.02), hsa-mir-124-1 rs531564 (aHR = 0.60, 95% CI: [0.53-0.90]; P = 0.05), and KIAA0423 rs1053667 (aHR = 0.51, 95% CI: [0.28-0.96]; P = 0.04) were found associated with OS. Furthermore, GEMIN3 rs197412 (aHR = 1.33, 95% CI: [1.03-1.74]; P = 0.03) and KRT81 rs3660 (aHR = 1.29, 95% CI: [1.01-1.64]; P = 0.04) were found associated with PFS. Although none of these polymorphisms were significant in the second cohort, hsa-mir-124-1 rs531564 and KIAA0423 rs1053667 had trends in the same direction; when both cohorts were combined together, GEMIN3 rs197412, hsa-mir-124-1 rs531564, and KIAA0423 rs1053667 remained significantly associated with OS. We demonstrate the association of multiple miRNA pathway polymorphisms with esophageal adenocarcinoma prognosis in a discovery cohort of patients, which did not validate in a separate cohort but had consistent associations in the pooled cohort. Larger studies are required to confirm/validate the prognostic value of these polymorphisms in esophageal adenocarcinoma.
authors.affiliation: Division of Medical Oncology and Hematology, Department of Medicine, Princess Margaret Cancer Centre and University of Toronto, Toronto, Ontario, Canada.
authors.forename: Olusola O
authors.initials: OO
authors.lastname: Faluyi
authors.affiliation: Division of Medical Oncology and Hematology, Department of Medicine, Princess Margaret Cancer Centre and University of Toronto, Toronto, Ontario, Canada.|Division of Applied Molecular Oncology, Ontario Cancer Institute-Princess Margaret Cancer Centre and University of Toronto, Toronto, Ontario, 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, Toronto, Ontario, Canada.|Department of Biostatistics, Princess Margaret Cancer Centre, Toronto, Ontario, 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, Toronto, Ontario, Canada.|Department of Biostatistics, Princess Margaret Cancer Centre, Toronto, Ontario, Canada.
authors.forename: Jiahua
authors.initials: J
authors.lastname: Che
authors.affiliation: Division of Applied Molecular Oncology, Ontario Cancer Institute-Princess Margaret Cancer Centre and University of Toronto, Toronto, Ontario, Canada.|Department of Biostatistics, Princess Margaret Cancer Centre, Toronto, Ontario, Canada.
authors.forename: Qihuang
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: Division of Applied Molecular Oncology, Ontario Cancer Institute-Princess Margaret Cancer Centre and University of Toronto, Toronto, Ontario, 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, Toronto, Ontario, Canada.|Institute of Biomedical Engineering, Hangzhou Dianzi University, Zhejiang, 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, Toronto, Ontario, 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, Toronto, Ontario, 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, Toronto, Ontario, Canada.
authors.forename: Lorin
authors.initials: L
authors.lastname: Dodbiba
authors.affiliation: British Columbia Cancer Agency, Department of Medical Oncology, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Renouf
authors.affiliation: Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Sharon
authors.initials: S
authors.lastname: Marsh
authors.affiliation: Discipline of Genetics, Memorial University of Newfoundland, St. John's, Newfoundland, 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, Toronto, Ontario, Canada.|Odette Cancer Centre, Sunnybrook Health Sciences Centre, Toronto, Ontario, 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, Toronto, Ontario, Canada.
authors.forename: Jennifer J
authors.initials: JJ
authors.lastname: Knox
authors.affiliation: Division of Thoracic Surgery, Department of Surgery, Toronto General Hospital, Toronto, Ontario, Canada.
authors.forename: Gail E
authors.initials: GE
authors.lastname: Darling
authors.affiliation: Department of Radiation Oncology, Princess Margaret Cancer Centre, Toronto, Ontario, Canada.
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, Toronto, Ontario, Canada.|Department of Biostatistics, Princess Margaret Cancer Centre, Toronto, Ontario, Canada.|Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Wei
authors.initials: W
authors.lastname: Xu
authors.affiliation: Division of Applied Molecular Oncology, Ontario Cancer Institute-Princess Margaret Cancer Centre and University of Toronto, Toronto, Ontario, Canada.|Department of Genitourinary Medical Oncology, Division of Cancer Medicine, University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Abul Kalam
authors.initials: AK
authors.lastname: Azad
authors.affiliation: Division of Medical Oncology and Hematology, Department of Medicine, Princess Margaret Cancer Centre and University of Toronto, Toronto, Ontario, Canada.|Division of Applied Molecular Oncology, Ontario Cancer Institute-Princess Margaret Cancer Centre and University of Toronto, Toronto, Ontario, Canada.|Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Geoffrey
authors.initials: G
authors.lastname: Liu
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018572:Disease-Free Survival; D004938:Esophageal Neoplasms / Q000235:genetics*; D005260:Female; D053263:Gene Regulatory Networks; D006801:Humans; D008297:Male; D035683:MicroRNAs / Q000235:genetics*; D008875:Middle Aged; D009362:Neoplasm Metastasis; D020641:Polymorphism, Single Nucleotide; D011379:Prognosis; D016016:Proportional Hazards Models; D016019:Survival Analysis
chemical_list: D035683:MicroRNAs
keywords: Esophageal adenocarcinoma; miRNA pathways; polymorphisms; prognosis