Kimio Yoshimura

Genetic variation in PSCA is associated with susceptibility to diffuse-type gastric cancer

Gastric cancer is classified into intestinal and diffuse types, the latter including a highly malignant form, linitis plastica. A two-stage genome-wide association study (stage 1: 85,576 SNPs on 188 cases and 752 references; stage 2: 2,753 SNPs on 749 cases and 750 controls) in Japan identified a significant association between an intronic SNP (rs2976392) in PSCA (prostate stem cell antigen) and diffuse-type gastric cancer (allele-specific odds ratio (OR) = 1.62, 95% CI = 1.38–1.89, P = 1.11 × 10−9). The association was far less significant in intestinal-type gastric cancer. We found that PSCA is expressed in differentiating gastric epithelial cells, has a cell-proliferation inhibition activity in vitro and is frequently silenced in gastric cancer. Substitution of the C allele with the risk allele T at a SNP in the first exon (rs2294008, which has r2 = 0.995, D′ = 0.999 with rs2976392) reduces transcriptional activity of an upstream fragment of the gene. The same risk allele was also significantly associated with diffuse-type gastric cancer in 457 cases and 390 controls in Korea (allele-specific OR = 1.90, 95% CI = 1.56–2.33, P = 8.01 × 10−11). The polymorphism of the PSCA gene, which is possibly involved in regulating gastric epithelial-cell proliferation, influences susceptibility to diffuse-type gastric cancer.

Is the genetic structure of human personality universal? A cross-cultural twin study from North America, Europe, and Asia.

This study examined whether universality of the 5-factor model (FFM) of personality operationalized by the Revised NEO Personality Inventory is due to genetic influences that are invariant across diverse nations. Factor analyses were conducted on matrices of phenotypic, genetic, and environmental correlations estimated in a sample of 1,209 monozygotic and 701 dizygotic twin pairs from Canada, Germany, and Japan. Five genetic and environmental factors were extracted for each sample. High congruence coefficients were observed when phenotypic, genetic, and environmental factors were compared in each sample as well as when each factor was compared across samples. These results suggest that the FFM has a solid biological basis and may represent a common heritage of the human species.

Clinicopathologic study of primary malignant gastrointestinal stromal tumor of the stomach, with special reference to prognostic factors: analysis of results in 140 surgically resected patients.

Abstract.Background: Malignant gastrointestinal stromal tumors (GISTs), previously termed leiomyosarcomas or epithelioid leiomyosarcomas, are known to show wide variability in their malignancy. We evaluated the clinicopathological features of a large number of primary malignant gastric GISTs to clarify which features were independent prognostic factors.Methods: Clinicopathologic features (age, sex, tumor location, mode of growth and size, surgical method, ulceration, cell type, nuclear atypia, cellularity, mitotic index, growth pattern, necrosis, hemorrhage, direct tumor invasion, peripheral lymphoid cuffing, expression of α-smooth muscle actin [α-SMA], desmin, caldesmon, vimentin, CD34, c-kit protein and S-100 protein, and MIB-1 index) were evaluated by multivariate analysis in 140 patients with resected primary malignant gastric GISTs to identify independent prognostic factors.Results: Univariate analysis showed that each of the following factors had a significant deleterious influence on prognosis: male sex, tumor size 10u2009cm or more, presence of ulceration, an epithelioid cell component, severe nuclear atypia, high cellularity, a mitotic index of more than 10, an exogastric or invasive growth pattern, necrosis, hemorrhage, direct tumor invasion of surrounding tissue, negative caldesmon immunoreactivity, positive S-100 protein immunoreactivity, and a MIB-1 antigen labeling index of more than 10%. Multivariate analysis showed that male sex, tumor size 10u2009cm or more, presence of an epithelioid cell component, and a mitotic index of more than 10 were statistically significant indicators of a poor prognosis (P = 0.013, 0.001, 0.014, and <0.001, respectively). Multivariate analysis using the MIB-1 index instead of a mitotic count showed that male sex, tumor size 10u2009cm or more, presence of necrosis, and a MIB-1 antigen labeling index of more than 10% were independent predictors of a poor prognosis (P = 0.009, 0.001, 0.043, and <0.001, respectively).Conclusion: Male sex, tumor size 10u2009cm or more, and cell proliferation as estimated by the mitotic index or MIB-1 index are independent indicators of a poor prognosis in primary malignant gastric GIST.

