Shimojima K.,Japan Science and Technology Agency |
Shimojima K.,Tokyo Womens Medical University |
Okumura A.,Juntendo University |
Okumura A.,Aichi Medical University |
And 6 more authors.
Brain and Development | Year: 2015
Objective: Hypomyelinating leukoencephalopathy is a heterogeneous disorder caused by mutations in several-different genes. Clinical entity of hypomyelination with atrophy of the basal ganglia and cerebellum (H-ABC) is one of them. Method: A male patient showed pendular nystagmus, infantile hypotonia, an abnormal pattern of brain auditory evoked potential, and hypomyelination on brain magnetic resonance imaging, which suggested Pelizaeus-Merzbacher disease (PMD) as the candidate diagnosis; however, no abnormality was found in the proteolipid protein 1 gene (PLP1) that is responsible for PMD. Whole exome sequencing was performed to identify pathogenic mutations in this patient. Results: A de novo mutation was identified in the tubulin 4a gene (TUBB4A), which has been recently reported to be associated with H-ABC. Although the patient did not show any neurological features suggesting H-ABC, such as extrapyramidal or cerebellar signs, radiological findings demonstrated the finding of cerebellar atrophy at the age of 36. months. Conclusion: This study suggested us the difficulty of clinical diagnosis for H-ABC early in the life of the patient, which makes predication of prognosis and genetic counseling difficult. © 2014 The Japanese Society of Child Neurology.
Shiraishi K.,National Cancer Center Research Institute |
Kunitoh H.,National Cancer Center Hospital |
Daigo Y.,Shiga University of Medical Science |
Daigo Y.,University of Tokyo |
And 15 more authors.
Nature Genetics | Year: 2012
Lung adenocarcinoma is the most common histological type of lung cancer, and its incidence is increasing worldwide. To identify genetic factors influencing risk of lung adenocarcinoma, we conducted a genome-wide association study and two validation studies in the Japanese population comprising a total of 6,029 individuals with lung adenocarcinoma (cases) and 13,535 controls. We confirmed two previously reported risk loci, 5p15.33 (rs2853677, P combined = 2.8 × 10 -40, odds ratio (OR) = 1.41) and 3q28 (rs10937405, P combined = 6.9 × 10 -17, OR = 1.25), and identified two new susceptibility loci, 17q24.3 (rs7216064, P combined = 7.4 × 10 -11, OR = 1.20) and 6p21.3 (rs3817963, P combined = 2.7 × 10 -10, OR = 1.18). These data provide further evidence supporting a role for genetic susceptibility in the development of lung adenocarcinoma. © 2012 Nature America, Inc. All rights reserved.
Low S.-K.,Tokyo Medical University |
Kuchiba A.,National Cancer Center Research Institute |
Zembutsu H.,Tokyo Medical University |
Saito A.,National Cancer Center Research Institute |
And 16 more authors.
PLoS ONE | Year: 2010
Pancreatic cancer shows very poor prognosis and is the fifth leading cause of cancer death in Japan. Previous studies indicated some genetic factors contributing to the development and progression of pancreatic cancer; however, there are limited reports for common genetic variants to be associated with this disease, especially in the Asian population. We have conducted a genome-wide association study (GWAS) using 991 invasive pancreatic ductal adenocarcinoma cases and 5,209 controls, and identified three loci showing significant association (P-value <5×10-7) with susceptibility to pancreatic cancer. The SNPs that showed significant association carried estimated odds ratios of 1.29, 1.32, and 3.73 with 95% confidence intervals of 1.17-1.43, 1.19-1.47, and 2.24-6.21; P-value of 3.30×10-7, 3.30×10-7, and 4.41×10-7; located on chromosomes 6p25.3, 12p11.21 and 7q36.2, respectively. These associated SNPs are located within linkage disequilibrium blocks containing genes that have been implicated some roles in the oncogenesis of pancreatic cancer. © 2010 Low et al.
Khor S.-S.,University of Tokyo |
Yang W.,StaGen Co. |
Kawashima M.,University of Washington |
Kamitsuji S.,Research Center for Hepatitis and Immunology |
And 8 more authors.
Pharmacogenomics Journal | Year: 2015
Statistical imputation of classical human leukocyte antigen (HLA) alleles is becoming an indispensable tool for fine-mappings of disease association signals from case-control genome-wide association studies. However, most currently available HLA imputation tools are based on European reference populations and are not suitable for direct application to non-European populations. Among the HLA imputation tools, The HIBAG R package is a flexible HLA imputation tool that is equipped with a wide range of population-based classifiers; moreover, HIBAG R enables individual researchers to build custom classifiers. Here, two data sets, each comprising data from healthy Japanese individuals of difference sample sizes, were used to build custom classifiers. HLA imputation accuracy in five HLA classes (HLA-A, HLA-B, HLA-DRB1, HLA-DQB1 and HLA-DPB1) increased from the 82.5-98.8% obtained with the original HIBAG references to 95.2-99.5% with our custom classifiers. A call threshold (CT) of 0.4 is recommended for our Japanese classifiers; in contrast, HIBAG references recommend a CT of 0.5. Finally, our classifiers could be used to identify the risk haplotypes for Japanese narcolepsy with cataplexy, HLA-DRB1∗15:01 and HLA-DQB1∗06:02, with 100% and 99.7% accuracy, respectively; therefore, these classifiers can be used to supplement the current lack of HLA genotyping data in widely available genome-wide association study data sets. © 2015 Macmillan Publishers Limited All rights reserved.
Ono H.,National Cancer Center Research Institute |
Ono H.,Tokyo Medical and Dental University |
Hiraoka N.,National Cancer Center Research Institute |
Lee Y.-S.,National Cancer Center |
And 12 more authors.
Genes Chromosomes and Cancer | Year: 2012
Gallbladder cancer (GBC) is relatively rare but has a high mortality rate. One candidate molecule which might be involved in GBC development is prostate stem cell antigen (PSCA), a glycosylphosphatidylinositol-anchored cell surface antigen with a tissue-specific pattern of expression in the epithelium of several organs, such as the prostate, stomach, bladder, and gallbladder. It is up-regulated in a number of cancers including prostate, urinary bladder, and pancreatic cancers, while it is down-regulated in esophageal and gastric cancers, suggesting that PSCA has an oncogenic activity in the former but a tumor suppressor activity in the latter. However, the precise function of PSCA and the regulatory mechanism for its expression in normal and cancer cells are yet to be determined. In this study, immunohistochemical analyses with a specific antibody revealed that PSCA is down-regulated in non-neoplastic gallbladder lesions such as cholesterolosis, cholecystolithiasis, and cholecystitis (9/17; 53%), and also in adenocarcinoma (40/44; 91%), a common neoplasm in gallbladder. Analyses of the DNA methylation status in the GBC cell lines by bisulfite-Pyrosequencing and a reporter assay for the PSCA promoter activity suggested that the down-regulation is explained, at least partly, by DNA methylation. Moreover, colony formation assay revealed that PSCA has cell-proliferation inhibition activity in the GBC cell lines, which was also observed in vivo. These lines of in vivo and in vitro evidence suggest that PSCA is acting as a tumor suppressor in GBC development. © 2011 Wiley Periodicals, Inc.