Kazuo Tajima

Extra-ovarian sex hormone production plays an important role in endometrial cancer in postmenopausal women. Aromatase, which is encoded by CYP19A1, is a key enzyme in estrogen biosynthesis after menopause. To examine the association between polymorphisms in CYP19A1 and endometrial cancer risk among postmenopausal Japanese women, we conducted a hospital-based case control study in 48 patients with histologically diagnosed incident endometrial cancer and 253 non-cancer control subjects. Information on lifestyle factors was obtained from a self-administered questionnaire. Twenty-five tag SNPs (single nucleotide polymorphisms) of CYP19A1 were examined by TaqMan methods and haplotype blocks were identified by LD analysis. Associations were assessed by an unconditional logistic regression model adjusted for potential confounders. We found no significant association between CYP19A1 genotypes and haplotypes and endometrial cancer risk. However, among women with a BMI (body mass index) >23, significantly positive associations were observed for rs2899473, rs1865803, rs16964220, rs2008691, rs17647707, rs17647719, rs1902586, rs936306, and rs1004982, while negative associations were seen for rs1902585, rs752760 and rs2445768. These showed significant interactions with BMI. Further, of the six haplotype blocks identified, the haplotype CTT of block 1, GATA of block 5 and CA of block 6 showed statistically significant interactions with BMI. These results suggest that CYP19A1 polymorphisms might play an important role in the etiology of endometrial cancer, and that the effect of these polymorphisms might be influenced by BMI.

Although many studies have shown that smoking is an established risk factor for gastric cancer, relatively few studies have investigated on which step smoking has effects in Helicobacter pylori (H. pylori) related gastric carcinogenesis. In this study we investigated the association of smoking with risk of three steps leading to gastric cancer: H. pylori infection, gastric atrophy, and gastric cancer. Among the participants who visited Aichi Cancer Center Hospital from year 2001 to 2005, 583 cases diagnosed as gastric cancer and age-and sex-frequency-matched 1,742 cancer free controls were sampled, from whom those without serum samples or without information about smoking habit were excluded, leaving 576 cases and 1,599 controls eligible for the analyses. Anti- H. pylori IgG antibody and serum pepsinogens (PG) were measured to detect H. pylori infection and gastric atrophy. Smoking status was asked by a self-administered questionnaire. The odds ratio (OR) of H. pylori infection, as well as the OR of gastric atrophy among the H. pylori seropositive controls was not significant for smokers. The age- and sex-adjusted OR of gastric cancer was significantly elevated relative to the subjects with gastric atrophy: OR=1.62 (95% confidence interval (CI), 1.19-2.22; P=0.002) for ever smokers and 2.52 (1.75-3.64; P<0.001) for current smokers, relative to never smokers. This study revealed that smoking behavior contributed to the increased risk of gastric carcinogenesis from gastric atrophy, and had little influence on H. pylori infection or gastric atrophy development.

To evaluate the relationship between body size, physical activity and risk of breast cancer, we conducted a case-control study with 669 cases and 682 population-based controls in Jiangsu Province of China. A structured questionnaire was used to elicit detailed information. All subjects completed an in-person interview. The body mass index (BMI) was calculated based on weights and heights. Unconditional logistic regression analysis was performed to calculate odds ratios (ORs) and 95% confidence intervals (CIs) as measures of risk for breast cancer. Current height, weight and weight at around age 20 years were significantly positively correlated with risk of breast cancer. Obese women (current BMI > or = 25 kg/m2) were at significantly increased risk for developing breast cancer (adjusted OR= 1.35, 95%CI: 1.01-1.81), but, between BMI at around age 20 years and risk of breast cancer showed an inverse association (P for trend = 0.001). Women who had middle physical force work were at significantly lowered OR (0.62, 95%CI: 0.41-0.93) compared with women of headwork. Using women who standing or ambulation per day less than one hour as the reference, women who standing or ambulation more than one hour had a decreased risk of breast cancer. Using women who slept less than 5 hours per day as the reference, the women who slept 5-8 hours were at significantly decreased risk of breast cancer. Women who had habit of recreational physical activity were at significantly decreased risk (adjusted OR= 0.68, 95%CI: 0.53-0.88), with an inverse association between the exercise times per week and risk of breast cancer (P for trend = 0.025). These findings support that breast cancer risk is associated with body size, and that moderate occupational and recreational physical activity has protective effects on breast cancer.