Clinicopathologic significance of laminin‐5 γ2 chain expression in squamous cell carcinoma of the tongue

The laminin‐5 γ2 chain plays an important role in cell migration during tumor invasion and tissue remodeling.

Association between dopamine D4 receptor (D4DR) Exon III polymorphism and novelty seeking in Japanese subjects

This study was designed to assess the association between novelty seeking and D4DR gene polymorphism in the Japanese population. The 48 bp repeat polymorphism in the third exon of the dopamine D4 receptor gene of 153 normal female students was correlated with personality feature results from the Japanese version of Cloningers Temperament and Character Inventory. The Novelty Seeking subscale of Exploratory Excitability had a significant association with long alleles of the polymorphic exon III repeat sequence of D4DR. Our results suggest that there is an association between long alleles of the polymorphic exon III repeat sequence of D4DR and the personality traits of the Novelty Seeking subscale of Exploratory Excitability, regardless of racial differences in the frequencies of D4DR exon III repeat polymorphism.

Predictive histopathologic factors for lymph node metastasis in patients with nonpedunculated submucosal invasive colorectal carcinoma.

PURPOSERisk factors for lymph node metastasis in patients with nonpedunculated submucosal invasive colorectal carcinoma remain to be characterized. This study examines the relationship between lymph node metastasis and clinicopathologic factors in nonpedunculated submucosal invasive colorectal carcinoma.METHODSThe study cohort comprised 155 patients who had undergone surgical treatment for nonpedunculated submucosal invasive colorectal carcinoma. The clinicopathologic factors investigated included gender, age, tumor location, macroscopic type, tumor size, histologic type and grade, intramucosal growth pattern, lymphatic invasion, venous invasion, degree of focal dedifferentiation at the submucosal invasive front, status of the remaining muscularis mucosa, and the depth and width of submucosal invasion.RESULTSLymph node metastases were found in 19 patients (12.3 percent). Univariate analysis showed that lymphatic invasion, focal dedifferentiation at the submucosal invasive front, status of the remaining muscularis mucosa, and depth of submucosal invasion all had a significant influence on lymph node metastasis. Multivariate analysis showed lymphatic invasion (P = 0.014) and high-grade focal dedifferentiation at the submucosal invasive front (P = 0.049) to be independent factors predicting lymph node metastasis. No lymph node metastasis was found in tumors with a depth of submucosal invasion of <1.3 mm.CONCLUSIONSLymphatic invasion and high-grade focal dedifferentiation at the submucosal invasive front are important predictors of lymph node metastasis in patients with nonpedunculated submucosal invasive colorectal carcinoma. Depth of submucosal invasion can be used as an identifying marker for patients who do not require subsequent surgery after endoscopic resection.

Folate, Vitamin B6, Vitamin B12, and Vitamin B2 Intake, Genetic Polymorphisms of Related Enzymes, and Risk of Colorectal Cancer in a Hospital-Based Case-Control Study in Japan

Abstract: We conducted a case-control study to investigate the association of nutrient intake involved in the one-carbon pathway of folate for DNA methylation and DNA synthesis and the related enzyme genetic polymorphisms with colorectal cancer. Cases were 107 patients newly diagnosed with colorectal cancer. Controls were 224 subjects matched with cases by sex, age, and residential area. Nutrient intake was assessed by a self-administered, semiquantitative food-frequency questionnaire. Four genetic polymorphisms—MTHFR C677T and A1298C, MTRR A66G, and ALDH2 Glu487Lys—were determined using blood samples. Odds ratios were calculated using conditional logistic regression analysis adjusted for smoking, alcohol consumption, body mass index, and dietary fiber intake. Although folate intake was inversely associated with colorectal cancer, this association was attenuated after further controlling for dietary fiber intake. Neither vitamin B6, vitamin B12, nor vitamin B2, nor any genetic polymorphism was significantly associated with colorectal cancer. MTRR polymorphism interacted with the association of folate (P for interaction = 0.04) or vitamin (P for interaction = 0.02) with colorectal cancer, although the other polymorphisms did not interact with any nutrient intake. In conclusion, the study did not support the existing hypothesis of gene-nutrient interaction in colorectal carcinogenesis.

