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Biallelic germline mutations of MUTYH, the gene encoding DNA glycosylase, cause MUTYH-associated polyposis (MAP), characterized by multiple colorectal adenomas and carcinoma(s). However, a considerable number of MUTYH variants are still functionally uncharacterized. Herein, we report the results of functional evaluation of nine missense-type MUTYH variant proteins in the Japanese population. The DNA glycosylase activity and ability to suppress mutations caused by 8-hydroxyguanine, an oxidized form of guanine, were examined for the nine variants of type 2 MUTYH, a nuclear form of the enzyme, by DNA cleavage activity assay and supF forward mutation assay, respectively. Both activities were severely defective in the p.N210S MUTYH type 2 variant corresponding to p.N238S in the reference MUTYH form and partially defective in p.R219G variant corresponding to p.R247G, but nearly fully retained in seven other variants examined. Our results suggest that p.N238S and p.R247G are likely to be pathogenic alleles for MAP., (© 2015 WILEY PERIODICALS, INC.)

Cytochrome P450 2A6 (CYP2A6) is an enzyme involved in the metabolism of tobacco carcinogens, which are important risk factors in lung cancer. We and others have previously reported that CYP2A6*4, a whole-gene deletion polymorphism, is associated with lower risk of lung cancer than the wild-type allele. However, the genotyping method used in these previous studies considered only the CYP2A6*4 allele; this lead to insufficient classification of the CYP2A6 genotype, thereby underestimating the frequencies of the deficient alleles. In this study, CYP2A6 genotypes of Japanese smokers (110 individuals with squamous cell lung cancer (SQCC) and 132 sex-matched cancer-free controls) were determined using a sequencing-based approach to determine CYP2A6 haplotypes. The risk of SQCC was evaluated using the activity score (AS) system to predict CYP2A6 phenotype from its genotype. The risk of developing SQCC was significantly lower in the poor metabolizers assigned as AS 0.5 (adjusted odds ratio [OR] = 0.13, 95% CI = 0.04-0.45, P = 0.001) and AS 0 (adjusted OR = 0.15, 95% CI = 0.03-0.82, P = 0.028) than in the extensive metabolizers assigned as AS 2.0. In conclusion, CYP2A6 genetic polymorphisms may play important roles in the development of SQCC in Japanese smokers., (Copyright © 2015 The Japanese Society for the Study of Xenobiotics. Published by Elsevier Ltd. All rights reserved.)

R-spondin (RSPO) gene fusions have recently been discovered in a subset of human colorectal cancer (CRC) in the U.S. population; however, whether the fusion is recurrent in CRC arising in patients from the other demographic areas and whether it is specific for CRC remain uncertain. In this study, we examined 75 primary CRCs and 121 primary lung cancers in the Japanese population for EIF3E-RSPO2 and PTPRK-RSPO3 fusion transcripts using RT-PCR and subsequent sequencing analyses. Although the expression of EIF3E-RSPO2 and PTPRK-RSPO3 was not detected in any of the lung carcinomas, RSPO fusions were detected in three (4%) of the 75 CRCs. Two CRCs contained EIF3E-RSPO2 fusion transcripts, and another CRC contained PTPRK-RSPO3 fusion transcripts. Interestingly, in one of the two EIF3E-RSPO2 fusion-positive CRCs, a novel fusion variant form of EIF3E-RSPO2 was identified: exon 1 of EIF3E was connected to exon 2 of RSPO2 by a 351-bp insertion. A quantitative RT-PCR analysis revealed that RSPO mRNA expression was upregulated in the three CRCs containing RSPO fusion transcripts, while it was downregulated in nearly all of the other CRCs. An immunohistochemical analysis and a mutational analysis revealed that the RSPO fusion-containing CRC had a CDX2 cell lineage, was positive for mismatch repair protein expression, and had the wild-type APC allele. Finally, the forced expression of RSPO fusion proteins were shown to endow colorectal cells with an increased growth ability. These results suggest that the expression of RSPO fusion transcripts is related to a subset of CRCs arising in the Japanese population.

Since the international gastric cancer linkage consortium first proposed screening criteria for the detection of CDH1 germline mutations in hereditary diffuse gastric cancer(HDGC), the low yields of previous attempts to identify patients with HDGC in Japan, where gastric cancer is endemic and mass screenings for it have been established, have made clinicians less enthusiastic about pursuing the genetic etiology of the peculiar occurrence of gastric cancer. A report published in 2011 described a case with a typical truncated mutation of CDH1 and another with an exon 3 deletion of this gene. These findings have rekindled the curiosity of practicians and pathologists confronted with unusual gastric cancers of various types such as younger- onset, familial clustering, or the exhibition of a specific characteristic morphology. The status and history of the investigation of the genetic backgrounds of Japanese gastric cancers are reviewed, and the pathological features of the Japanese cases of HDGC are described.

