Tumor Biology

, Volume 37, Issue 2, pp 1835–1844 | Cite as

Association of cancer stem cell markers genetic variants with gallbladder cancer susceptibility, prognosis, and survival

  • Anu Yadav
  • Annapurna Gupta
  • Neeraj Rastogi
  • Sushma Agrawal
  • Ashok Kumar
  • Vijay Kumar
  • Balraj Mittal
Original Article


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.


Cancer stem cell (CSC) Gallbladder cancer (GBC) Treatment outcomes Survival recursive partitioning (Rpart) 



The authors would like to thank the Department of Biotechnology, Indian Council of Medical Research, and the Department of Science and Technology, Government of India, for financial support.

Conflicts of interest


Supplementary material

13277_2015_3929_MOESM1_ESM.docx (56 kb)
ESM 1 (DOCX 56 kb)


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Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2015

Authors and Affiliations

  • Anu Yadav
    • 1
  • Annapurna Gupta
    • 1
  • Neeraj Rastogi
    • 2
  • Sushma Agrawal
    • 2
  • Ashok Kumar
    • 3
  • Vijay Kumar
    • 4
  • Balraj Mittal
    • 1
  1. 1.Department of GeneticsSanjay Gandhi Post Graduate Institute of Medical SciencesLucknowIndia
  2. 2.Department of RadiotherapySanjay Gandhi Post Graduate Institute of Medical SciencesLucknowIndia
  3. 3.Department of GastroenterologySanjay Gandhi Post Graduate Institute of Medical SciencesLucknowIndia
  4. 4.Surgical OncologyKGMULucknowIndia

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