Division of Gastroenterology, Department of Medicine, University of Minnesota, Minneapolis, Minnesota, USA.
Am J Gastroenterol. 2010 May;105(5):1189-95. doi: 10.1038/ajg.2009.699. Epub 2009 Dec 15.
Colon cancers diagnosed in the interval after a complete colonoscopy may occur due to limitations of colonoscopy or due to the development of new tumors, possibly reflecting molecular and environmental differences in tumorigenesis resulting in rapid tumor growth. In a previous study from our group, interval cancers (colon cancers diagnosed within 5 years of a complete colonoscopy) were almost four times more likely to demonstrate microsatellite instability (MSI) than non-interval cancers. In this study we extended our molecular analysis to compare the CpG island methylator phenotype (CIMP) status of interval and non-interval colorectal cancers and investigate the relationship between the CIMP and MSI pathways in the pathogenesis of interval cancers.
We searched our institution's cancer registry for interval cancers, defined as colon 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 colon cancers diagnosed on a patient's first recorded colonoscopy). Archived cancer specimens for all subjects were retrieved and tested for CIMP gene markers. The MSI status of subjects identified between 1989 and 2004 was known from our previous study. Tissue specimens of newly identified cases and controls (between 2005 and 2006) were tested for MSI.
There were 1,323 cases of colon cancer diagnosed over the 17-year study period, of which 63 were identified as having interval cancer and matched to 131 subjects with non-interval cancer. Study subjects were almost all Caucasian men. CIMP was present in 57% of interval cancers compared to 33% of non-interval cancers (P=0.004). As shown previously, interval cancers were more likely than non-interval cancers to occur in the proximal colon (63% vs. 39%; P=0.002), and have MSI 29% vs. 11%, P=0.004). In multivariable logistic regression model, proximal location (odds ratio (OR) 1.85; 95% confidence interval (CI) 1.01-3.8), MSI (OR 2.7; 95% CI 1.1-6.8) and CIMP (OR 2.41; 95% CI 1.2-4.9) were independently associated with interval cancers. CIMP was associated with interval cancers independent of MSI status. There was no difference in 5-year survival between the two groups.
Interval cancers are more likely to arise in the proximal colon and demonstrate CIMP, which suggests there may be differences in biology between these and non-interval CRC. Additional studies are needed to determine whether interval cancers arise as a result of missed lesions or accelerated neoplastic progression.
在完全结肠镜检查后的间隔期内诊断出的结肠癌可能是由于结肠镜检查的局限性或新肿瘤的发展引起的，这可能反映了肿瘤发生中分子和环境差异导致肿瘤快速生长。在我们小组的先前研究中，间隔期癌症（在完全结肠镜检查后 5 年内诊断出的结肠癌）表现出微卫星不稳定性（MSI）的可能性是无间隔期癌症的近四倍。在这项研究中，我们扩展了我们的分子分析，以比较间隔期和无间隔期结直肠癌的 CpG 岛甲基化表型（CIMP）状态，并研究 CIMP 和 MSI 通路在间隔期癌症发病机制中的关系。
我们在我们机构的癌症登记处搜索间隔期癌症，将其定义为在完全结肠镜检查后 5 年内发生的结肠癌。通过年龄和性别与非间隔期癌症（定义为在患者首次记录的结肠镜检查中诊断出的结肠癌）进行 1:2 比例的频率匹配。检索所有受试者的存档癌症标本并测试 CIMP 基因标志物。我们之前的研究已经知道了在 1989 年至 2004 年期间确定的 MSI 状态的受试者。对新确定的病例和对照（2005 年至 2006 年）的组织标本进行 MSI 测试。
在 17 年的研究期间共诊断出 1323 例结肠癌，其中 63 例被确定为间隔期癌症，并与 131 例非间隔期癌症患者相匹配。研究对象几乎都是白种男性。与非间隔期癌症（33%）相比，间隔期癌症的 CIMP 阳性率为 57%（P=0.004）。如前所述，与非间隔期癌症相比，间隔期癌症更有可能发生在近端结肠（63% vs. 39%；P=0.002），并且 MSI 为 29% vs. 11%，P=0.004）。在多变量逻辑回归模型中，近端位置（比值比（OR）1.85；95%置信区间（CI）1.01-3.8）、MSI（OR 2.7；95% CI 1.1-6.8）和 CIMP（OR 2.41；95% CI 1.2-4.9）与间隔期癌症独立相关。CIMP 与间隔期癌症独立于 MSI 状态相关。两组的 5 年生存率无差异。
间隔期癌症更有可能发生在近端结肠，并表现出 CIMP，这表明这些癌症与非间隔期 CRC 之间可能存在生物学差异。需要进一步研究以确定间隔期癌症是由于遗漏病变还是加速肿瘤进展所致。
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