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Risk of Microsatellite-Unstable Colorectal Cancer Is Associated Jointly with Smoking and Nonsteroidal Anti-inflammatory Drug Use

¹ Public Health Sciences, Fred Hutchinson Cancer Research Center; ² Department of Epidemiology, University of Washington, Seattle, Washington; ³ University of Wisconsin, Comprehensive Cancer Center, Madison, Wisconsin; and ⁴ Department of Laboratory Medicine and Pathology, Mayo Clinic College of Medicine, Rochester, Minnesota

Requests for reprints: Polly A. Newcomb, Cancer Prevention Research Program, Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue North, P.O. Box 19024, M4-B402, Seattle, WA 98109-1024. Phone: 206-667-3476; Fax: 206-667-7850; E-mail: pnewcomb{at}fhcrc.org.

Smoking has been consistently associated with an increased risk of colorectal adenomas and hyperplastic polyps as well as colorectal cancer. Conversely, nonsteroidal anti-inflammatory drugs (NSAID) have been associated with reduced colorectal cancer risk. We conducted a population-based case-control study to evaluate the joint association between smoking and regular NSAID use with colorectal cancer risk; we also examined these associations stratified by tumor microsatellite instability (MSI). We analyzed 1,792 incident colorectal cancer cases and 1,501 population controls in the Seattle, Washington area from 1998-2002. MSI, defined as MSI high (MSI-H) or MSI-low/microsatellite stable (MSI-L/MSS), was assessed in tumors of 1,202 cases. Compared with nonsmokers, colorectal cancer risk was modestly increased among individuals who had ever smoked. Current NSAID use was associated with a 30% lower risk compared with nonusers. There was a statistically significant interaction between smoking duration and use of NSAIDs (P_interaction = 0.05): relative to current NSAID users who never smoked, individuals who had both smoked for >40 years and had never used NSAIDs were at the highest risk for colorectal cancer (adjusted odds ratio, 2.8; 95% confidence intervals, 1.8-4.1). Compared with nonsmokers, there was a stronger association within MSI-H tumors with current smoking than there was within MSI-L/MSS tumors. Smokers of long duration were at elevated risk of MSI-H tumors even with NSAID use. The risk of MSI-L/MSS tumors was not elevated among long-duration smokers with long exposure to NSAIDs but was elevated among long-duration smokers who had never used NSAIDs. There seems to be a synergistic inverse association (implying protection) against colorectal cancer overall as a result of NSAID use and nonsmoking, but risk of MSI-H colorectal cancer remains elevated among smokers even when they have a history of NSAID use. (Cancer Res 2006; 66(13): 6877-83)

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