CYP2A6 genetic polymorphisms and biomarkers of tobacco smoke constituents in relation to risk of lung cancer in the Singapore Chinese Health Study.

Cytochrome P450 2A6 (CYP2A6) catalyzes the metabolism of nicotine and the tobacco-specific lung carcinogen, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). Genetic variation in CYP2A6 may affect smoking behavior and contribute to lung cancer risk. A nested case-control study of 197 lung cancer cases and 197 matched controls was conducted within a prospective cohort of 63 257 Chinese men and women in Singapore. Quantified were five genetic variants of CYP2A6 (*1A, *4, *7, *9 and *12) and urinary metabolites of nicotine [total nicotine, total cotinine, total trans-3'-hydroxycotinine (3HC)] and NNK (total NNAL, free NNAL, NNAL-glucuronide, NNAL-N-glucuronide, and NNAL-O-glucuronide). Higher urinary metabolites of nicotine and NNK were significantly associated with a 2- to 3-fold increased risk of lung cancer after adjustment for smoking intensity and duration. Lower CYP2A6-determined nicotine metabolizer status was significantly associated with a lower ratio of total 3HC over total cotinine, lower total nicotine equivalent and reduced risk of developing lung cancer (all Ptrend < 0.001). Compared with normal metabolizers, odds ratios (95% confidence intervals) of developing lung cancer for intermediate, slow and poor metabolizers determined by CYP2A6 genotypes were 0.85 (0.41-1.77), 0.55 (0.28-1.08) and 0.32 (0.15-0.70), respectively, after adjustment for smoking intensity and duration and urinary total nicotine equivalents. Thus the reduced risk of lung cancer in smokers with lower CYP2A6 activity may be explained by lower consumption of cigarettes, less intense smoking and reduced CYP2A6-catalyzed activation of the tobacco-specific lung carcinogen NNK.

Genetic determinants of cytochrome P450 2A6 activity and biomarkers of tobacco smoke exposure in relation to risk of lung cancer development in the Shanghai cohort study.

Cytochrome P450 2A6 (CYP2A6) catalyzes nicotine metabolism and contributes to the metabolism of the tobacco-specific lung carcinogen, NNK. Genetic variation in CYP2A6 may affect smoking behavior and contribute to lung cancer risk. A nested case-control study of 325 lung cancer cases and 356 controls was conducted within a prospective cohort of 18,244 Chinese men in Shanghai, China. Quantified were 4 allelic variants of CYP2A6 [*1(+51A), *4, *7, and *9] and urinary total nicotine, total cotinine, total trans-3'-hydroxycotinine (3HC) and total NNAL (an NNK metabolite). Calculated were total nicotine equivalents (TNE), the sum of total nicotine, total cotinine and total 3HC and the total 3HC:total cotinine ratio as a measure of CYP2A6 activity. The nicotine metabolizer status (normal, intermediate, slow and poor) was determined by CYP2A6 genotypes. The smoking-adjusted odds ratios (95% confidence intervals) of lung cancer for the highest vs lowest quartile of total nicotine, total cotinine, total 3HC, TNE and total NNAL were 3.03 (1.80-5.10), 4.70 (2.61-8.46), 4.26 (2.37-7.68), 4.71 (2.61-8.52), and 3.15 (1.86-5.33) (all Ptrend < 0.001), respectively. Among controls CYP2A6 poor metabolizers had a 78% lower total 3HC:total cotinine ratio and 72% higher total nicotine (Ptrend ≤ 0.002). Poor metabolizers had an odds ratio of 0.64 (95% confidence interval = 0.43-0.97) for lung cancer, which was statistically nonsignificant (odds ratio = 0.74, 95% confidence interval = 0.48-1.15) after adjustment for urinary TNE and smoking intensity and duration. The lower lung cancer risk observed in CYP2A6 poor metabolizers is partially explained by the strong influence of CYP2A6 genetic polymorphisms on nicotine uptake and metabolism.

Skin Cancer Risk Is Modified by KIR/HLA Interactions That Influence the Activation of Natural Killer Immune Cells.

Natural killer (NK)-cell phenotype is partially mediated through binding of killer-cell immunoglobulin-like receptors (KIR) with HLA class I ligands. The KIR gene family is highly polymorphic and not well captured by standard genome-wide association study approaches. Here, we tested the hypothesis that variations in KIR gene content combined with HLA class I ligand status is associated with keratinocyte skin cancers using a population-based study of basal cell carcinoma (BCC) and squamous cell carcinomas (SCC). We conducted an interaction analysis of KIR gene content variation and HLA-B (Bw4 vs. Bw6) and HLA-C (C1 vs. C2). KIR centromeric B haplotype was associated with significant risk of multiple BCC tumors (OR, 2.39; 95% confidence interval, 1.10-5.21), and there was a significant interaction between HLA-C and the activating gene KIR2DS3 for BCC (Pinteraction = 0.005). Furthermore, there was significant interaction between HLA-B and telomeric KIR B haplotype (containing the activating genes KIR3DS1 and KIR2DS1) as well as HLA-B and the activating KIR gene KIR2DS5 (Pinteraction 0.001 and 0.012, respectively). Similar but greatly attenuated associations were observed for SCC. Moreover, previous in vitro models demonstrated that p53 is required for upregulation of NK ligands, and accordingly, we observed there was a strong association between the KIR B haplotype and p53 alteration in BCC tumors, with a higher likelihood that KIR B carriers harbor abnormal p53 (P < 0.004). Taken together, our data suggest that functional interactions between KIR and HLA modify risks of BCC and SCC and that KIR encoded by the B genes provides selective pressure for altered p53 in BCC tumors.

HLA-C -35kb expression SNP is associated with differential control of ß-HPV infection in squamous cell carcinoma cases and controls.

A single nucleotide polymorphism (SNP) 35 kb upstream of the HLA-C gene is associated with HLA-C expression, and the high expressing genotype (CC) has been associated with HIV-I control. HLA-C is unique among the classical MHC class I molecules for its role in the control of viral infections and recognition of abnormal or missing self. This immunosurveillance is central to the pathogenesis of non-melanoma skin cancer (NMSC), and of squamous cell carcinoma (SCC) in particular. While sun exposure is a major risk factor for these cancers, cutaneous infections with genus ß-HPV have been implicated in the development of SCC. We hypothesized that the high expression HLA-C genotype is associated with ß-HPV infections. Therefore, we investigated the association between ß-HPV serology and the -35 kb SNP (rs9264942) in a population-based case-control study of 510 SCC cases and 608 controls. Among controls, the high expression -35 kb SNP genotype (CC) reduced the likelihood of positive serology for multiple (≥2) ß-HPV infections (OR = 0.49, 95% CI: 0.25-0.97), and ß-HPV species 2 infection (OR = 0.43, 95% CI: 0.23-0.79). However, no association with ß-HPV status was observed among SCC cases. Our findings suggest that underlying immunogenotype plays an important role in differential control of ß-HPV in SCC cases and controls.