The dopaminergic brain pathway is involved in many addictive behaviours, hence represents a good candidate in the study of smoking behaviour and nicotine addiction. Dopamine beta hydroxylase (DBH) is an enzyme that catalyses the conversion of dopamine into noradrenaline. This study, the first of its kind, was done to investigate the role of DBH rs5320 polymorphism in smoking behaviour of elderly Japanese. This was done by collecting blood samples from 2521 subjects with various smoking habits to genotype the DBH rs5320 polymorphism. Participants also had to fill out a questionnaire containing questions regarding their lifestyles. Some of the questions were from the Fagerström Test for Nicotine Dependence (FTND) and the Tobacco Dependence Screener (TDS). It was found that male ever-smokers with AA genotype smoked less cigarettes per day than those with GG and AG genotypes. FTND scores were also lowest in male ever-smokers with AA genotype and in female ever-smokers with AG genotype. There was no correlation detected between the TDS scores and any of the genotypes. This study shows that DBH rs5320 polymorphism influences nicotine dependence.

Molecular heterogeneity of neuropeptide Y (NPY) and its three receptors (1, 2 and 5) has recently been discovered. NPY2R polymorphisms have been shown to be related to cocaine and alcohol dependence in European Americans. To test our hypothesis that these polymorphisms influence the smoking behavior of Japanese population, we investigated the prevalence of the rs4425326 and rs6857715 polymorphisms, which have been suggested to be related to alcohol dependence in European Americans, in 2517 Japanese elderly subjects for whom information on smoking behaviors was available. The prevalence of current smokers was greater among Japanese men having the rs4425326 C allele than ex-smokers. Among the ever-smokers, the Fagerström Test for Nicotine Dependence scores were higher in men having the rs4425326 homozygous T allelotype, and the numbers of cigarettes smoked per day were also significantly higher in the male smokers having the TT genotype. No correlations between the Tobacco Dependence Screener scores and any genotypes were detected. These results suggest that rs4425326 polymorphism may be related to smoking behavior in the Japanese elderly population. This study for the first time suggests NPY2R genotype as a possible genetic factor in nicotine dependence.

To evaluate the roles of CYP1A1 polymorphisms [Ile 462Val and T 6235C (MspI)] and deletion of GSTM1 and GSTT1 in lung cancer development in Asian populations, a pooled analysis was conducted on 13 existing studies included in Genetic Susceptibility to Environmental Carcinogenesis database. This pooled analysis included 1,971 cases and 2,130 controls. Lung cancer risk was estimated as odds ratios (OR) and 95% confidence intervals (95% CI) using unconditional logistic regression model adjusting for age, sex, and pack-year. The CYP1A1 6235C variant was associated with squamous cell lung cancer (TC versus TT: OR, 1.42; 95% CI, 0.96-2.09; CC versus TT: OR, 1.97; 95% CI, 1.26-3.07; P trend = 0.003). In haplotype analysis, 462Val-6235T and Ile-C haplotypes were associated with lung cancer risk with reference to the Ile-T haplotype (OR, 3.41; 95% CI, 1.78-6.53 and OR, 1.39; 95% CI, 1.12-1.71, respectively). The GSTM1-null genotype increased squamous cell lung cancer risk (OR, 1.36; 95% CI, 1.05-1.77). When the interaction was evaluated with smoking, increasing trend of lung cancer risk as pack-year increased was stronger among those with the CYP1A1 6235 TC/CC genotype compared with those with TT genotype (P interaction = 0.001) and with the GSTM1-null genotype compared with the present type (Pinteraction = 0.08, when no genotype effect with no exposure was assumed). These results suggest that genetic polymorphisms in CYP1A1 and GSTM1 are associated with lung cancer risk in Asian populations. However, further investigation is warranted considering the relatively small sample size when subgroup analyses were done and the lack of environmental exposure data other than smoking.

Background & Aims: Interleukin-1 beta (IL-1beta) polymorphisms are associated with increased risk of gastric cancer in whites. This study aimed to examine effects of these polymorphisms on gastric acid secretion, atrophic gastritis, and risk of peptic ulcer in Japan., Methods: We determined IL-1B-511/-31 and IL-1RN genotypes and measured gastric juice pH, serum pepsinogen (PG) I and II levels, and gastritis and atrophy scores in Helicobacter pylori-positive patients with gastritis only, gastric ulcers, or duodenal ulcers (DUs), and H. pylori-negative controls., Results: In the H. pylori-positive group, subjects with the proinflammatory IL-1B-511 T/T genotype had the highest atrophy and gastritis scores, the highest median gastric juice pH, and the lowest median serum PG I/PG II ratios. Although gastric juice pH significantly increased and serum PG I and PG I/PG II ratios significantly decreased in the IL-1B-511 T/T genotype group with age, no such age-dependent changes were observed in the C/C genotype group. Changes in the C/T genotype group were intermediate. In the H. pylori-negative group, the IL-1 loci had no effect on any of the physiologic or morphologic parameters. Carriage of IL-1RN allele 2 significantly protected against DU disease while the IL-1B-511 T/T genotype significantly protected against DU recurrence in patients older than 60 years., Conclusions: Proinflammatory IL-1beta polymorphisms are associated with hypochlorhydria and atrophic gastritis in Japan. The effects are dependent on H. pylori infection and become more significant with advancing age. This may explain the high incidence of gastric cancer in Japan and also the age-dependent decrease in DU recurrence in infected subjects.