Table II.
List of gene polymorphism affecting the susceptibility to cigarette-smoke-induced pancreatic cancer
| Gene | Function | Observed polymorphism(s) and associated genotypes/alleles | Polymorphism affecting the susceptibility to PC (Refs) |
|---|---|---|---|
| Tobacco-carcinogen metabolizing genes | |||
| Cytochrome P450 (CYP2A6) | Metabolization of nicotine to cotinine | CYP2A6*2, CYP2A6*4, CYP2A6*9, CYP2A6*12 | CYP2A6*2 and CYP2A6*4 genotypes: slow metabolism of nicotine in Caucasian population. No association in Japanese population (54,55,69,70). |
| Cytochrome P450 (CYP2A13) | Metabolization of nicotine to cotinine, metabolic activation of nitrosamines | CYP2A13*1/*7 (Arg101Stop) | CYP2A13*1/*7 (Arg101Stop): Inactive enzyme, no significant association with PC risk was observed due to lack of carrier of CYP2A13*7 among the PC cases (158). |
| N-acetyl-transferase 1 (NAT1) | O-acetylation of aromatic and HCA | C1095A (NAT1*10, 3′UTR, C97T, Arg33Stop, NAT1*19), C190T (Arg64Trp, NAT1*17), G445A (Val149lIe, NAT1*11) | NAT1*10: Rapid acetylator (4-fold higher risk of PC in female smokers in comparison to never smokers who did not carry the NAT1*10 allele (59,82)). |
| N-acetyl-transferase 2 (NAT2) | O-acetylation of aromatic and HCA | G191A (Arg64Gln) C282T, T341C (Ile114Thr), C481T, G590A (Arg197Gln), A803G (Lys268Arg), G857A (Gly286Thr) | Slow acetylator increases the susceptibility to PC in smokers (82,159). |
| Glutathione S-transferase T1 (GSTT1) | Adding reduced glutathione | Wild type/heterozygous del, Null/homozygous del (deletion) | GSTT1-null genotype: Increases the susceptibility to PC in smokers (160) |
| Tumor suppressors genes | |||
| p21 | Critical mediator of G1-phase cell cycle arrest preventing the G1/S transition by inhibiting various CDK–cyclin complexes | p21 exon 2 (C/A) Ser31Arg | p21 C-to-A SNP: Increases the susceptibility to PC among homozygous wild-type carrier of p27 especially among non-smokers (71) |
| Methylene-tetrahydro- folate reductase (MTHFR) | Catalyzes conversion of THF to 5-methyl THF during folate metabolism | MTHFR C677T (exon 4) (Ala/Val) MTHFR A1298C (exon 7) Glu429Ala | MTHFR 677T: Increases susceptibility to PC in ever-smokersMTHFR 1298C: Significantly reduced risk for PC (161,162). |
| Somatostatin receptor 5 (SSTR5) | Inhibits proliferation of normal and neoplastic cells | Pro109Ser (CC,CT) Leu48Met (CC, AC) Pro335Leu (TT, TC) | Leu48Met: Increases the risk for PC in combination with smoking (73) |
| Proliferator-activated receptor gamma (PPARG) | Regulate the adipose cell differentiation and inhibits the invasive behavior of PC cells in vitro | PPARG exon 2(C/G) Pro12Ala | Pro12Ala: Increases the risk for PC among high-risk smokers in vitamin-administered subject in comparison to placebo-administered subjects (163) |
| Tumor protein p53 (TP53) | Protection from DNA damage | TP53 exon 4 (G/C), Arg 72 Pro, Arg/Arg, Arg/Pro and Pro/Pro | TP53 Pro/Pro: Profound effect on PC risk heavy smoker males (83) |
| Pro-inflammatory genes | |||
| Cyclooxygenase-2 (COX-2) | Converts free arachidonic acid into PGH2 (precursor of prostaglandins and thromboxanes) | Promoter region—765G/C—1195G/A—1290A/G | 765C: Increased COX2 promoter activity upon cigarette smoking in comparison to −765G allele (164). |
| DNA repair genes | |||
| X-ray repair cross-complementing group 2 (XRCC2) | Double-strand break repair gene | XRCC2 exon 3 (G/A) (Arg 188His), Arg/Arg, Arg/His, His/His | XRCC2 Arg188Arga: Increased risk of PC among ever-smokers in comparison to never-smokers (79,165). |
| XRCC3 | Double-strand break repair gene | XRCC3 exon 7 (C/T) Thr(241)Thra, Thr(241)Met, Met (241) Meta, XRCC3.241C/T | Combination of smoking and XRCC3 variant (XRCC3.241* and XRCC3 Thr241Met) associated with increased risk of PC (80) |
| Xeroderma pigmentosum group D (XPD)/(ERCC2) | Member of the human transcriptional initiation factor TFIIH with ATP-dependent helicase activity | XPD exon 10 (G/A) Asp(312)Asn and exon 23 (A/C) Lys(751)Gln | Asn(312)Asna: Reduced risk of PC in ever smokers in comparison to carriers of Asp(312)Aspa allele (81,166). |
| Aldehyde dehydrogenase 2 (ALDH2) | Catalyzes the chemical transformation of acetaldehyde to carboxylic acid in mitochondria | Glu504 homozygotes (ALDH2*1/1), Glu504/Lys504 (active enzyme) heterozygotes (ALDH2*1/2) (inactive enzyme) | The OR of smoking patients with ALDH2*1/2*2 polymorphism was more than 7-fold higher than that of non-smoking patients with the active form of ALDH2 (84). |
| ABO | A, B, and O glycosyl-transferases transfer GalNAc, Gal, and no sugar residue, respectively, to H histo-blood group antigen expressed by red blood cells, endothelial cells, and epithelial cells | Genotype derived from ABO, O, A, B, AB | In a joint model with smoking, current smokers with non-O blood type had an adjusted OR of 2.68 (95% CI, 2.03–3.54) compared with non-smokers of blood type O (167, 168). |
CS, Cigarette smoke; THF, 5,6,7,8-tetrahydrofolate; PGH2, prostaglandin H2; ERCC2, excision repair cross-complementing repair deficiency; GalNAc, N-acetyl-D-galactosamine; Gal, D-galactose; OR, odd ratio;
PC, pancreatic cancer.
*The variant alleles of the gene.
aNo amino acid change due to the alteration in the wobble nucleotide.