Dihydropyrimidine dehydrogenase (DPD) is the enzyme catalyzing the first step of pyrimidine metabolism. To date, genetic polymorphisms of pyrimidine-synthesizing enzymes have been reported to be associated with the risk of malignant lymphoma or colon cancer. Accordingly, there may be associations between dihydropyrimidine dehydrogenase (DPYD) polymorphism and the risk of malignancies. We conducted a prevalent case-control study to investigate the associations between a functional polymorphism of dihydropyrimidine dehydrogenase, DPYD T85C, and the risk of six malignancies. Controls were 445 Nagoya City inhabitants without a history of malignancy who had participated in a health check-up between August and September 2000. Case subjects were 901 patients with malignancies (99 esophageal, 131 gastric, 143 colon, 179 lung, 243 breast, and 106 malignant lymphomas) who had visited Aichi Cancer Center Hospital between March 1999 and December 2000. No DPYD CC individuals were found in either cases or controls. The frequency of DPYD TC genotype was 6.3% in control subjects and 5.9% in all case subjects (not significant). In a subgroup analysis, the frequency of TC genotype was highest in patients with gastric cancer (9.1%), followed by those with lung cancer (8.3%), with the lowest frequency in those with malignant lymphoma (1.9%). The gender- and age- adjusted odds ratios and 95% confidence intervals for the TC genotype of gastric cancer and malignant lymphoma were 1.52 (0.71-3.28) and 0.31 (0.71-1.34), respectively. Although prevalent cases were used, this study suggested that the influence of DPYD T85C posed only a limited risk for the six malignancies.

An epidemiological study of hepatitis viruses type B (HBV) and type C (HCV) and human T-cell leukemia virus type I (HTLV-I) was carried out among 103 residents (male:female=61:42) regarded as Sherpas, at Lukla (Solukhumbu district), Nepal in 2004. Blood was drawn from apparently healthy volunteers at ages of 28.8+12.3 (range 15-66) years. HBsAg, HBsAb, HBcAb, and HCV Ab were measured by microparticle enzyme-immunoassay, and HTLV-I Ab was measured by particle agglutination. Prevalence of HBsAg(+), HBsAb(+), HBcAb(+), and HBsAb(+) or HBcAb(+) were 1.9% 22.3%, 24.3%, and 28.2%, respectively. For HCV Ab, only a borderline reaction was observed in one sample, and for HTLV-I Ab all samples were negative. Nucleotide sequencing of the PreS1, PreS2, and S genes revealed that HBV among Sherpas to be of the A' (or Aa) genotype, which is prevalent among Nepalese but rare in native Tibetans, suggesting transmission within Nepal rather than association with ancestors' migration from Tibet as the origin. This is the first report of Himalayan Sherpas' state of infection with HBV, HCV, and HTLV-I.

Thymidylate synthetase (TS) and methylenetetrahydrofolate reductase (MTHFR) are major enzymes in the metabolism of folates, involved in DNA 'breaks', instability and hypomethylation. To investigate the possible relations between the TS 3'-UTR and MTHFR C677T polymorphisms and environmental factors impacting on risk of esophageal and stomach cancers, we conducted a case-control study in a high incidence region of China for these cancers. We recruited 138 esophageal and 155 stomach cancer cases, and 223 controls. The TS 3' -UTR and MTHFR C677T genotypes were detected by RFLP assay, using PCR products. The frequency of the -6 bp homozygous TS 3' -UTR genotype was 37.7 % in controls, higher than in Caucasians, although the present distribution was not in Hardy-Weinberg equilibrium. Ever-smoking with the -6 bp/-6 bp TS genotype elevated the ORs (2.61, 1.24-5.49; 3.54, 1.60-7.82) for cases of esophageal and stomach cancers, respectively, when compared with never-smoking with the +6 bp/+6 bp and +6 bp/-6 bp genotypes. No combination between the TS and MTHFR genotypes gave increased ORs. The present results suggest that TS polymorphism may modify the risk of esophageal and stomach cancer with smoking, pointing to the necessity for further investigations with information on folate and methionine intake with a larger population.

