Søreide Kjetil, Gudlaugsson Einar, Skaland Ivar, Janssen Emiel A M, Van Diermen Bianca, Körner Hartwig, Baak Jan P A
Department of Pathology, Stavanger University Hospital, P.O. Box 8100, 4068 Stavanger, Norway.
Int J Colorectal Dis. 2008 Apr;23(4):389-400. doi: 10.1007/s00384-007-0424-6.
Accurate, long-term risk predictors for colorectal cancer development in patients with sporadic adenomas are lacking. We sought to validate biomarkers predictive of metachronous colorectal cancer (mCRC) in patients with sporadic colorectal adenomas, using 374 consecutive patients from a large defined population.
Risk evaluation was performed for patient and adenoma risk factors (morphometric longest nuclear axis and immunohistochemical markers survivin, human telomerase reverse transcriptase (hTERT), beta-catenin, p16INK4a, p21CIP1, and cyclin D1). Diagnostic accuracy was assessed by receiver-operating characteristics curve analysis, and uni- and multivariate survival analysis was performed.
RESULTS/FINDINGS: Of the 374 patients, 26 (7%) developed mCRC with a median of 5.6 years (range 2-19) from index adenoma. Independent risk factors included age greater than or equal to 60 years, proximal location, multiplicity (greater than or equal to three adenomas), and high-grade neoplasia, with high-grade intraepithelial neoplasia and proximal location as the strongest on multivariate analysis (hazard ratio [HR] of 4.1 and 5.2, respectively; both p< 0.05). The molecular markers hTERT (HR 11.3, 95% confidence interval [CI] 3.9-33.1; p < 0.001) and survivin (HR 7.0, 95% CI 2.4-20.5; p < 0.001) were independent predictors for mCRC, and proximal location (4 of 16 = 25% with mCRC) was the only clinical one. The value of hTERT and survivin were retained in the validation set. Survivin and hTERT together yielded high mCRC risk when both were positive (15 of 51 = 29%; HR 14.3, 5.6-36.5), modest with one positive (survivin 4 of 90 = 4.4%; hTERT 4 of 60 = 6.7%), and no risk with both negative (0 of 144 = 0%).
INTERPRETATION/CONCLUSION: hTERT and survivin are the best risk predictors for long-term, mCRC development in patients with sporadic colorectal adenomas.
散发性腺瘤患者结直肠癌发生的准确长期风险预测指标尚缺乏。我们利用来自一个大型特定人群的374例连续患者，试图验证散发性结直肠腺瘤患者异时性结直肠癌（mCRC）的预测生物标志物。
对患者和腺瘤风险因素（形态学最长核轴以及免疫组化标志物生存素、人端粒酶逆转录酶（hTERT）、β-连环蛋白、p16INK4a、p21CIP1和细胞周期蛋白D1）进行风险评估。通过受试者工作特征曲线分析评估诊断准确性，并进行单因素和多因素生存分析。
结果/发现：374例患者中，26例（7%）发生mCRC，距索引腺瘤的中位时间为5.6年（范围2 - 19年）。独立风险因素包括年龄大于或等于60岁、近端位置、多发性（大于或等于3个腺瘤）和高级别瘤变，多因素分析显示高级别上皮内瘤变和近端位置风险最强（风险比[HR]分别为4.1和5.2；均p < 0.05）。分子标志物hTERT（HR 11.3，95%置信区间[CI] 3.9 - 33.1；p < 0.001）和生存素（HR 7.0，95% CI 2.4 - 20.5；p < 0.001）是mCRC的独立预测指标，近端位置（16例中有4例 = 25%发生mCRC）是唯一的临床指标。hTERT和生存素的值在验证集中得以保留。当生存素和hTERT均为阳性时，发生mCRC的风险很高（51例中有15例 = 29%；HR 14.3，5.6 - 36.5），一个阳性时风险中等（生存素90例中有4例 = 4.4%；hTERT 60例中有4例 = 6.7%），两者均为阴性时无风险（144例中有0例 = 0%）。
解读/结论：hTERT和生存素是散发性结直肠腺瘤患者长期发生mCRC的最佳风险预测指标。
