Prevalent hyper-methylation of the CDH13 gene promoter in malignant B cell lymphomas

Ogama, Yoichiro; Ouchida, Mamoru; Yoshino, Tadashi; Ito, Sachio; Takimoto, Hidetaka; Shiote, Yasuhiro; Ishimaru, Fumihiko; Harada, Mine; Tanimoto, Mitsune; Shimizu, Kenji

doi:10.3892/ijo.25.3.685

Cited by 20 publications

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“…Inactivation of CDH13 expression through deletion or hypermethylation has been linked to lung cancer [48] and ovarian cancer [49]. Additionally, aberrant promoter methylation has been associated with tumor progression in a subset of diffuse large B cell lymphomas [50]. In our study, there was one intronic SNP (rs17758876) in CDH13 with the CC genotype associated with greater sensitivity to 10 μmol/l cisplatin.…”

Section: Discussionmentioning

confidence: 60%

“…Although association analysis has power to pick up alleles of modest effect, linkage analysis is useful because it is more robust to allelic heterogeneity; (iii) the triangle approach focused on genetic variants common and unique to CEPH and Yoruban populations. Yoruban cell lines from large pedigrees are not available; therefore, the examination of population differences in cytotoxicity using linkage analysis was not possible for our pedigree study; (iv) the current linkage-directed approach limited the number of nonredundant SNPs to 191 973 in the 11 LOD > 1.5 regions, in contrast to the earlier approach evaluating over 387 000 SNPs; (v) the SNPs significantly associated with cytotoxicity in this study were further interrogated by correlating them to apoptosis; and (vi) only the IC 50 phenotype was evaluated in the earlier study and we did not find any linkage peaks with LOD > 1.5 for the IC 50 phenotype; hence association was not performed on this phenotype in the current analysis. These differences may explain why none of the SNPs in this study overlap with the SNPs found to associate with cytotoxicity in the 'expression focused-triangle approach'.…”

Section: Discussionmentioning

confidence: 99%

“…In another study, upregulation or downregulation of oncogenes and tumor suppressor genes depended on the concentration of drug used [30]. The IC 50 phenotype is thought to be representative of the cytotoxic curve for each cell line; however, no linkage peaks greater than LOD of 1.5 were found for this phenotype. One possibility is that the IC 50 phenotype may have more genes contributing to a smaller extent, thereby producing more signals but with LOD scores below the threshold used for this study.…”

Section: Discussionmentioning

confidence: 99%

“…We developed a cell-based model incorporating expression to identify genetic variants important in cisplatin-induced cytotoxicity referred to as the 'triangle approach' [39]. This approach differs from the current approach in the following manner: (i) The earlier study focuses on gene expression in only 90 HapMap cell lines by implementing a three-way model that first correlates SNP genotypes to cisplatin IC 50 . Next, those significant SNPs are evaluated for association with gene expression, and a final linear correlation between gene expression and drug cytotoxicity is performed.…”

Section: Discussionmentioning

confidence: 99%

“…IC 50 was determined for 318 of the 343 cell lines treated with cisplatin because some cell lines did not have percentage survival values above or below 50% owing to extreme resistance or sensitivity. The average IC 50 value for 48 h cisplatin was 7.5 ± 6.3 μmol/l with a range 1.52 −58.9 μmol/l.…”

Section: Cisplatin-induced Cytotoxicitymentioning

confidence: 99%

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Susceptibility loci involved in cisplatin-induced cytotoxicity and apoptosis

