Ritsu Kusama

Dietary intake of folate, vitamin B2, vitamin B6, vitamin B12, genetic polymorphism of related enzymes, and risk of breast cancer: a case-control study in Japan.

We investigated associations among intake of folate, vitamin B2, vitamin B6, vitamin B12, and polymorphisms of 5,10-methylenetetrahydrofolate reductase (MTHFR) and methionine synthase (MTR) genes and breast cancer risk in a Japanese population. A hospital based, case-control study was conducted in Nagano Prefecture, Japan, in 388 pairs of patients with histologically confirmed invasive breast cancer and age- and area-matched controls selected from medical checkup examinees. Energy-adjusted intakes of folate and other B vitamins were derived from a validated food frequency questionnaire. Genotyping was completed for MTHFR (C677T and A1298T) and MTR (A2756G). Odds ratios and 95% confidence intervals were calculated by the conditional logistical regression model. Median dietary folate intake (μg/day) in the control group was 438.2 (interquartile range: 354.9–542.9). Neither dietary intake of folate, vitamin B2, vitamin B6, or vitamin B12 nor polymorphisms of MTHFR or MTR genes were significantly associated with breast cancer risk. Further, no significant interaction was found among nutrients, polymorphisms, and breast cancer risk. Associations of nutrients with breast cancer risk did not differ by hormone receptors status. We conclude that dietary intake of folate and related B vitamins and genotypes of MTHFR or MTR have no overall association with breast cancer risk in Japanese women.

Dietary cadmium intake and breast cancer risk in Japanese women: a case-control study.

Cadmium, an environmental pollutant, may act like an estrogen and be a potential risk factor for estrogen-dependent diseases such as breast cancer. We examined the hypothesis that higher dietary cadmium intake is associated with risk of overall and hormone receptor-defined breast cancer in Japanese women, a population with a relatively high cadmium intake. The study was conducted under a case-control design in 405 eligible matched pairs from May 2001 to September 2005 at four hospitals in Nagano Prefecture, Japan. Dietary cadmium intake was estimated using a food frequency questionnaire. Multivariable-adjusted odds ratios (ORs) and 95% confidence intervals (CIs) of breast cancer and its hormone-receptor-defined subtypes were calculated by tertile of dietary cadmium intake. We found no significant association between dietary cadmium and risk of total breast cancer in either crude or multivariable-adjusted analysis. Adjusted ORs for tertiles of cadmium intake were 1.00, 1.19, and 1.23 (95% CI, 0.76-2.00; P for trend=0.39) for whole breast cancer. Further, no significant associations were seen across strata of menopausal status, smoking, and diabetes in multivariable-adjusted models except for adjusted OR for continuous cadmium intake in postmenopausal women. A statistically significant association was found for estrogen receptor-positive (ER+) tumors among postmenopausal women (adjusted OR=1.00, 1.16, and 1.94 [95% CI, 1.04-3.63; P for trend=0.032]). Although the present study found no overall association between dietary cadmium intake and breast cancer risk, higher cadmium intake was associated with increased risk of ER+ breast cancer in postmenopausal women, at least at regular intake levels in Japanese women in the general population. Further studies are needed to confirm this association.

Serum organochlorines and breast cancer risk in Japanese women: a case-control study.

ObjectiveMost epidemiological studies of the association between breast cancer risk and exposure to organochlorine pesticides or polychlorinated biphenyls (PCBs), which are suspected endocrine disrupters and potential risk factors for human breast cancer, have been conducted in western countries, and the majority of results have been null and the rest inconsistent. Here, we examined these associations in Japanese women in the largest study in Asian women to date.MethodsThe study was a matched case–control study of breast cancer with 403 eligible matched pairs from May 2001 to September 2005 at four hospitals in Nagano Prefecture, Japan.MeasurementsSerum samples were measured for PCBs and nine pesticide-related organochlorines, including dichlorodiphenyltrichloroethane (DDT). Odds ratios of breast cancer or its hormone-receptor-defined subtypes according to serum organochlorines were calculated.ResultsNo increase in the risk of breast cancer was seen among women with higher serum concentrations of any organochlorine: o,p′-DDT, p,p′-DDT, p,p′-dichlorodiphenyldichloroethylene, hexachlorobenzene, β-hexachlorocyclohexane, trans-nonachlor, cis-nonachlor, oxychlordane, mirex, or PCBs. Rather, higher serum levels of cis-nonachlor, mirex, or total PCBs were associated with a decreased risk of breast cancerConclusionsOverall, these results suggest that breast cancer risk in Japan, a low-incidence country, is similar to that in western countries in terms of organochlorine exposure.

