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Evidence for the role of aberrant DNA methylation in the pathogenesis of Lynch syndrome adenomas
Author(s) -
Kaz Andrew,
Kim YoungHo,
Dzieciatkowski Slavomir,
Lynch Henry,
Watson Patrice,
Kay Washington Mary,
Lin Li,
Grady William M.
Publication year - 2007
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.22544
Subject(s) - lynch syndrome , mlh1 , cdkn2a , dna methylation , cancer research , epigenetics , methylation , biology , cancer , colorectal cancer , msh2 , dna mismatch repair , genetics , gene , gene expression
Colorectal cancer (CRC) forms through a series of histologic steps that are accompanied by mutations and epigenetic alterations, which is called the polyp‐cancer sequence. The role of epigenetic alterations, such as aberrant DNA methylation, in the polyp‐cancer sequence in sporadic CRC and particularly in hereditary colon cancer is not well understood. Consequently, we assessed the methylation status of CDKN2A/p16, MGMT , MLH1 and p14 ARF in adenomas arising in the Lynch syndrome, a familial colon cancer syndrome caused by MLH1 and MSH2 mutations, to determine if DNA methylation is a “second hit” mechanism in CRC and to characterize the role of DNA methylation in the polyp phase of the Lynch syndrome. We found MLH1 and p14 ARF are methylated in 53 and 60% of the Lynch syndrome adenomas and in 4 and 20% of sporadic adenomas, whereas CDKN2A/p16 and MGMT are methylated in 6 and 14% of the Lynch syndrome adenomas versus 50 and 64% of sporadic adenomas. Therefore, the frequency and pattern of gene methylation varies between the Lynch syndrome and sporadic colon adenomas, implying differences in the molecular pathogenesis of the tumors. MLH1 methylation in the Lynch syndrome adenomas suggests gene methylation might have a role in the initiation of these neoplasms. © 2007 Wiley‐Liss, Inc.