The Sami is an ethnic group with ill-defined genetic origins, living in the northern areas of the Scandinavian Peninsula and Russia. Distinct from other European populations in culture and language, they are generally deemed to be remote from the Caucasian lineage. In order to ascertain whether the Sami are genetically linked to Asiatic Mongoloids, we investigated serological markers of human T-cell leukemia virus type I (HTLV-I) infection. Particle agglutination tests for serum HTLV-I antibody were performed for 400 Sami living in Finnmark, the northernmost county of Norway, and in 380 Caucasians (or Norse) in the same region, using serum samples collected for the purpose of studying cardiovascular disease among Northland people in 1974-75. One sample from a Sami showed a tentatively positive reaction, and 4 sera from Sami and 4 from Norse individuals exhibited non-specific agglutination. However, none of the 9 sera showed a positive result in western blotting for HTLV-I proteins, namely, gp46, p53, p24, and p19. Since HTLV-I is distributed most prevalently among northern and southwestern Japanese in Asia and Andeans in South America, the absence of HTLV-I in the Sami might suggest their genetic remoteness from these ethnic groups.

To examine an association between the mitochondrial DNA (mt5178) genotype and various cancers, we genotyped 1120 non-cancer controls and 930 cancer cases including esophageal, stomach, colorectal, lung, breast and malignant lymphoma in a sample of Japanese patients. The mt5178A/C was genotyped by the polymerase chain reaction with confronting two-pair primers (PCR-CTPP). The frequency of mt5178A/C within the non-cancer and cancer groups, and age distribution of subjects with mt5178A and C were investigated. Odd ratios (ORs) of the mt5178A and C genotypes were also examined. The frequency of mt5178A was 39.1% in non-cancer subjects while frequencies in those having cancer included 39.0% in breast, 37.4% in colorectal, 45.1% in esophageal, 38.0% in lung, 41.5% in malignant lymphoma, and 38.8% in stomach cancer. There was no significant difference in the frequency of the mt5178 genotype among the six types of cancer studied. There was also no significant difference in the frequency of the mt5178 genotype between non-cancer and cancer subjects regardless of total age with the exception that ages 40-49 years (the frequency of the mt5178A was higher in cancer subjects). There was a significant interaction term between age and the mt5178 genotype in older (age>=60) lung cancer patients. The cumulative frequency of mt5178C increased more markedly than that of mt5178A after age 40 in non-cancer subjects, and after age 50 in cancer subjects ORs of the genotype were not significant for all cancers combined or for any individual site of cancer. In the present study, the mt5178 genotype seems to have no association with any of the cancers examined here. But an interaction term between the mt5178 genotype and aging on cancer was suggested with the Japanese population under study.

To evaluate the effects of glucose metabolism related factors, such as insulin and insulin-like growth-factors (IGFs), on breast cancer development among Japanese women, we conducted a case-referent study comparing 187 women presenting with operable breast cancer and 190 women of the same age having no breast cancer. Odds ratios (OR) and 95% confidence intervals (95%CI) were determined by multiple logistic regression analysis. In the present study, no association in risk was observed with increasing levels of IGF-I or IGF binding protein-3 (IGFBP-3), before or after adjustment these factors. However, a suggestion of a positive association of an increased breast cancer risk was evident in postmenopausal women with elevated plasma insulin levels, particularly those with BMI>23.07. The OR for plasma insulin in the top tertile was 4.48 (95%CI:1.07-18.7) compared to the bottom tertile. For C-peptide, there was a similar positive association, with a corresponding OR of 2.28. In addition, we observed strong links between plasma insulin, C-peptide levels and estrogen receptor (ER) negative breast cancer, with ORs of 2.79(95%CI:1.09-7.16), and 2.52 (95%CI:0.91-6.97) respectively, for the top versus bottom tertiles. In conclusion, the present study suggested that plasma insulin level is a predictor of postmenopausal breast cancer in obese women and ER negative breast cancer. Additional studies are needed to clarify the role of glucose metabolism pathways in breast cancer development and interaction of IGF systems.