title: DNA methylation patterns in hereditary human cancers mimic sporadic tumorigenesis.
abstract: Cancer cells have aberrant patterns of DNA methylation including hypermethylation of gene promoter CpG islands and global demethylation of the genome. Genes that cause familial cancer, as well as other genes, can be silenced by promoter hypermethylation in sporadic tumors, but the methylation of these genes in tumors from kindreds with inherited cancer syndromes has not been well characterized. Here, we examine CpG island methylation of 10 genes (hMLH1, BRCA1, APC, LKB1, CDH1, p16(INK4a), p14(ARF), MGMT, GSTP1 and RARbeta2) and 5-methylcytosine DNA content, in inherited (n = 342) and non-inherited (n = 215) breast and colorectal cancers. Our results show that singly retained alleles of germline mutated genes are never hypermethylated in inherited tumors. However, this epigenetic change is a frequent second "hit", associated with the wild-type copy of these genes in inherited tumors where both alleles are retained. Global hypomethylation was similar between sporadic and hereditary cases, but distinct differences existed in patterns of methylation at non-familial genes. This study demonstrates that hereditary cancers "mimic" the DNA methylation patterns present in the sporadic tumors.
authors.affiliation: The Johns Hopkins Oncology Center, 1650 Orleans Street, Baltimore, MD 21231, USA.
authors.forename: M
authors.initials: M
authors.lastname: Esteller
authors.forename: M F
authors.initials: MF
authors.lastname: Fraga
authors.forename: M
authors.initials: M
authors.lastname: Guo
authors.forename: J
authors.initials: J
authors.lastname: Garcia-Foncillas
authors.forename: I
authors.initials: I
authors.lastname: Hedenfalk
authors.forename: A K
authors.initials: AK
authors.lastname: Godwin
authors.forename: J
authors.initials: J
authors.lastname: Trojan
authors.forename: C
authors.initials: C
authors.lastname: Vaurs-Barrière
authors.forename: Y J
authors.initials: YJ
authors.lastname: Bignon
authors.forename: S
authors.initials: S
authors.lastname: Ramus
authors.forename: J
authors.initials: J
authors.lastname: Benitez
authors.forename: T
authors.initials: T
authors.lastname: Caldes
authors.forename: Y
authors.initials: Y
authors.lastname: Akiyama
authors.forename: Y
authors.initials: Y
authors.lastname: Yuasa
authors.forename: V
authors.initials: V
authors.lastname: Launonen
authors.forename: M J
authors.initials: MJ
authors.lastname: Canal
authors.forename: R
authors.initials: R
authors.lastname: Rodriguez
authors.forename: G
authors.initials: G
authors.lastname: Capella
authors.forename: M A
authors.initials: MA
authors.lastname: Peinado
authors.forename: A
authors.initials: A
authors.lastname: Borg
authors.forename: L A
authors.initials: LA
authors.lastname: Aaltonen
authors.forename: B A
authors.initials: BA
authors.lastname: Ponder
authors.forename: S B
authors.initials: SB
authors.lastname: Baylin
authors.forename: J G
authors.initials: JG
authors.lastname: Herman
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism; D003110:Colonic Neoplasms / Q000235:genetics* / Q000378:metabolism; D018899:CpG Islands; D019175:DNA Methylation; D016147:Genes, Tumor Suppressor; D020022:Genetic Predisposition to Disease; D006801:Humans; D009154:Mutation; D009386:Neoplastic Syndromes, Hereditary / Q000235:genetics* / Q000503:physiopathology; D009857:Oncogenes; D011401:Promoter Regions, Genetic