title: Frequent CpG island methylation in serrated adenomas of the colorectum.
abstract: Serrated adenomas are characterized by a saw-toothed growth pattern with epithelial dysplasia (intraepithelial neoplasia). The CpG island methylator phenotype (CIMP) is a recently described mechanism for tumorigenesis in colorectal carcinomas and adenomas characterized by methylation of multiple CpG islands. The role of these epigenetic alterations in the pathogenesis of serrated adenomas is not clear. We therefore evaluated CIMP in 22 sporadic serrated adenomas and 6 serrated adenomas with multiple (6 to 10) hyperplastic polyps, including 5 with admixed hyperplastic glands and adenomatous glands, and compared the results with 34 conventional adenomas. Bisulfite methylation-specific polymerase chain reaction was used for the p16 and hMLH1 genes, and three MINT (methylated in tumor) loci (MINT1, MINT2, and MINT31). Patients with sporadic serrated adenomas had a higher frequency of hyperplastic polyps (1.3 +/- 1.6) as compared to patients with tubular adenomas (0.4 +/- 0.9, P = 0.02). Mean number of methylated sites was significantly higher in sporadic serrated adenomas (2.0 +/- 1.7) than in tubular adenomas (0.8 +/- 0.9, P = 0.00001). Sporadic serrated adenomas had significantly more frequent methylation of MINT1 (48%, 10 of 22) and MINT2 (71%, 15 of 21) than tubular adenomas (9%, 3 of 34, P = 0.001; and 18%, 6 of 34, P = 0.0001), respectively. Concordant methylation of two or more sites (CIMP-high) was also more frequent in sporadic serrated adenomas (68%, 15 of 22) than in tubular adenomas (18%, 6 of 34, P = 0.0005). All five serrated adenomas with admixed hyperplastic glands and adenomatous glands were CIMP-high. Our results indicate that CpG island methylation is common in sporadic serrated adenomas and may play an important role in their pathogenesis.
authors.affiliation: Department of Pathology, University of Texas, M. D. Anderson Cancer Center, Houston, Texas 77030-4095, USA.
authors.forename: Seun-Ja
authors.initials: SJ
authors.lastname: Park
authors.forename: Asif
authors.initials: A
authors.lastname: Rashid
authors.forename: Jae-Hyuk
authors.initials: JH
authors.lastname: Lee
authors.forename: Sang Geol
authors.initials: SG
authors.lastname: Kim
authors.forename: Stanley R
authors.initials: SR
authors.lastname: Hamilton
authors.forename: Tsung-Teh
authors.initials: TT
authors.lastname: Wu
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000236:Adenoma / Q000235:genetics* / Q000473:pathology*; D001483:Base Sequence; D001706:Biopsy; D015820:Cadherins; D002352:Carrier Proteins / Q000235:genetics; D003110:Colonic Neoplasms / Q000235:genetics / Q000473:pathology; D003111:Colonic Polyps / Q000235:genetics / Q000473:pathology; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000473:pathology*; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000032:analysis / Q000235:genetics; D019175:DNA Methylation; D017931:DNA Primers; D015226:Dinucleoside Phosphates / Q000235:genetics*; D005260:Female; D006801:Humans; D006965:Hyperplasia; D008297:Male; D008565:Membrane Proteins; D008875:Middle Aged; D009419:Nerve Tissue Proteins / Q000235:genetics; D010641:Phenotype; D011506:Proteins / Q000235:genetics; D012004:Rectal Neoplasms / Q000235:genetics / Q000473:pathology; D012008:Recurrence
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D015820:Cadherins; D002352:Carrier Proteins; D019941:Cyclin-Dependent Kinase Inhibitor p16; D017931:DNA Primers; D015226:Dinucleoside Phosphates; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D011506:Proteins; C079091:APBA1 protein, human; C491636:APBA2 protein, human; C117536:APBA3 protein, human; C513071:Apba1 protein, rat; C485532:Apba3 protein, rat; C015772:CpG dinucleotide