Shukla

Duan²,

Badner³

et al. 2008

Pharmacogenetics and Genomics

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Objectives-Cisplatin is a widely used chemotherapeutic agent; however, nephrotoxicity and neuropathy are obstacles for drug efficacy. Little is known about the genes or genetic variants contributing to the risk of developing these toxicities or chemotherapeutic response. Thus, we have applied a cell-based model to identify and characterize previously unknown genes that may be involved in cellular susceptibility to cisplatin.Methods-Lymphoblastoid cell lines from 27 large Centre d'Etude du Polymorphisme Humain pedigrees were used to elucidate the genetic contribution to cisplatin-induced cytotoxicity. Phenotype was defined as cell growth inhibition following exposure of cell lines to increasing concentrations of cisplatin for 48 h.Results-Significant heritability, ranging from 0.32 to 0.43 (P < 10 −7 ), was found for the cytotoxic effects of each concentration (1, 2.5, 5, 10, and 20 μmol/l) and IC50, the concentration required for 50% cell growth inhibition. Linkage analysis revealed 11 genomic regions on six chromosomes with logarithm of odds (LOD) scores above 1.5 for cytotoxic phenotypes. The highest LOD score was found on chromosome 4q21.3−q35.2 (LOD = 2.65, P = 2.4 × 10 −4 ) for 5 μmol/l cisplatin. Quantitative transmission disequilibrium tests were performed using 191 973 nonredundant single nucleotide polymorphisms (SNPs) located in the 1 LOD confidence interval of these 11 regions. Twenty SNPs, with 10 SNPs located in five genes, were significantly associated with cisplatin-induced cytotoxicity (P ≤ 1 × 10 −4 ). Four of these 20 SNPs were found to explain over 10% of the variation in cisplatininduced apoptosis.Conclusions-Our results suggest that genetic factors involved in cytotoxicity also contribute to cisplatin-induced apoptosis. These cell lines provide a paradigm to identify previously unknown pharmacogenetic variants associated with drug cytotoxicity.

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Section: Discussionmentioning

confidence: 60%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Cisplatin-induced Cytotoxicitymentioning

confidence: 99%

See 3 more Smart Citations

Susceptibility loci involved in cisplatin-induced cytotoxicity and apoptosis

Shukla

Duan²,

Badner³

et al. 2008

Pharmacogenetics and Genomics

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Cytologic scoring of endometrioid adenocarcinoma of the endometrium

Nishimura

Watanabe

Jobo

et al. 2004

Cancer

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We describe two sisters with a mild‐onset variant of Canavan's disease who presented at age 50 and 19 months with developmental delay but without macrocephaly, hypotonia, spasticity, or seizures. Remarkably, both patients had age‐appropriate head control, gross motor development, and muscle tone. There were very mild deficits in fine motor skills, coordination, and gait. Both sisters had a history of strabismus, but otherwise vision was normal. The older child showed evidence of mild cognitive and social impairment, whereas language and behavior were normal for age in the infant. Both patients were found to be compound heterozygotes for C914A (A305E) and G212A (R71H) mutations in ASPA. Like all other known ASPA mutations, this previously unknown G212A mutation appears to have low absolute enzyme activity. Nevertheless, it is associated in these patients with an extremely benign phenotype that is highly atypical of Canavan's disease. Biochemical and clinical data were evaluated using a generalized linear mixed model generated from 25 other subjects with Canavan's disease. There were statistically significant differences in brain chemistry and clinical evaluations, supporting a distinct variant of Canavan's disease. Future studies of ASPA enzyme structure and gene regulation in these subjects could lead to a better understanding of Canavan's pathophysiology and improvements in ASPA gene therapy Ann Neurol 2006;59:428–431

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Cadherin 13 in cancer

Андреева

Kutuzov

2010

Genes Chromosomes & Cancer

126

113

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We review the evidence suggesting the involvement of Cadherin 13 (CDH13, T-cadherin, H-cadherin) in various cancers. CDH13 is an atypical member of the cadherin family, devoid of a transmembrane domain and anchored to the exterior surface of the plasma membrane via a glycosylphosphatidylinositol anchor. CDH13 is thought to affect cellular behavior largely through its signaling properties. It is often down-regulated in cancerous cells. CDH13 down-regulation has been associated with poorer prognosis in various carcinomas, such as lung, ovarian, cervical and prostate cancer. CDH13 re-expression in most cancer cell lines inhibits cell proliferation and invasiveness, increases susceptibility to apoptosis, and reduces tumor growth in in vivo models. These properties suggest that CDH13 may represent a possible target for therapy in some cancers. At the same time, CDH13 is up-regulated in blood vessels growing through tumors and promotes tumor neovascularization. In contrast to most cancer cell lines, CDH13 overexpression in endothelial cells promotes their proliferation and migration, and has a pro-survival effect. We also discuss molecular mechanisms that may regulate CDH13 expression and underlie its roles in cancer.

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Prevalent hyper-methylation of the CDH13 gene promoter in malignant B cell lymphomas

Cited by 20 publications

References 0 publications

Susceptibility loci involved in cisplatin-induced cytotoxicity and apoptosis

Susceptibility loci involved in cisplatin-induced cytotoxicity and apoptosis

Cytologic scoring of endometrioid adenocarcinoma of the endometrium

Cadherin 13 in cancer

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