Pharma Strategy Blog

During yesterday’s discussion with Dr Ray DuBois (MD Anderson Cancer Center) about inflammation and methylation, the topic of CpG island methylator phenotype (CIMP) in colorectal cancer (CRC) came up as you can see from the brief audio clip below:

Steve Baylin’s paper sounded most interesting, so I tracked it down – see O’Hagan et al., (2011) in the References below for the direct link.

CIMP is interesting to look at because it can occur in some 30% of colorectal cancer cases and has been previously shown to be an independent predictor of survival with 5FU in early or adjuvant CRC (van Rijnsoever, 2003). It is, therefore, a potentially useful molecular marker in this disease.

In O’Hagan et al’s (2011) current research, they stated:

“We demonstrate that inducing cellular oxidative stress by hydrogen peroxide treatment recruits DNA methyltransferase 1 (DNMT1) to damaged chromatin.”

Essentially, a link between several proteins involved in transcriptional repression to the DNA damage response was observed. A key part of this damage response is reactive oxygen species (ROS), elevated levels of which were shown by Federico et al., (2007) to constitute a key risk state for increased cancer susceptibility. Raised levels of ROS tend to occur as a result of alterations in cellular metabolism and inflammatory responses.

The current research from O’Hagan et al., (2011) takes our understanding of this process further:

“One of the intriguing implications of our data is the potential role for increased levels of cellular ROS that accompany cancer risk states such as inflammation in the formation of cancer-specific aberrant patterns of DNA methylation and transcriptional silencing.”

What is useful from a practical standpoint, is that the current findings build on their existing model, which considers a promoter CpG island, double-strand break DNA damage concept:

“We hypothesize that such localization of the DNMT-PRC4 complex and increase in DNA methylation at low-expression promoter CpG island-containing genes might be more persistent over the course of chronic ROS damage during tumorigenesis, setting up a scenario for the expansion of DNA methylation in the CpG islands involved.”

In other words, Dr Baylin’s lab have shown that chronic inflammation over time may lead to DNA hypermethylation. If we then consider the work from Dr DuBois’s lab discussed yesterday (in Xia et al., 2012), the connection between inflammation, DNA methylation and early development of colorectal cancer starts to make a lot of sense.

Tomorrow, I’ll be looking at early colorectal cancer in more detail and discussing how the roles of BRAF, KRAS and PIK3CA mutations and CIMP may play a role in tumorigenesis in colorectal polyps. Do check back to follow the ongoing story.

References:

O’Hagan, H., Wang, W., Sen, S., DeStefano Shields, C., Lee, S., Zhang, Y., Clements, E., Cai, Y., Van Neste, L., Easwaran, H., Casero, R., Sears, C., & Baylin, S. (2011). Oxidative Damage Targets Complexes Containing DNA Methyltransferases, SIRT1, and Polycomb Members to Promoter CpG Islands Cancer Cell, 20 (5), 606-619 DOI: 10.1016/j.ccr.2011.09.012

Federico A, Morgillo F, Tuccillo C, Ciardiello F, & Loguercio C (2007). Chronic inflammation and oxidative stress in human carcinogenesis. International journal of cancer. Journal international du cancer, 121 (11), 2381-6 PMID: 17893868

Xia, D., Wang, D., Kim, S., Katoh, H., & DuBois, R. (2012). Prostaglandin E2 promotes intestinal tumor growth via DNA methylation Nature Medicine DOI: 10.1038/nm.2608