Gallbladder cancer predisposition: A multigenic and multianalytical approach to genetic variants of steroidal, inflammatory and tumor suppressor genes

3^rd International Conference & Exhibition on Biometrics & Biostatistics

October 20-21, 2014 DoubleTree by Hilton Baltimore - BWI Airport, USA

Kiran Lata Sharma, Sanjeev Misra, Ashok Kumar and Balraj Mittal

Scientific Tracks Abstracts: J Biom Biostat

Abstract :

Introduction: Gallbladder cancer (GBC) is a violent neoplasm associated with late diagnosis, unsatisfactory treatment and poor prognosis. The disease shows complex interplay between multiple genetic variants. 15 polymorphisms in 9 genes involved in various pathways to find out combinations of genetic variants contributing to GBC risk were analyzed. Methods: The genes included in the study were (MMP-2, 7, 9) TIMP-2, CYP1A1, CYP1B1, PLCE1, LXR-alpha and LXR-beta. Genotypes were determined by PCR-RFLP and Taqman probes. Statistical analysis was done by SPSSver16. Multilocus analysis was performed by Classification and Regression Tree Analysis (CART) and Multifactor dimensionality reduction (MDR) for higher order gene-gene interactions in modifying GBC risk. In-silico analysis was done using various bioinformatics tools (F-SNP, FAST-SNP). Results: Single locus analysis showed association of MMP2 (-735 C>T, -1306 C>T), MMP7 -181 A>G, MMP-9 (P574R, R668Q), TIMP2-418 G>C, CYP1A1-MspI, CYP1A1-Ile462Val, PLCE1 (rs2274223 A>G, rs7922612 T>C) and LXR-beta T>C (rs3546355 G>A, rs2695121 T>C) polymorphisms with GBC risk (p<0.05) whereas CYP1B1 and LXR-α variants were not associated with GBC risk. Multidimensional reduction analysis revealed LXR-β (rs3546355 G>A, rs2695121 T>C), MMP-2 (-1306C>T), MMP-9 (R668Q) and PLCE1 rs2274223A>G to be key players in GBC causation (p<0.001, CVC=7/10). The results were further supported by independent CART analysis ((p<0.001). Sub-group analysis based on gender and gallstone status showed distinct subsets of genetic signatures in GBC susceptibility. In-silico analysis of associated variants suggested change in splicing, transcriptional and translational regulation. Interactome and String analysis showed network of associated genes. Conclusion: The study found PLCE1 rs2274223, LXR-β (rs35463555, rs2695121), MMP-2(1306C>T) and MMP 9 R668Q variations and their interactions contributing to GBC risk.