Opposite impact of NKG2D genotype by lifestyle exposure to risk of aerodigestive tract cancer among Japanese.

It was reported that there are 2 haplotypes in natural killer complex (NKC) region. One of them could be divided by NKG2D polymorphism into 2 haplotype alleles (high and low natural killer (NK) cell activity) and were associated with overall cancer risks. However, its impact on a specific cancer is unclear. Therefore, by a case-control study, we analyzed the association between NKG2D genotype and aerodigestive tract cancer risk. Subjects were 502 aerodigestive tract cancer patients (276 with head and neck, 226 with esophageal) and 1,004 sex-age matched noncancer controls. Exposures to 2 lifestyle factors, smoking and drinking, were evaluated by a self-administered questionnaire. The genotype of NKG2D was determined by the TaqMan method, and its impact was assessed by multivariable logistic regression models. Association strength was measured by the odds ratio (OR) and its confidence intervals (CI). An overall analysis revealed no statistically significant association between NKG2D genotype and the risk of aerodigestive tract cancer. However, we found protective effects of G allele among never smokers (OR 0.35; 95% CI 0.15-0.84) and never drinkers (0.42; 0.19-0.94). In contrary, increased risks were observed for G allele among heavy smokers (5.92; 3.23-10.85) and heavy drinkers (4.13; 2.29-7.47). Interactions between NKG2D genotype and lifestyle exposure were statistically significant (interaction p = 0.001 for smoking, 0.005 for drinking). The same trends were observed in both sexes, and in head and neck cancer and esophageal cancer independently. These results suggest an opposite impact of NKG2D genotype by lifestyle exposure to the risk of aerodigestive tract cancer among a Japanese population.

Decreased risk of colorectal cancer with the high natural killer cell activity NKG2D genotype in Japanese.

BACKGROUND: NKG2D is an immune receptor on natural killer (NK) and other cells active in the immune system. It recognizes ligands expressed on mainly transformed cells and plays a role in their elimination through the so-called 'cancer immune surveillance'. It was reported that there are two haplotypes of NKG2D, HNK1 (high NK activity) and LNK1 (low NK activity). Harboring the HNK1 is reported to reduce the overall cancer risk. To elucidate its impact on colorectal cancer (CRC), we conducted the present case-control study. METHOD: The subjects were 379 CRC patients and 1137 sex-age-matched non-cancer controls. Data on lifestyle factors including diet were obtained by self-administered questionnaire. The NKG2D genotypes (rs1049174: G-C, LNK1/LNK1:CC; LNK1/HNK1:CG and HNK1/HNK1:GG) were assessed by the TaqMan method. Associations were then assessed by multivariate logistic regression models, considering potential confounders. The measure of association was the odds ratio (OR) and its confidence intervals (CIs). RESULTS: We found a reduced risk of CRC with the NKG2D HNK1. Adjusted ORs were 0.77 for LNK1/HNK1 (95% CI: 0.60-0.99) and 0.48 for HNK1/HNK1 (0.32-0.72) relative to LNK1/LNK1. The same association was consistently observed with stratified analyses across all confounders except regular exercise and body mass index (BMI). Thus, the impact of harboring HNK1 was more evident among those with BMI >/= 25 and those exercising regularly, suggesting possible interactions between NKG2D genotype and these factors. CONCLUSION: We found that the HNK1 genotype, associated with high NK cell activity, might be an independent protective factor for CRC among the Japanese population. This possibility warrants further analysis.

Narrow-band UVB induces more carcinogenic skin tumors than broad-band UVB through the formation of cyclobutane pyrimidine dimer.

