title: Frequent loss of hMLH1 by promoter hypermethylation leads to microsatellite instability in adenomatous polyps of patients with a single first-degree member affected by colon cancer.
abstract: The first-degree relatives of patients affected by colorectal cancer, who do not belong to familial adenomatous polyposis and hereditary nonpolyposis colorectal cancer families, have a doubled risk of developing tumors of the large intestine. We have previously demonstrated that subjects with a single first-degree relative (SFDR) with colon cancer have a doubled risk for developing colorectal adenomas, and in these cases, polyps recur more frequently. The mechanism underlying this predisposition has not been clarified. In this study, we evaluated the frequency of microsatellite instability (MSI) using the five markers suggested by the National Cancer Institute workshop, target gene mutations, hMLH1 and hMSH2 expression, and hMLH1 promoter hypermethylation in the adenomas of patients with and without a SFDR affected by colon cancer. Seventy polyps were obtained from 70 patients: 27 with a single FDR with colon cancer and 43 without such a history. Of the 70 polyps, 12 were MSI-H (17.1%), 20 were MSI-L (28.6%), and 30 were microsatellite stable (42.9%). Of the 27 patients with positive family history, 8 polyps (29.6%) were MSI-H compared with those with negative history in which 4 polyps (9.3%) were MSI-H (P < 0.02). Of the 12 MSI-H polyps, all of the polyps obtained from patients with positive family history had loss of hMLH1 immunostaining versus one with negative family history (P < 0.02). Of the MSI-H polyps, 2 had a somatic frameshift mutation of the MBD4 gene, 1 of MSH6, 1 of BAX, and 2 of transforming growth factor betaRII. Furthermore, 6 of 8 polyps from patients with positive family history with MSI-H and loss of MLH1 had hypermethylation of the MLH1promoter versus none of the MSI-H with negative family history (P < 0.02). All 6 polyps of the 27 from SFDR positive subjects, with hMLH1 promoter hypermethylation loss of hMLH1 and MSI, were located in the right colon (P < 0.02). Hypermethylation of the promoter of hMLH1, consequent loss of hMLH1 expression, and MSI are at the basis of approximately 25% of adenomatous polyps developed in subjects with a SFDR affected by colorectal cancer.
authors.affiliation: Dipartimento di Medicina Interna e Gastroenterologia e Centro di Ricerca Biomedica Applicata, Università degli Studi di Bologna, 40138 Bologna, Italy.
authors.forename: Luigi
authors.initials: L
authors.lastname: Ricciardiello
authors.forename: Ajay
authors.initials: A
authors.lastname: Goel
authors.forename: Vilma
authors.initials: V
authors.lastname: Mantovani
authors.forename: Tania
authors.initials: T
authors.lastname: Fiorini
authors.forename: Stefania
authors.initials: S
authors.lastname: Fossi
authors.forename: Dong K
authors.initials: DK
authors.lastname: Chang
authors.forename: Veronica
authors.initials: V
authors.lastname: Lunedei
authors.forename: Paolo
authors.initials: P
authors.lastname: Pozzato
authors.forename: Rocco M
authors.initials: RM
authors.lastname: Zagari
authors.forename: Luca
authors.initials: L
authors.lastname: De Luca
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Fuccio
authors.forename: Giuseppe N
authors.initials: GN
authors.lastname: Martinelli
authors.forename: Enrico
authors.initials: E
authors.lastname: Roda
authors.forename: C Richard
authors.initials: CR
authors.lastname: Boland
authors.forename: Franco
authors.initials: F
authors.lastname: Bazzoli
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D011125:Adenomatous Polyposis Coli / Q000235:genetics* / Q000378:metabolism; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002352:Carrier Proteins; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000378:metabolism; D019175:DNA Methylation; D004268:DNA-Binding Proteins; D005260:Female; D016368:Frameshift Mutation; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D018895:Microsatellite Repeats / Q000235:genetics; D008875:Middle Aged; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics*; D009687:Nuclear Proteins; D011401:Promoter Regions, Genetic; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis / Q000235:genetics
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; C501486:MLH1 protein, human; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; C497172:MSH2 protein, human; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein