Smoking-related colorectal cancer in older women is associated with molecularly-defined DNA changes

Smoking, an established risk factor for colon cancer, may induce specific epigenetic changes and gene mutations that may be involved in the development of colon cancer, according to an online study published June 29 in the Journal of The National Cancer Institute.

Cigarette smoking is a risk factor for colorectal cancer, with a recent meta-analysis estimating that people who currently smoke or smoked in the past are 18% more likely to develop colorectal cancer than non-smokers. But few studies have looked at the effect smoking may have on the specific molecular pathways of colorectal cancer. This study investigated how smoking may cause colorectal cancer at the molecular level.

To explore the molecular pathways of smoking-related colorectal cancer, Paul J. Limburg, M.D., of the Mayo Clinic, and colleagues, evaluated smoking patterns among women in the Iowa Women's Health Study (IWHS), who were between the ages of 55 and 69 years. They looked at the age at which women started smoking, the average number of cigarettes per day and per year.

The researchers sent a questionnaire to the 98,029 women enrolled in IWHS as of January 1986, to which 43% or 41,836 women responded. Non-smokers constituted 66% of the respondents, with 34% identifying themselves as active or former smokers.

The researchers found that there was only a modest association between cigarette smoking and overall colorectal cancer incidence but that smoking was strongly associated with a certain subtype of colorectal cancer, namely tumors that had high levels of microsatellite instability (MSI), epigenetic changes (alterations that do not affect the DNA sequence), and BRAF mutations.

The authors write that the results "have provided additional support that cigarette smoking is a risk factor for colorectal cancer but further indicate that the smoking-related risk may pertain to specific molecularly defined colorectal cancer subtypes that develop through epigenetically mediated carcinogenic pathways."

Furthermore, they write: "These findings indicate that epigenetic modification may be functionally involved in smoking-related colorectal carcinogenesis."

The sub-type of colorectal cancer that emerged in the study is more prevalent among older women, making them a rich sample pool for studies. However, for that same reason, the authors caution against generalizing the results to the general public.

The study could have important clinical implications: "Emerging colorectal cancer screening technologies, such as stool assays that are based on methylation markers [signs of epigenetic changes] might be particularly informative for patients with a history of prolonged tobacco use," the authors write.

In an accompanying editorial, C. Richard Boland, M.D. and Ajay Goel, Ph.D., of Baylor University Medical Center, write: "The most important message to take from the study by Limsui et al. is that colorectal cancer is a complex collection of diseases and that causation might be different for each of the categories. Cigarette smoking is associated with a specific subset of these tumors."