E‐cadherin gene variants in gastric cancer families whose probands are diagnosed with diffuse gastric cancer

To identify germline E‐cadherin mutations responsible for the predisposition to diffuse gastric cancer (DGC) among the Japanese, we screened 17 patients with familial aggregation of gastric cancer by sequencing analysis. All the patients were diagnosed with DGC and had at least 1 sibling with gastric cancer. Two novel E‐cadherin gene variants were detected. One was detected in 1 patient only and associated with an amino acid substitution (Val/Met) at codon 832 in the region essential for binding to β‐catenin. The M832 variant was detected not only in the proband but also in 2 other gastric cancer patients in the family. Immunohistochemical analysis of gastric cancer tissue from the proband revealed that E‐cadherin expression was markedly reduced and β‐catenin expression was also reduced in cancer cells. However, no significant difference in the activity of β‐catenin binding was detected between the M832 variant and V832 wild‐type E‐cadherin in immunofluorescence and immunoprecipitation/Western blot analyses. The other was detected in 5 patients and was located in the splice donor site (IVS1+6T/C); however, RT‐PCR analysis indicated that the IVS+6C variant did not cause an aberrant splicing. Thus, the M832 variant could be a germline mutation causative of familial aggregation of DGC, although further functional studies are needed to understand the pathogenic significance of this variant.

The genetic structure of Cloninger's seven-factor model of temperament and character in a Japanese sample

Theoretical assumptions regarding the genetic and environmental structure of personality proposed in Cloningers seven-factor model of temperament and character were verified in a Japanese sample by using the twin method. The Temperament and Character Inventory (TCI) was administered to 296 twin pairs ranging in age from 14 to 28 years old. Among four temperament dimensions (novelty seeking [NS], harm avoidance [HA], reward dependence [RD], and persistence [PS]), HA and PS showed significant additive genetic contributions and no shared environmental effect, supporting the original theoretical assumption. NS and RD could be explained by either genetic or shared environmental factors with nonshared environment. All three character dimensions (cooperativeness [CO], self-directedness [SD], and self-transcendence [ST]) could be explained exclusively by additive contributions and no shared environmental effect. Multivariate genetic analysis indicated that there were no significant associations between NS, HA, and RD, as the theory predicts, and the genetic components of PS, SD, and CO were derived from those of the temperament dimensions. The fourth genetic component, which had a substantial load specifically on ST and overlapped with PS, was identified. Although most of the nonshared environmental effects were trait-specific, the phenotypic correlation between NS and HA could be explained by nonshared environmental overlap.

Allele frequencies of single nucleotide polymorphisms (SNPs) in 40 candidate genes for gene-environment studies on cancer: Data from population-based Japanese random samples

AbstractKnowledge of genetic polymorphisms in gene-environment studies may contribute to more accurate identification of avoidable risks and to developing tailor-made preventative measures. The aim of this study was to describe the allele frequencies of single nucleotide polymorphisms (SNPs) of select genes, which may be included in future gene-environment studies on cancer in Japan. SNP typing was performed on middle-aged Japanese men randomly selected from the general population in five areas of Japan. We genotyped and calculated allele frequencies of 153 SNPs located on 40 genes: CYP1A1, CYP1B1, CYP2C9, CYP2C19, CYP2E1, CYP17A1, CYP19A1, AHR, ESR1, ESR2, ERRRG, PGR, EPHX1, EPHX2, HSD17B2, HSD17B3, GSTM2, GSTM3, GSTT2, GSTP1, NAT1, NAT2, COMT, ADH1A, ADH1B, ADH1C, ALDH2, NOS2A, NOS3, IL1A, IL1B, OGG1, NUDT1 [MTH1], DRD2, DRD3, DRD4, SLC6A4, NR3C1 [GCCR], MTHFR, and NQO1. In the present study, the Japanese allele frequencies were verified by using nationwide population samples.