Dataset Information

Deletion or epigenetic silencing of AJAP1 on 1p36 in glioblastoma.

ABSTRACT: Glioblastoma is universally fatal because of its propensity for rapid recurrence due to highly migratory tumor cells. Unraveling the genomic complexity that underlies this migratory characteristic could provide therapeutic targets that would greatly complement current surgical therapy. Using multiple high-resolution genomic screening methods, we identified a single locus, adherens junctional associated protein 1 (AJAP1) on chromosome 1p36 that is lost or epigenetically silenced in many glioblastomas. We found AJAP1 expression absent or reduced in 86% and 100% of primary glioblastoma tumors and cell lines, respectively, and the loss of expression correlates with AJAP1 methylation. Restoration of AJAP1 gene expression by transfection or demethylation agents results in decreased tumor cell migration in glioblastoma cell lines. This work shows the significant loss of expression of AJAP1 in glioblastoma and provides evidence of its role in the highly migratory characteristic of these tumors.

SUBMITTER: Lin N

PROVIDER: S-EPMC3288240 | biostudies-literature | 2012 Feb

REPOSITORIES: biostudies-literature

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Deletion or epigenetic silencing of AJAP1 on 1p36 in glioblastoma.

Lin Ningjing N Di Chunhui C Bortoff Kathy K Fu Jinrong J Truszkowski Peter P Killela Patrick P Duncan Chris C McLendon Roger R Bigner Darell D Gregory Simon S Adamson David Cory DC

Molecular cancer research : MCR 20120112 2

Glioblastoma is universally fatal because of its propensity for rapid recurrence due to highly migratory tumor cells. Unraveling the genomic complexity that underlies this migratory characteristic could provide therapeutic targets that would greatly complement current surgical therapy. Using multiple high-resolution genomic screening methods, we identified a single locus, adherens junctional associated protein 1 (AJAP1) on chromosome 1p36 that is lost or epigenetically silenced in many glioblast ...[more]

PMID: 22241217

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Project description:IntroductionBRCA1 or BRCA2 germline mutations increase the risk of developing breast cancer. Tumour cells from germline mutation carriers have frequently lost the wild-type allele. This is predicted to result in genomic instability where cell survival depends upon dysfunctional checkpoint mechanisms. Tumorigenic potential could then be acquired through further genomic alterations. Surprisingly, somatic BRCA mutations are not found in sporadic breast tumours. BRCA1 methylation has been shown to occur in sporadic breast tumours and to be associated with reduced gene expression. We examined the frequency of BRCA1 methylation in 143 primary sporadic breast tumours along with BRCA1 copy number alterations and tumour phenotype.MethodsPrimary sporadic breast tumours were analysed for BRCA1alpha promoter methylation by methylation specific PCR and for allelic imbalance (AI) at BRCA1 and BRCA2 loci by microsatellite analysis and TP53 (also known as p53) mutations by constant denaturing gel electrophoresis. The BRCA1 methylated tumours were analysed for BRCA1 copy alterations by fluorescence in situ hybridisation and BRCA1 expression by immunostaining.ResultsBRCA1 methylation was found in 13/143 (9.1%) sporadic breast tumours. The BRCA1 methylated tumours were significantly associated with estrogen receptor (ER) negativity (P = 0.0475) and displayed a trend for BRCA1 AI (P = 0.0731) as well as young-age at diagnosis (< or = 55; P = 0.0898). BRCA1 methylation was not associated with BRCA2 AI (P = 0.5420), although a significant association was found between BRCA1 AI and BRCA2 AI (P < 0.0001).Absent/markedly reduced BRCA1 expression was observed in 9/13 BRCA1 methylated tumours, most of which had BRCA1 deletion. An elevated TP53 mutation frequency was found among BRCA1 methylated tumours (38.5%) compared with non-methylated tumours (17.2%). The BRCA1 methylated tumours were mainly of tumour grade 3 (7/13) and infiltrating ductal type (12/13). Only one methylated tumour was of grade 1.ConclusionBRCA1 methylation is frequent in primary sporadic breast tumours. We found an indication for BRCA1 methylation to be associated with AI at the BRCA1 locus. Almost all BRCA1 methylated tumours with absent/markedly reduced BRCA1 expression (8/9) displayed BRCA1 deletion. Thus, epigenetic silencing and deletion of the BRCA1 gene might serve as Knudson's two 'hits' in sporadic breast tumorigenesis. We observed phenotypic similarities between BRCA1 methylated and familial BRCA1 tumours, based on BRCA1 deletion, TP53 mutations, ER status, young age at diagnosis and tumour grade.

Dataset Information

Deletion or epigenetic silencing of AJAP1 on 1p36 in glioblastoma.

Publications

Deletion or epigenetic silencing of AJAP1 on 1p36 in glioblastoma.

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