title: Association of cancer stem cell markers genetic variants with gallbladder cancer susceptibility, prognosis, and survival.
abstract: Genes important to stem cell progression have been involved in the genetics and clinical outcome of cancers. We investigated germ line variants in cancer stem cell (CSC) genes to predict susceptibility and efficacy of chemoradiotherapy treatment in gallbladder cancer (GBC) patients. In this study, we assessed the effect of SNPs in CSC genes (surface markers CD44, ALCAM, EpCAM, CD133) and (molecular markers NANOG, SOX-2, LIN-28A, ALDH1A1, OCT-4) with GBC susceptibility and prognosis. Total 610 GBC patients and 250 controls were genotyped by using PCR-RFLP, ARMS-PCR, and TaqMan allelic discrimination assays. Chemotoxicity graded 2-4 in 200 patients and tumor response was recorded in 140 patients undergoing neoadjuvant chemotherapy (NACT). Differences in genotype and haplotype frequency distributions were calculated by binary logistic regression. Gene-gene interaction model was analyzed by generalized multifactor dimensionality reduction (GMDR). Overall survival was assessed by Kaplan-Meier survival curve and multivariate Cox-proportional methods. ALCAM Ars1157Crs10511244 (P = 0.0035) haplotype was significantly associated with GBC susceptibility. In GMDR analysis, ALCAM rs1157G>A, EpCAM rs1126497T>C emerged as best significant interaction model with GBC susceptibility and ALDH1A1 rs13959T>G with increased risk of grade 3-4 hematological toxicity. SOX-2 rs11915160A>C, OCT-4 rs3130932T>G, and NANOG rs11055786T>C were found best gene-gene interaction model for predicting response to NACT. In both Cox-proportional and recursive partitioning ALCAM rs1157GA+AA genotype showed higher mortality and hazard ratio. ALCAM gene polymorphisms associated with GBC susceptibility and survival while OCT-4, SOX-2, and NANOG variants showed an interactive role with treatment response.
authors: Department of Genetics, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, UP, India.
authors: Anu
authors: A
authors: Yadav
authors: Department of Genetics, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, UP, India.
authors: Annapurna
authors: A
authors: Gupta
authors: Department of Radiotherapy, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, UP, India.
authors: Neeraj
authors: N
authors: Rastogi
authors: Department of Radiotherapy, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, UP, India.
authors: Sushma
authors: S
authors: Agrawal
authors: Department of Gastroenterology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, UP, India.
authors: Ashok
authors: A
authors: Kumar
authors: Surgical Oncology, KGMU, Lucknow, UP, India.
authors: Vijay
authors: V
authors: Kumar
authors: Department of Genetics, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, UP, India. bml_pgi@yahoo.com.
authors: Balraj
authors: B
authors: Mittal
mesh_terms: D000328:Adult; D000483:Alleles; D014408:Biomarkers, Tumor / Q000235:genetics*; D016022:Case-Control Studies; D005260:Female; D005706:Gallbladder Neoplasms / Q000235:genetics* / Q000473:pathology*; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D014411:Neoplastic Stem Cells / Q000378:metabolism* / Q000473:pathology; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011379:Prognosis
chemical_list: D014408:Biomarkers, Tumor
keywords: Cancer stem cell (CSC); Gallbladder cancer (GBC); Survival recursive partitioning (Rpart); Treatment outcomes