Molecular Markers of Rapidly Growing Tumors

Abstract

Purpose: Sporadic colorectal cancers developing after complete colonoscopy (interval cancers) are likely to be rapidly growing tumors, and comparison of these tumors with non-interval cancers offers a unique means to identify the genetic pathways responsible for rapid tumor growth. The aim of this study was to compare the CpG island methylator phenotype (CIMP) status of interval versus non-interval colorectal cancers in the Minneapolis VA population and to determine the relationship between CIMP, microsatellite instability (MSI) in interval and non-interval colon cancers. Methods: We searched our institution's cancer registry for interval cancers, defined as colorectal cancers that developed within 5 years of a complete colonoscopy. These were frequency matched in a 1:2 ratio by age and sex to patients with non-interval cancers, defined as cancers diagnosed on a patient's first colonoscopy. Over a 17 year period, we identified 194 cancers that met the study criteria. MSI testing had been performed in 163 of these cancers in a previous study. Tumor DNA was extracted and tested for MSI and CIMP gene markers (MINT1, MINT2, MINT31, p16INK4, MGMT, hMLH1). CIMP was defined as methylation in 3 or more genes. Results: Of the 1323 colorectal cancers diagnosed during the study period, 63 (4.7%) were identified as an interval cancer, and 131 subjects with non-interval cancer served as controls. Study subjects were almost all Caucasian men. Interval cancers were significantly more likely to be CIMP+ than non-interval cancers (56% vs. 31%, P= 0.004), right-sided (63% vs. 39%, P= 0.002), and consistent with our previous study more likely to have MSI than non-interval cancers (29% vs. 11%, P= 0.004). In multivariable logistic regression model, proximal location of cancer (OR 1.85; 95% CI 1.01–3.8), MSI (OR 2.6; 95% 1.08–6.7) and CIMP+ (OR 2.41; 95% CI 1.1–4.9) were associated with interval cancers. The McNemar's test for discordance between MSI and CIMP was significant suggesting that MSI and CIMP were independently associated with interval cancers. There was no difference in 5 year survival between the two groups. Conclusion: CIMP+ and MSI are more frequently present in interval cancers compared to non-interval cancers. MSI and CIMP+ are factors independently associated with interval cancers. CIMP+ adds information in addition to MSI in explaining rapid tumor growth and biology. Whether CIMP and MSI lead to rapid tumor growth, or occur in rapidly growing tumors after their development.