Nobuhiko Kataoka

Association of Genetic Polymorphisms in the VEGF Gene with Breast Cancer Survival

The vascular endothelial growth factor (VEGF) is an important regulator of angiogenesis and vascular permeability. VEGF overexpression has been associated with advanced stage and poor survival of several cancers. We evaluated the association of functional polymorphisms in the VEGF gene with breast cancer survival in a cohort of 1,193 breast cancer patients who were recruited as part of a population-based case-control study in Shanghai, China from 1996 to 1998 and followed for cancer recurrence and mortality between March 2000 and December 2002. Included in the study were three functional polymorphisms (C-460T, G+405C, and C+936T) in the VEGF gene. Carrying the -460C or +405G allele was associated with decreased overall survival. The age-adjusted hazard ratios (HR) were 1.5 [95% confidence interval (95% CI), 0.9-2.5] for -460CC genotype carriers and 1.6 (95% CI, 1.0-2.5) for +405GG genotype carriers compared with noncarriers. Further analyses showed that the -460T/+450C/+936C haplotype was related to increased survival (HR, 0.57; 95% CI, 0.4-0.9), whereas the -460C/+405G/+936T haplotype was associated with nonsignificantly decreased survival (HR, 2.1; 95% CI, -0.9 to 4.7). The C+936T polymorphism alone was not related to overall or disease-free survival. This study suggests that VEGF polymorphisms may be a significant genetic marker for breast cancer prognosis.

Population-Based Case-Control Study of VEGF Gene Polymorphisms and Breast Cancer Risk among Chinese Women

Vascular endothelial growth factor (VEGF) is a major angiogenic factor involved in a number of pathologic processes, including neovascularization, a crucial step in the development of solid malignancies. Using data and specimens collected in the Shanghai Breast Cancer Study, a population-based case-control study conducted in urban Shanghai, China from 1996 to 1998, we evaluated the association of VEGF gene polymorphisms with breast cancer risk. Included in this study were 1,093 cases and 1,184 age-matched controls who had completed an in-person interview and donated a blood sample to the study. Polymorphisms in the promoter region (T−460C), 5′ untranslated region (C+405G), and 3′untranslated region (C936T) were genotyped using the Taqman allelic discrimination assay. No statistically significant case-control difference was found for the C+405G and T−460C polymorphisms. However, the C936T polymorphism was associated with a reduced risk of breast cancer. Compared with CC genotype carriers, women who had the TT genotype showed a decreased risk [odds ratio (OR), 0.65; 95% confidence interval (95% CI) 0.41-1.02], and the inverse association was restricted to premenopausal women (OR, 0.45; 95% CI, 0.25-0.79). Six common haplotypes were identified. Compared with the most common haplotype (−460T/405C/936C), the −460T/405G/936T haplotype was associated with a reduced risk of breast cancer (OR, 0.67; 95% CI, 0.43-1.04), particularly in premenopausal women (OR, 0.47; 95% CI, 0.27-0.81). Our study suggests that the VEGF C936T polymorphism might be a susceptibility factor for breast cancer among Chinese women. (Cancer Epidemiol Biomarkers Prev 2006;15(6):1148–52)

Genetic polymorphisms of the CYP19A1 gene and breast cancer survival.

