Abstract
Gall bladder cancer (GBC) is a gastro-intestinal cancer with high prevalence among north Indian women. Platelet derived growth factor-B (PDGFB) and human epidermal growth factor receptor-2 (HER2) may play roles in the etiology of GBC through the inflammation-hyperplasia-dysplasia-carcinoma pathway. To study the association of PDGFB and HER2 polymorphisms with risk of GBC, 200 cases and 300 controls were considered. PDGFB +286A>G and +1135A>C polymorphisms were investigated with an amplification refractory mutation system and the HER2 Ile655Val polymorphism by restriction fragment length polymorphism. Significant risk associations for PDGFB +286 GG (OR=5.25) and PDGFB +1135 CC (OR=3.19) genotypes were observed for GBC. Gender wise stratification revealed susceptibility for recessive models of PDGFB +1135A>C (OR=3.00) and HER2 Ile655Val (OR=2.52) polymorphisms among female GBC cases. GBC cases with gall stones were predisposed to homozygous +286 GG and +1135 CC genotypes. Significant risk associations were found for ACIle (OR=1.48), GAVal (OR=1.70), GAIle (OR=2.00) haplotypes with GBC cases and GCIle haplotype with female GBC cases (OR=10.37, P=<0.0001). Pair-wise linkage disequilibrium revealed negative associations among variant alleles. On multi-dimensional reduction analysis, a three factor model revealed significant gene-gene interaction for PDGFB +286A>G, PDGFB +1135A>C and HER2 Ile165Val SNPs with GBC. Protein-protein interaction showed significant association of PDGFB and HER2 with the epidermal growth factor receptor signaling pathway.
Highlights
Gall bladder cancer (GBC) is an uncommon etiology with late diagnosis, limited treatment options and poor prognosis with overall five year survival rate of less than 10%
Amplification and over expression of Platelet derived growth factor-B (PDGFB) and human epidermal growth factor receptor-2 (HER2) are usually involved in the growth, progression and metastasis of established tumors
Prominent associations of the PDGFB gene polymorphisms with GBC were found in the present study
Summary
Gall bladder cancer (GBC) is an uncommon etiology with late diagnosis, limited treatment options and poor prognosis with overall five year survival rate of less than 10%. Remarkable variation in the incidence of GBC has been reported across the globe with low prevalence in the United States, United Kingdom and western Europe, and higher frequency in central and south America, central and eastern Europe, Japan (Randi et al, 2006) and China (Qu et al, 2012). Chile in south America has one of the highest incidence rates of GBC in world and GBC is the major cause of cancer deaths in females (Randi et al, 2006). It is reported as a disease of elderly females (Hamdani et al, 2012). Earlier association of single nucleotide polymorphisms (SNPs) with GBC has been reported (Mishra et al, 2013)
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