Clinicopathological characteristics of atypical cystic duct (ACD) of the breast: Assessment of ACD as a precancerous lesion

To clarify the clinicopathological features of an atypical cystic duct (ACD) as defined by Tsuchiya’s criteria as a precancerous lesion of the breast, we used 200 whole mammary gland serial sections of breast cancer. Forty‐four (22%) of the 200 breast cancer patients had ACD breast lesions. The frequency of patients with ACD increased in premenopausal women (P= 0.001). There was no correlation between the ACD‐present group and the ACD‐absent group for immunohistochemical status of the estrogen receptor (ER), progesterone receptor (PgR), p53, or c‐erbB2; Ki‐67 labeling index of cancer tissues; size of tumor, or lymph node metastases. A number of ACD lesions displayed continuity to cancer lesions. In 500 serial sections of a paraffin‐embedded tissue of a ACD case at 3 μm intervals, an apparent transition from ACD into ductal carcinoma in situ was observed. Immunohistochemical analysis using α‐smooth muscle actin showed that myoepithelial cells of ACD stained strongly, and their nuclei and cytoplasm were thinning. In 16 of the 44 (36%) ACD‐present patients, carcinoma cells stained positive for p53. Within those 16 cases, 12 cases (75%) were positive for p53 in ACD lesions. There was a significant correlation between the expression of p53 protein in malignant cells and ACD (P= 0.001). All 44 ACD lesions had no staining of c‐erbB2, regardless of staining in malignant lesions. The mean Ki‐67 labeling index of ACD lesions was low (0.3%), suggesting that ACD had a low proliferative rate. We suggest that ACD is the precancerous breast lesion because of a histologic continuum between ACD and malignancy, and because of p53 protein expression in ACD.

Isoflavone, polymorphisms in estrogen receptor genes and breast cancer risk in case-control studies in Japanese, Japanese Brazilians and non-Japanese Brazilians

Epidemiologic studies have shown an inverse association between isoflavones and breast cancer risk. Because isoflavones bind estrogen receptors, we hypothesized that polymorphisms in the estrogen receptor genes might modify the association between isoflavone intake and breast cancer risk. We conducted hospital‐based case‐control studies of patients aged 20–74 years with primary, incident, histologically confirmed invasive breast cancer, and matched controls from among medical checkup examinees in Nagano, Japan, and from cancer‐free patients in São Paulo, Brazil. A total of 846 pairs (388 Japanese, 79 Japanese Brazilians and 379 non‐Japanese Brazilians) completed validated food frequency questionnaires, and provided blood samples. Five single nucleotide polymorphisms in the estrogen receptor alpha (rs9340799, rs1913474, and rs2234693) and beta (rs4986938 and rs1256049) genes were genotyped. We found no consistent association between the five single nucleotide polymorphisms and breast cancer risk among the three populations. In analyses of combinations of isoflavone intake and single nucleotide polymorphisms, an inverse association between intake and risk was limited to women with the GG genotype of the rs4986938 polymorphism for postmenopausal Japanese (odds ratio for highest versus lowest tertile = 0.47; P for trend = 0.01), Japanese Brazilians (odds ratio for highest versus lowest median = 0.31) and non‐Japanese Brazilians (odds ratio for consumers versus non‐consumers = 0.37) (P for interaction = 0.11, 0.08, and 0.21, respectively). We found no remarkable difference for the other four polymorphisms. Our findings suggest that polymorphisms in the estrogen receptor beta gene may modify the association between isoflavone intake and breast cancer risk. (Cancer Sci 2009; 100: 927–933)

Genetic polymorphisms in estrogen metabolism and breast cancer risk in case-control studies in Japanese, Japanese Brazilians and non-Japanese Brazilians

Although many studies have examined associations between single nucleotide polymorphisms (SNPs) in the CYP1A1, CYP1A2 and CYP1B1 genes and breast cancer risk, no study has examined functional SNPs in the CYP3A5 gene and only a small number of studies have been investigated in Japanese populations. To examine the association between six SNPs, CYP1A1*2A, CYP1A1*2C, CYP1A2*1F, CYP1B1 Arg48Gly, CYP1B1 Leu432Val and CYP3A5*3 and breast cancer risk, therefore, we conducted hospital-based case–control studies in Nagano, Japan and São Paulo, Brazil including 873 pairs (403 Japanese (JJ), 81 Japanese Brazilians (JB) and 389 non-Japanese Brazilians (NJB)). Although we found no significant association in the three populations combined, subgroup analyses revealed statistically significant associations of CYP1A2*1F in NJB, and CYP1B1 Leu432Val and CYP3A5*3 in JJ with breast cancer risk. Compared to women with the AA genotype in CYP1A2*1F, the odds ratio (OR) (95% confidence interval (CI)) for NJB with the CC genotype was 0.54 (0.32–0.90); that for JJ with Leu/Val+Val/Val versus Leu/Leu genotype in CYP1B1 Leu432Val was 0.68 (0.48–0.97); and that for JJ with *3/*1+*1/*1 versus *3/*3 genotype in CYP3A5*3 was 1.49 (1.10–2.04). Our findings provide further evidence that genetic polymorphisms related to estrogen metabolism may play a role in the development of breast cancer.

