摘要
Allelic loss of the short arm of chromosome 1 has been observed frequently in a wide spectrum of cancers,most frequently in oligodendroglioma.In our previous studies,we evaluated 177 oligodendroglial tumor samples and identified the AJAP1 gene(formerly Shrew1) in the consensus region of deletion.AJAP1 is a transmembrane protein found in adheren junctions and functions to inhibit glioma cell adhesion and migration.Whereas a putative tumor suppressor gene,we did not detect AJAP1 gene mutations.In subsequent studies,we found that AJAP1 was underexpressed in oligodendrogliomas relative to normal brain tissues.Bioinformatic analysis revealed the presence of CpG islands in the promoter of AJAP1.Methylation analysis of the AJAP1 promoter identified hypermethylation in 21% of oligodendrogliomas(n = 27),and the degree of methylation correlated with low levels of AJAP1 expression(P = 0.045).The AJAP1 promoter was also highly methylated in a wide spectrum of cell lines(n = 22),including cell lines of glioblastoma.Analysis of the National Cancer Institute's REMBRANDT dataset,which contains 343 glioma samples,indicated that low AJAP1 gene expression was associated with decreased survival.Thus,both genetic(gene deletion) and epigenetic alterations(promoter methylation) are likely mechanisms that inactivate the putative tumor suppressor AJAP1 in gliomas,which contributes to poor prognosis.
Allelic loss of the short arm of chromosome 1 has been observed frequently in a wide spectrum of cancers, most frequently in oligodendroglioma. In our previous studies, we evaluated 177 oligodendroglial tumor samples and identified the AJAP1 gene （formerly Shrew1） in the consensus region of deletion. AJAP1 is a transmembrane protein found in adheren junctions and functions to inhibit glioma cell adhesion and migration. Whereas a putative tumor suppressor gene, we did not detect AJAP1 gene mutations. In subsequent studies, we found that AJAP1 was underexpressed in oligodendrogliomas relative to normal brain tissues. Bioinformatic analysis revealed the presence of CpG islands in the promoter of AJAPI. Methylation analysis of the AJAP1 promoter identified hypermethylation in 21% of oligodendrogliomas （n = 27）, and the degree of methylation correlated with low levels of AJAP1 expression （P = 0.045）. The AJAP1 promoter was also highly methylated in a wide spectrum of cell lines （n = 22）, including cell lines of glioblastoma. Analysis of the National Cancer Institute＇s REMBRANDT dataset, which contains 343 glioma samples, indicated that low AJAP1 gene expression was associated with decreased survival. Thus, both genetic （gene deletion） and epigenetic alterations （promoter methylation） are likely mechanisms that inactivate the putative tumor suppressor AJAP1 in gliomas, which contributes to poor prognosis.
基金
supported by the Anthony Bullock Ⅲ Research Fund and Cancer Center Support Grant CA016672 from the National Institutes of Health to the MD Anderson Cancer Center