Phototherapy with narrow-band UVB (NB-UVB), with a peak exclusively at 311 nm wavelength, has been found to be more effective in treating a variety of skin diseases than conventional broad-band UVB (BB-UVB). To assess the difference in carcinogenic activity between NB-UVB and BB-UVB, we investigated skin tumor formation by irradiating albino hairless, Ogg1 knockout mice and C57BL/6J wild counterparts with these two UV sources. We found that the ratio of malignant skin tumors induced by NB-UVB was significantly higher than that induced by BB-UVB. There was no significant difference in carcinogenicity of skin tumor induced by NB-UVB between Ogg1 knockout and wild-type mice. To investigate the possible cause of different carcinogenic activity by the different UV sources, we examined three types of DNA damage: cyclobutane pyrimidine dimer (CPD), (6-4) photoproduct, and 8-oxoguanine (8-oxoG) induced by each UV source. We found that CPD formation following a minimum erythema dose (MED) by NB-UVB was significantly higher than that following 1 MED by BB-UVB, whereas the formation of (6-4) photoproducts and 8-oxoG following BB-UVB was significantly higher than those following NB-UVB exposure. These results suggest that CPD formation is closely related to the higher carcinogenic characteristics of NB-UVB. JID JOURNAL CLUB ARTICLE: For questions, answers and open discussion about this article please go to http://network.nature.com/.

Gene-environment interaction involved in oral carcinogenesis: molecular epidemiological study for metabolic and DNA repair gene polymorphisms.

BACKGROUND: Exposure to environmental carcinogens leads to oral squamous cell carcinoma (OSCC); however, the impact of genetic variations in carcinogen metabolisms and DNA repair on OSCC risk considering environmental exposures has not been clearly elucidated. METHODS: We conducted a case-control study with 122 cases and 241 controls. The risk of OSCC was evaluated in 10 genetic polymorphisms of nine genes, such as CYP1A1, CYP2E1, GSTM1, GSTT1, XPA, XPC, XPC, XPF and ERCC1. Gene-environment interaction was also evaluated. RESULTS: We found that CYP2E1 and XPA polymorphisms significantly affected the OSCC risk. Gene-environment interactions with smoking were significant for CYP2E1 and ERCC1 polymorphisms. Odds ratios for gene-environment interaction were 7.98 (P = 0.036), 9.67 (P = 0.017) and 8.49 (P = 0.031) for CYP2E1RsaI, DraI and ERCC1 polymorphisms, respectively. No interaction was observed with heavy drinking and any polymorphisms. CONCLUSION: CYP2E1, XPA and ERCC1 polymorphisms may affect the risk of OSCC.

An intervention study of smoking cessation with feedback on genetic cancer susceptibility in Japan.

BACKGROUND: To evaluate whether feedback of genetic information regarding an L-myc polymorphism, identified as impacting on tobacco-related cancer risk, has an influence on smoking cessation, an intervention study was conducted. METHODS: We recruited smokers from first-visit outpatients at Aichi Cancer Center Hospital. Six hundred and seventeen participated and were allocated into two groups: the biomarker feedback group (BF) and the follow-up smoking status group (FS). The subjects were asked for their smoking status at enrolment and at 3- and 9-month follow-ups. BF subjects were notified about their L-myc genotype. RESULTS: The smoking cessation rate at 9-month follow-up was essentially the same for both BF and FS cases, at 18.8% and 17.0%, respectively (P = 0.798). However, a difference in the rate was evident with non-cancer subjects (12.7% and 8.4%, respectively, P = 0.237), especially in females (15.0% and 4.2%, respectively, P = 0.024). The non-cancer subjects informed of their genotype were more likely to quit smoking than the FS patients; particularly in those having a risky genotype, this was significant (odds ratio: 2.87, P = 0.003). Again it was most prominent in females. CONCLUSION: Feedback regarding an L-myc polymorphism did not impact on smoking cessation overall but appeared to benefit smokers without cancer. In addition, gender could affect the response to the feedback.

Two haplotypes of 5' untranslated region in L-myc gene with different internal ribosome entry site activity.

