ORIGINAL ARTICLE Association of Wnt signaling pathway genetic variants in gallbladder cancer susceptibility and survival Anu Yadav 1 & Annapurna Gupta 1 & Saurabh Yadav 1 & Neeraj Rastogi 2 & Sushma Agrawal 2 & Ashok Kumar 3 & Vijay Kumar 4 & Sanjeev Misra 5 & Balraj Mittal 1 Received: 9 October 2015 /Accepted: 21 December 2015 # International Society of Oncology and BioMarkers (ISOBM) 2015 Abstract Gallbladder cancer (GBC) is the most common ma- lignancy of the biliary tract with adverse prognosis and poor survival. Wnt signaling plays an important role in embryonic development and regeneration of tissues in all the species. Deregulation of expression and mutations in this pathway may lead to disease state such as cancer. In this study, we assessed the association of common germline variants of Wnt pathway genes (SFRP2, SFRP4, DKK2, DKK3, WISP3, APC, β-catenin, AXIN-2, GLI-1) to evaluate their contribution in predisposition to GBC and treatment outcomes. The study in- cluded 564 GBC patients and 250 controls. Out of 564, 200 patients were followed up for treatment response and survival. Tumor response (RECIST 1.1) was recorded in 116 patients undergoing non-adjuvant chemotherapy (NACT). Survival was assessed by Kaplan-Meier curve and Cox-proportional hazard regression. Single locus analysis showed significant as- sociation of SFRP4 rs1802073G > T [p value = 0.0001], DKK2 rs17037102C > T [p value = 0.0001], DKK3 rs3206824C > T [p value = 0.012], APC rs4595552 A/T [p value = 0.021], APC rs11954856G > T [ p value = 0.047], AXIN-2 rs4791171C > T [p value = 0.001], β-catenin rs4135385A > G [p value = 0.031], and GLI-1 rs222826C > G [p value = 0.001] with increased risk of GBC. Gene-gene interaction using GMDR analysis predicted APC rs11954856 and AXIN2 rs4791171 as significant in conferring GBC susceptibility. Cox-proportional hazard model showed GLI-1 rs2228226 CG/GG and AXIN-2 rs4791171 TT genotype higher hazard ratio. In recursive partitioning, AXIN-2 rs4791171 TT geno- type showed higher mortality and hazard. Most of studied ge- netic variants influence GBC susceptibility. APC rs11954856, GLI-1 rs2228226, and AXIN-2 rs4791171 were found to be associated with poor survival in advanced GBC patients. Keywords Wnt pathway genes . Haplotype . Generalized multifactor dimensionality reduction (GMDR) . Survival . Recursive partitioning Introduction Gallbladder cancer (GBC) is a common gastrointestinal ma- lignancy with specific geographical and ethnic variation. It is highly prevalent in the Indo-Gangetic belt (north India) and females in North India have one of the highest incidences of GBC in the world. The cancer is rarely diagnosed in early stages because of its non-symptomatic nature. Late diagnosis makes it an aggressive disease with poor prognosis and low survival. Predisposition to various cancers is well studied and has helped us to identify than more than 100 genes. Germline variants in these predisposition genes confer highly or moder- ately increased risks of cancer. Genomic variations, especially single nucleotide polymorphisms (SNPs) of genes belonging to Wnt signaling pathway, have been implicated in various cancers. Similar efforts to study the potential of predisposition Electronic supplementary material The online version of this article (doi:10.1007/s13277-015-4728-9) contains supplementary material, which is available to authorized users. * Balraj Mittal bml_pgi@yahoo.com 1 Department of Genetics, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, India 2 Department of Radiotherapy, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, India 3 Department of Gastroenterology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, India 4 Surgical Oncology, Kgmu, Lucknow (U.P.), Lucknow, India 5 Director of AIIMS, Jodhpur, Rajasthan Tumor Biol. DOI 10.1007/s13277-015-4728-9