Association of dietary and genetic factors related to one-carbon metabolism with global methylation level of leukocyte DNA.

Global hypomethylation of leukocyte DNA has been associated with an increased risk of cancer. As dietary and genetic factors related to one‐carbon metabolism may influence both the methylation and synthesis of DNA, we investigated associations between these factors and the global methylation level of peripheral blood leukocyte DNA based on a cross‐sectional study of 384 Japanese women. Dietary intake of folate and vitamins B2, B6, and B12 was assessed with a validated semiquantitative food frequency questionnaire. Five polymorphisms in methylenetetrahydrofolate reductase (MTHFR) (rs1801133 and rs1801131), methionine synthase (MTR) (rs1805087), and methionine synthase reductase (MTRR) (rs10380 and rs162049) were genotyped. Global DNA methylation of leukocyte DNA was quantified using Luminometric Methylation Assay. A linear trend of association between methylation and dietary and genetic factors was evaluated by regression coefficients in a multivariable linear regression model. Mean global methylation level (standard deviation) was 70.2% (3.4) and range was from 59.0% to 81.2%. Global methylation level significantly decreased by 0.36% (95% confidence interval, 0.03–0.69) per quartile category for folate level. Subgroup analysis suggested that alcohol drinking modified the association between folate intake and global methylation level (Pinteraction = 0.01). However, no statistically significant association was observed for intake of vitamins B2, B6, and B12, alcohol consumption, or five single nucleotide polymorphisms of MTHFR, MTR, and MTRR. We found that higher folate intake was significantly associated with a lower level of global methylation of leukocyte DNA in a group of healthy Japanese females.

Macroscopic extranodal invasion is a risk factor for tumor recurrence in papillary thyroid cancer

Papillary thyroid cancer patients, upon whom curative operation was performed, were investigated to clarify whether or not macroscopic extranodal invasion is a risk factor for recurrence. They were divided into three groups: group A, patients whose primary tumor showed extrathyroidal invasion (n=31); group B, those whose metastatic lymph nodes showed extranodal invasion (n=6); group C, those who showed both extrathyroidal and extranodal invasion (n=9). Recurrence was significantly higher in groups B and C than in group A (P<0.05). It was concluded that macroscopic extranodal invasion to the adjacent structures was a risk factor for recurrence in patients with papillary thyroid cancer.

The Likely Transformation of Papillary Thyroid Carcinoma into Anaplastic Carcinoma During Postoperative Radioactive Iodine-131 Therapy : Report of a Case

We report herein a case of papillary carcinoma which appeared to transform into anaplastic carcinoma during postoperative radioactive iodine-131 (131I) therapy. A 67-year-old man who was diagnosed as having papillary thyroid carcinoma with bilateral neck lymph node involvement and multiple lung metastases underwent total thyroidectomy prior to131I therapy. Immediately after a second course of131I therapy, the patient complained of right neck pain and swelling, and a biopsy of the swollen neck lymph node was taken. Histologic examination of this biopsy specimen revealed anaplastic carcinoma. With p53 immunohistochemical staining, both the primary tumor and the biopsy specimen were positive. We speculate that first, some DNA damage in tumor cells was induced by the initial131I therapy, but neither DNA repair nor cell apoptosis occurred because the p53 gene was already mutated; then further DNA damage was induced by the second131I therapy, leading to anaplastic transformation.

MRI of the breast : comparison of MRI signals and histological characteristics of the same slices

The development of MRI with high spatial resolution and a special breast coil has contributed to more-accurate diagnosis of breast tumor, such as determination of morphologic characteristics including internal architecture of the breast lesion. To clarify how individual MRI findings reflect the pathological findings, we made slices of resected breast lesions identical to those obtained with axial MRI and compared them respectively according to histological subtype of tumors. In this article, we present MRI findings on the basis of histopathological evidence. In general, fibroadenomas (FA) show a well-defined border on contrast-enhanced fat-suppressed T1-weighted images (CFT1). However, a subtype of fibroadenoma, mastopathic type, with a poorly defined border on CFT1 and carcinoma-like enhancement, is similar to cancer on MRI. Scirrhous carcinomas take either of two patterns on dynamic MRI, i.e., homogeneous enhancement or thick irregular peripheral ring enhancement. The latter type shows central fibrosis zones histologically. Papillotubular carcinoma shows a spotted pattern on dynamic MRI. The low-enhancement areas within the spotted pattern reflect parenchyma between clusters of cancer. Solid-tubular carcinoma shows thin peripheral enhancement on dynamic MRI and linear high signal on CFT1. This finding of CFT1 corresponds to infiltration of lymph cells and fibroblast cells in the adjacent zone. Invasive lobular carcinoma shows nonmass lesions and a slow gradual enhancement pattern. Mucinous carcinomas show high signal intensity on T2-weighted images because of mucin and reveal gradual enhancement. The ill-defined border of mucinous carcinoma on CFT1 is useful to distinguish it from FA.