We found two polymorphisms, A or C, at position 63 from the L-myc transcription start site, and 8- or 9-base Gs stretch between positions 82 and 89 or 90, in L-myc 5' UTR, which exhibited a strong linkage disequilibrium as two haplotypes, A-9G and C-8G. We analyzed whether both haplotypes of 5' UTR of the L-myc gene, each of which is approximately 200 nt long, are involved in translational regulation of the L-myc gene. Each haplotype of 5' UTR was inserted between Renilla luciferase and firefly luciferase genes to construct a bicistronic vector which was transcribed as a single mRNA. A translation of the downstream cistron was increased 70-100-fold in cos 7 cells, and 7-10-fold in HeLa S3 cells compared with a control vector without insertion. However, in this bicistronic assay system, both haplotypes of the L-myc 5' UTR showed similar internal ribosome entry site (IRES) activity. When a stable hairpin loop with a palindromic sequence was inserted into a 5'-end of bicistronic mRNA, the hairpin loop decreased only the activity of an upstream luciferase in both cos 7 and HeLa S3 cells, supporting the presence of an IRES. We also inserted 5' UTR of the L-myc gene into the 5'-end of reporter mRNA. C-8G showed approximately 2-fold higher IRES activity than A-9G in both cos 7 and HeLa S3 cells, suggesting that two polymorphisms in the L-myc exon 1 might be involved in regulation of L-myc protein expression.

Frequent somatic mutations of mitochondrial DNA in esophageal squamous cell carcinoma.

Recent studies of various cancers, such as those of the breast, head and neck, bladder and lung, reported that 46-64% of somatic mutations in the D-loop region of mitochondrial DNA (mtDNA) are observed. However, in esophageal cancer, only a low rate (5%) of somatic mutations has so far been reported in one article (Hibi, K. et al., Int J Cancer 2001;92:319-321). Thus, to confirm this we analyzed the somatic mutations for hypervariable regions (HVR-I and HVR-II) in the D-loop of mtDNA to reevaluate the possibility of mitochondrial genetic instability in this cancer. We amplified both HVRs by PCR and DNA samples obtained from 38 esophageal tumors and matched normal tissues, and then sequenced them. Comparing the sequences of tumors to those of normal tissues, we found 14 somatic mutations in 13 patients (34.2%). Eleven mutations were at the C consecutive stretch from position 303 to 309 of MITOMAP in the mitochondria databank (http://www.mitomap.org/), 1 at position 215 in HVR-II and 2 at positions 16,304 and 16,324 in HVR-I. There were 41 types of germ line variations in HVR-I including 2 not so far recorded in the mtDNA databank and 17 in HVR-II including 1 not yet recorded. We also determined nuclear genome instability of these 38 specimens by analyzing 3 independent microsatellite sequences. While 4 specimens showed a single microsatellite change, which is tumor specific, we did not find any co-relation between a somatic mtDNA mutation and microsatellite instability of nuclear genome DNA. These results suggest that mtDNA mutations might show a genetic instability in esophageal cancer independently from a nuclear genome instability.

Frequent polymorphic changes but rare tumor specific mutations of the LATS2 gene on 13q11-12 in esophageal squamous cell carcinoma.

We previously reported that loss of heterozygosity on 13q12-13 is related with poor prognosis of esophageal cancer. However, a target tumor-suppressor gene on this region is not yet identified. Recently, LATS2, a new human homologue of the Drosophila tumor suppressor gene (lats/warts) was identified on 13q11-12. We therefore screened esophageal tumor cell lines and tumor tissues to detect tumor specific mutations of the LATS2 gene. Although we found 5 different polymorphisms in this gene (4 kinds of single-base changes and a 6-bp insertion), a tumor specific mutation was identified in only one out of 60 tumor tissues. These results indicated that the LATS2 gene is inactivated in only a small part of esophageal tumors, if any.

L-myc genotype is associated with different susceptibility to lung cancer in smokers.

We have shown that L-myc genotype is associated with the risk of esophageal cancer from smoking and heavy drinking. In this study, we have analyzed the relationship between the L-myc genotypes and lung cancer risk from smoking in 191 Japanese lung-cancer patients and 241 non-cancer controls. The odds ratios (ORs) were markedly higher in SS and LS genotypes than in LL genotype; age-sex-adjusted ORs were 3.19, 2.30 and 0.92, respectively. This result suggests that the L-myc polymorphism may affect the induction of lung cancer by smoking. The OR for smoking in SS-genotype patients diagnosed within 2 years was higher than that in other SS patients, suggesting that smoking-related lung cancer in SS genotype might exhibit a poorer prognosis.