The CYP19A1 protein (aromatase) plays a critical role in estrogen biosynthesis and thus may be related to the progression of breast cancer. We examined the association between CYP19A1 genetic polymorphisms and breast cancer survival in a cohort of 1,136 patients who were recruited as part of a population-based case-control study in Shanghai, China from 1996 to 1998 and who has donated a DNA sample to the study. Patients were followed for cancer recurrence and mortality through July 2005. Nineteen haplotype tagging single-nucleotide polymorphisms (SNP) in the CYP19A1 gene were evaluated. For each of the five SNPs located in haplotype block 2, patients homozygous for the minor alleles had a reduced 5-year disease-free survival rate compared with those carrying the major allele. The age-adjusted hazard ratios (HR) and 95% confidence intervals (95% CI) were 1.5 (1.1-2.1), 2.1 (1.2-3.6), 1.5 (1.1-2.0), 1.4 (1.0-2.0), and 1.4 (1.0-2.0) for hCV1664178, rs12900137, rs730154, rs936306, and rs1902586, respectively. Haplotype analyses showed that the haplotype CCCTA (all minor alleles of the five SNPs in block 2) was associated with decreased disease-free survival (HR, 1.9; 95% CI, 1.1-3.3). The nonsynonymous SNP, rs700519 (Arg264Cys), located in haplotype block 4, was also associated with breast cancer survival. The age-adjusted HR for the Cys/Cys (T/T) genotype was 2.2 (95% CI, 1.2-4.1) for overall survival and 2.1 (95% CI, 1.1-3.9) for disease-free survival, compared with those carrying the Arg (C) allele. These results suggest that polymorphisms in the CYP19A1 gene may have effects on breast cancer prognosis. (Cancer Epidemiol Biomarkers Prev 2006;15(11):2115–22)

Immunohistochemical Expressions of Ki-67, Cyclin D1, β-Catenin, Cyclooxygenase-2, and Epidermal Growth Factor Receptor in Human Colorectal Adenoma: A Validation Study of Tissue Microarrays

Background: Tissue microarray (TMA) holds promise as a high-throughput method for the analysis of biomarkers in tissue specimens. The validity and reliability of this method, however, may vary for different biomarkers in different tissue specimens. Objectives: In this study, we evaluated the validity and reliability of using TMA to assess biomarkers in colorectal adenomas. Methods: Sixty-three consecutive patients with colorectal adenomas were recruited in this study. Two TMA blocks were constructed using four punches from each adenoma (one periphery, one deep, and two middle zones). The immunostaining of five markers (Ki-67, cyclin D1, β-catenin, cyclooxygenase-2, and epidermal growth factor receptor) was analyzed, and the concordance between data obtained from TMAs and standard whole-tissue sections was evaluated by Spearmans correlation and kappa analysis. Results: Colorectal adenoma exhibited zonal, heterogeneous expression patterns for all five markers. The concordance rates for the semiquantitative evaluation of markers between data from TMAs and whole sections ranged from 87% to 93% with corresponding kappa statistics of 77% to 90%. In addition, both quantitative and semiquantitative methods were used to score TMA sections, and good correlations between these two methods were shown for all five markers with intraclass correlation coefficients ranging from 0.5 to 0.8. Conclusion: Our study indicates that TMA can be used to reliably assess the expression levels of Ki-67, cyclin D1, β-catenin, cyclooxygenase-2, and epidermal growth factor receptor in colorectal adenoma tissues. (Cancer Epidemiol Biomarkers Prev 2006;15(9):1719–26)

Polymorphisms in the CYP19A1 (Aromatase) Gene and Endometrial Cancer Risk in Chinese Women

Aromatase, encoded by the CYP19A1 gene, is a key enzyme in estradiol biosynthesis, which catalyzes the conversion of androstenedione and testosterone to estrone and estradiol, respectively. Given the critical role of estrogen in the development of endometrial cancer risk, we evaluated genetic polymorphisms of the CYP19A1 gene, including rs1065779, rs700519, rs28566535, rs752760, and rs1870050, in association with endometrial cancer in a population-based case-control study conducted in Shanghai, China. Genotypes of 1,040 incident endometrial cancer cases and 1,031 frequency-matched controls were included in the study. We applied a logistic regression model to derive adjusted odds ratios (OR) and their 95% confidence intervals (95% CI). Six common haplotypes with a frequency ≥5% were estimated; the highest frequency haplotype was GCACA (27.8% in cases and 26.2% in controls). We observed an inverse association between CYP19A1 haplotype TCATC and endometrial cancer in our population (OR, 0.76; 95% CI, 0.62-0.92). An inverse association was found between endometrial cancer and single nucleotide polymorphism rs1870050 in the promoter region with ORs of 0.81 (95% CI, 0.68-0.97) and 0.58 (95% CI, 0.42-0.80) for the AC and CC genotypes, respectively. We observed a multiplicative interaction between single nucleotide polymorphism rs700519 and body mass index among postmenopausal women (P = 0.01), with stronger associations between rs700519 genotypes and endometrial cancer risk among heavier (body mass index, ≥25) postmenopausal women. In summary, our data show that polymorphisms in the CYP19A1 gene may contribute to endometrial carcinogenesis. (Cancer Epidemiol Biomarkers Prev 2007;16(5):943–9)

