Polymorphisms In Microrna (Mirna) Pathways And Survival In Esophageal Cancer (Ec) Patients.

Introduction: Polymorphisms within miRNA and in genes regulating miRNA biogenesis can regulate a variety of cancer pathways in EC patients. Comprehensive pathway analyses of miRNA-related genes were performed on EC outcomes. Methods: 324 EC patients from Princess Margaret Hospital (Toronto, Canada) were screened for 62 single nucleotide polymorphisms (SNPs) in 21 miRNA or miRNA biogenesis pathway genes. Multivariate Cox-proportional hazard models, adjusted for key prognostic factors evaluated the association of each SNP with overall survival (OS) and progression free survival (PFS). Significant SNPs were further analysed for joint effects, and also in subgroup and pathway analyses. All results were internally validated through bootstrapping. Results: Five polymorphisms belonging to the miRNA biogenesis pathway and one in a miRNA were nominally associated with OS or PFS, where adjusted hazard ratios (aHR) were between 1.23-1.41 for each comparison; p=0.003-0.04: AGO1 (rs595961; chromosome (chr) 1), GEMIN3 (rs197412; chr1) CD86 (rs17281995; chr 3) hs-miRNA-26a1 (rs7372209; chr 3), GEMIN4 (rs7813 and rs910924; chr 17). Joint effect analysis of SNPs in the same chromosome found additive effects of these risk alleles (RA) on outcome: chr 1 (2-4 vs 0-1: aHR OS =1.82 [1.21-2.75], p=0.004), chr 3 (3-4 vs 0: aHR OS =4.07 [1.91-8.67], p=0.003), chr 17 (4 vs 0: aHR PFS =2.21 [1.13-4.31], p=0.02). Pathway based analysis found each additional RA conferring a strong additive effect on OS (per 2 RA: aHR=1.50 [1.25-1.81], p=1.9x10E-5). Results on PFS were similar, with aHR PFS per 2RA of 1.51 [1.26-1.82], p=1.3x10E-5. Internal validation found consistent results for all analyses. Exploratory subgroup analysis identified two SNPs that had differential effects on OS based on histology: for adenocarcinomas, the aHR for KIAA0423 (rs1053667) was 0.51 [0.28-0.96], p=0.03, while for squamous cell carcinomas, the aHR was 7.36 [2.07-26.1], p=0.002. Similarly, for DICER (rs13078), aHR adenocarcinoma =0.96 [0.72-1.28], p=0.78 vs aHR squamous =2.51[1.21-5.21], p=0.01). In subset analyses, hsa-mir-30a (rs1358379), hsa-mir-492 (rs2289030), hsa-mir-499 (rs3746444), and DGCR8 (rs1640299) were significantly associated with different outcomes by nodal status. Conclusion: We identified the miRNA biogenesis pathway as having an important role in the prognosis of EC patients, with a 50% increase in death or disease progression when carrying two additional miRNA risk alleles. Although some of the identified polymorphisms have been previously associated with risk or prognosis in other cancer disease sites, we report for the first time, their associations with esophageal cancer prognosis. Citation Format: Lawson Eng, Olusola O. Faluyi, Xin Qiu, Dangxiao Cheng, Daniel J. Renouf, Lorin Dodbiba, Sevtap Savas, Sharon Marsh, Jennifer J. Knox, Gail E. Darling, Rebecca KS Wong, Wei Xu, Geoffrey Liu, Abul K. Azad. Polymorphisms in microRNA (miRNA) pathways and survival in esophageal cancer (EC) patients. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2562. doi:10.1158/1538-7445.AM2013-2562 Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.