Evidence for the role of aberrant DNA methylation in the pathogenesis of Lynch syndrome adenomas

Andrew Kaz, Young Ho Kim, Slavomir Dzieciatkowski, Henry Lynch, Patrice Watson, Mary Kay Washington, Li Lin, William M. Grady

Research output: Contribution to journalArticle

24 Scopus citations

Abstract

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 p14ARF 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 p14ARF 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 molecu-lar pathogenesis of the tumors. MLH1 methylation in the Lynch syndrome adenomas suggests gene methylation might have a role in the initiation of these neoplasms.

Original languageEnglish (US)
Pages (from-to)1922-1929
Number of pages8
JournalInternational Journal of Cancer
Volume120
Issue number9
DOIs
StatePublished - May 1 2007

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

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    Kaz, A., Kim, Y. H., Dzieciatkowski, S., Lynch, H., Watson, P., Washington, M. K., Lin, L., & Grady, W. M. (2007). Evidence for the role of aberrant DNA methylation in the pathogenesis of Lynch syndrome adenomas. International Journal of Cancer, 120(9), 1922-1929. https://doi.org/10.1002/ijc.22544