Haplotype Analyses of CYP19A1 Gene Variants and Breast Cancer Risk: Results from the Shanghai Breast Cancer Study

Estrogens play a central role in the etiology of breast cancer. The CYP19A1 gene encodes aromatase, a key enzyme in the biosynthesis of estrogens. Several single nucleotide polymorphisms (SNP) or haplotypes in the CYP19A1 gene have been evaluated in relation to breast cancer risk. However, the results have been inconsistent. In this study, we constructed haplotypes of the CYP19A1 gene using 19 haplotype-tagging SNPs in Chinese women and evaluated the variation of this gene in relation to breast cancer risk in a population-based case-control study involving 1,140 cases and 1,244 community controls of the Shanghai Breast Cancer Study. Five common haplotypes in block 1, three common haplotypes in block 2, five common haplotypes in block 3, and four common haplotypes in block 4 were identified. No apparent association was observed between common haplotypes and breast cancer risk in analyses including all subjects nor in analyses stratified by menopausal status. Similarly, no statistically significant differences were found between cases and controls in the genotype distributions of the 19 individual SNPs and the (TTTA)n repeat polymorphism evaluated in the study. No overall association of breast cancer risk with common CYP19A1 gene variants among Chinese women was observed in this large-scale, comprehensive study. Further studies are needed to explore CYP19A1 gene-environment interactions in relation to breast cancer risk. (Cancer Epidemiol Biomarkers Prev 2008;17(1):27–32)

CYP19A1 genetic polymorphisms may be associated with obesity-related phenotypes in Chinese women.

Object:To examine the relationship between genetic polymorphisms of the CYP19A1 gene and obesity-related phenotypes, body mass index (BMI) and waist-to-hip ratio (WHR).Subjects:In total, 1241 Chinese women, who were recruited as community controls for a population-based case–control study of breast cancer.Methods:Nineteen haplotype tagging single nucleotide polymorphisms (htSNPs) in four haplotype blocks were genotyped.Results:Significant associations were observed for WHR at three SNPs that are located in haplotype block 1, including rs2445765, rs1004984 and rs1902584 (P=0.05, 0.04 and 0.01, respectively). Women, particularly premenopausal women, who carried the minor allele at any of these SNPs, had higher WHR than those without it. Of these three SNPs, the strongest association was observed at rs1902584, which is the closest to Promoter I.4, the major promoter for adipose tissue. Haplotype analyses indicated an association between the haplotype TCCAT in block 1 and WHR with a P-value of 0.02.Conclusion:These results suggested that CYP19A1 genetic polymorphisms may be associated with the risk of obesity among Chinese women, especially among premenopausal women.The CYP19A1 protein (aromatase) plays a critical role in estrogen biosynthesis and thus affects body fat distribution and regulation.

Cytochrome P450 1B1 and Catechol-O-Methyltransferase Genetic Polymorphisms and Endometrial Cancer Risk in Chinese Women

Metabolic conversion of estrogen to hydroxyl estrogens has been postulated to be involved in the carcinogenesis of the endometrium. Highly expressed in endometrial tissue, cytochrome P 450 1B1 (CYP1B1) catalyzes the hydroxylation of 17β-estradiol (E2) to catechol estrogens 4-hydroxyestradiol (4-OH-