title: Frequent somatic demethylation of RAPGEF1/C3G intronic sequences in gastrointestinal and gynecological cancer.
abstract: RAPGEF1 (also known as C3G and GRF2) is a guanine nucleotide exchange factor that releases GDP from the inactive Rap1 protein, facilitating its subsequent activation by the binding of GTP. Rap1 plays regulatory roles in proliferation, differentiation and apoptosis. Amplification and overexpression of RAPGEF1 have been found in small cell lung cancers, suggesting an oncogenic role. In contrast, hypermethylation of a promoter CpG island (CGI-A) of RAPGEF1 has been reported in squamous cervical tumors, suggesting an anti-oncogenic role in these gynecological cancers. In our studies of DNA methylation alterations in gastrointestinal cancer we found somatic demethylation of a relaxed-criterion CpG island (CGI-B) located in the first intron of RAPGEF1 in 40% of colon cancers and 8% of gastric cancers relative to their matching normal tissues that were always methylated. We also found somatic demethylation in 47% of squamous cervical carcinomas as well as 33% of ovarian cancers. This somatic change in methylation, however, did not extend to the strict-criterion CpG island located in the promoter region (CGI-A) that was unmethylated in all normal and tumor tissues analyzed. Thus, promoter hypermethylation of RAPGEF1 seems insignificant in colorectal, cervical and ovarian cancers. In contrast, tumor-specific hypomethylation of the gene appears to be frequent in gastrointestinal and gynecological cancers.
authors.affiliation: Graduate School of Biomedical Sciences, Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Johanna
authors.initials: J
authors.lastname: Samuelsson
authors.forename: Sergio
authors.initials: S
authors.lastname: Alonso
authors.forename: Tatiana
authors.initials: T
authors.lastname: Ruiz-Larroya
authors.forename: Tak Hong
authors.initials: TH
authors.lastname: Cheung
authors.forename: Yick Fu
authors.initials: YF
authors.lastname: Wong
authors.forename: Manuel
authors.initials: M
authors.lastname: Perucho
mesh_terms: D018899:CpG Islands / Q000235:genetics; D019175:DNA Methylation; D057890:Epigenomics; D005260:Female; D005770:Gastrointestinal Neoplasms / Q000235:genetics / Q000503:physiopathology*; D015972:Gene Expression Regulation, Neoplastic; D023061:Gene Order; D005833:Genital Neoplasms, Female / Q000235:genetics / Q000503:physiopathology*; D020735:Guanine Nucleotide-Releasing Factor 2 / Q000235:genetics*; D006801:Humans; D007438:Introns / Q000235:genetics*; D011401:Promoter Regions, Genetic / Q000235:genetics
chemical_list: D020735:Guanine Nucleotide-Releasing Factor 2