Gallbladder Cancer Predisposition: A Multigenic Approach to DNA-Repair, Apoptotic and Inflammatory Pathway Genes

Kshitij Srivastava,Ashok Kumar,Balraj Mittal,Anvesha Srivastava

doi:10.1371/journal.pone.0016449

Kshitij Srivastava, Ashok Kumar + Show 2 more

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Gallbladder cancer (GBC) is a multifactorial disease with complex interplay between multiple genetic variants. We performed Classification and Regression Tree Analysis (CART) and Grade of Membership (GoM) analysis to identify combinations of alleles among the DNA repair, inflammatory and apoptotic pathway genetic variants in modifying the risk for GBC. We analyzed 16 polymorphisms in 8 genes involved in DNA repair, apoptotic and inflammatory pathways to find out combinations of genetic variants contributing to GBC risk. The genes included in the study were XRCC1, OGG1, ERCC2, MSH2, CASP8, TLR2, TLR4 and PTGS2. Single locus analysis by logistic regression showed association of MSH2 IVS1+9G>C (rs2303426), ERCC2 Asp312Asn (rs1799793), OGG1 Ser326Cys (rs1052133), OGG1 IVS4-15C>G (rs2072668), CASP8 -652 6N ins/del (rs3834129), PTGS2 -1195G>A (rs689466), PTGS2 -765G>C (rs20417), TLR4 Ex4+936C>T (rs4986791) and TLR2 –196 to –174del polymorphisms with GBC risk. The CART analysis revealed OGG1 Ser326Cys, and OGG1 IVS4-15C>G polymorphisms as the best polymorphic signature for discriminating between cases and controls. In the GoM analysis, the data was categorized into six sets representing risk for GBC with respect to the investigated polymorphisms. Sets I, II and III described low intrinsic risk (controls) characterized by multiple protective alleles while sets IV, V and VI represented high intrinsic risk groups (GBC cases) characterized by the presence of multiple risk alleles. The CART and GoM analyses also showed the importance of PTGS2 -1195G>A polymorphism in susceptibility to GBC risk. In conclusion, the present multigenic approach can be used to define individual risk profiles for gallbladder cancer in North Indian population.

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Carcinoma of the gallbladder (GBC) is an aggressive malignancy and the most common biliary tract tumor in the world with highest incidence and mortality rates in Northern India (21.5/100,000) [1,2]
The Classification and Regression Tree Analysis (CART) and Grade of Membership (GoM) analyses showed the importance of PTGS2 -1195G.A polymorphism in susceptibility to Gallbladder cancer (GBC) risk
We have extended our previous work by jointly investigating 16 single nucleotide polymorphisms (SNPs) genotypes in 8 genes belonging to DNA repair pathway [ERCC2 Asp312Asn (Ex10-16G.A; rs1799793) and Lys751Gln (Ex23+61A.C; rs13181); MSH2 (IVS1+9G.C; rs2303426) and (-118T.C; rs2303425); OGG1 Ser326Cys (Ex6315C.G; rs1052133) and (IVS4-15C.G; rs2072668); XRCC1 Arg194Trp (Ex6-22C.T; rs1799782) and Arg399Gln (Ex10-4A.G; rs25487)], apoptotic pathway [CASP8 -652 6N ins/del, Asp302His (Ex13+51G.C; rs1045485) and (IVS12-19G.A; rs3769818)] and inflammatory pathway [PTGS2 (-1195G.A; rs689466), (-765G.C; rs20417) and (Ex10+837T.C or +8473; rs5275); TLR2 –196 to –174del (TLR2 D22); and TLR4 Thr399Ile (Ex4+936C.T; rs4986791)], avoiding the problem of dimensionality and multiple comparisons

Summary

Introduction

Carcinoma of the gallbladder (GBC) is an aggressive malignancy and the most common biliary tract tumor in the world with highest incidence and mortality rates in Northern India (21.5/100,000) [1,2]. We have extended our previous work by jointly investigating 16 SNP genotypes in 8 genes belonging to DNA repair pathway [ERCC2 Asp312Asn (Ex10-16G.A; rs1799793) and Lys751Gln (Ex23+61A.C; rs13181); MSH2 (IVS1+9G.C; rs2303426) and (-118T.C; rs2303425); OGG1 Ser326Cys (Ex6315C.G; rs1052133) and (IVS4-15C.G; rs2072668); XRCC1 Arg194Trp (Ex6-22C.T; rs1799782) and Arg399Gln (Ex10-4A.G; rs25487)], apoptotic pathway [CASP8 -652 6N ins/del (rs3834129), Asp302His (Ex13+51G.C; rs1045485) and (IVS12-19G.A; rs3769818)] and inflammatory pathway [PTGS2 (-1195G.A; rs689466), (-765G.C; rs20417) and (Ex10+837T.C or +8473; rs5275); TLR2 –196 to –174del (TLR2 D22); and TLR4 Thr399Ile (Ex4+936C.T; rs4986791)], avoiding the problem of dimensionality and multiple comparisons These polymorphisms have been reported to alter the risk for developing various malignancies [9,10,11,12,13,14]

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