Different genetic features associated with colon and rectal carcinogenesis
Different genetic features associated with colon and rectal carcinogenesis
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DOI：
10.1158/1078-0432.ccr-04-0031
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发表时间：
2004-06-15
影响因子：
11.5
通讯作者：
Pierotti, MA
中科院分区：
文献类型：
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作者：
Frattini, M;Balestra, D;Pierotti, MA
目的：关于结肠癌和直肠癌是一个实体还是两个不同实体的问题仍然存在争议，需要改进导致散发性结直肠癌的致病途径的异质性的研究，以及确定结直肠癌之间的生物学和/或分子差异。实验设计：分析散发性结直肠癌标本中APC、K-ras和TP53基因的体细胞突变和18号染色体杂合性缺失。结果：11例散发性结直肠癌表现出微卫星不稳定性。微卫星不稳定性(MIN+)组APC突变频率显著低于MIN-SCC组。所有MIN-SCRC均有β-连环素的过度表达。生物标志物的联合分析揭示了两条途径，即APC-K-ras-TP53-Ch18q和APC-TP53-Ch18q。结论：在Min-SCRCs中，APC-β-catenin途径失活，代表了SCRC发生的第一次冲击。SCRCs遵循两条优先途径，一条依赖于K-ras，符合Fearon和Vogelstein模型，另一条不依赖于K-ras。在我们的MIN-SCRC系列中，结肠癌和直肠肿瘤之间存在显著差异。所观察到的不同途径及其分布可概括如下：(A)K-ras突变在结肠中比在直肠中更常见；(B)在结肠中检测到的突变数量明显高于直肠肿瘤；以及(C)APC基因限制性突变模式在直肠肿瘤中比在结肠癌中更常见。这种分子特征可以转化为临床环境，以改善诊断并指导药物治疗的理论基础。
Purpose: The issue of whether colon and rectal cancer should be considered as a single entity or two distinct entities is still debated, and there is a need to improve studies addressing the heterogeneity of the pathogenetic pathway leading to sporadic colorectal cancers (SCRCs) as well as to identify biological and/or molecular differences between colon and rectal cancers.Experimental Design: Specimens of SCRCs were analyzed for somatic mutations in APC, K-ras, and TP53 genes and loss-of-heterozygosity of chromosome 18.Results: Eleven SCRCs showed microsatellite instability. APC mutation frequency was significantly lower in microsatellite instability (MIN+) than in MIN- SCRCs. All MIN- SCRCs showed beta-catenin overexpression. A combined analysis of the biomarkers revealed two pathways mainly represented by MIN- SCRCs and differently followed on the basis of tumor location, APC-K-ras-TP53-Ch18q and APC-TP53-Ch18q.Conclusions: The APC-beta-catenin pathway is inactivated in MIN-SCRCs and represents the first hit of SCRC development. Two preferential pathways followed by SCRCs occur, one K-ras dependent, in agreement with the Fearon and Vogelstein model, and the other K-ras independent. Significant differences between colon and rectal tumors occur in our series of MIN-SCRCs. The different pathways observed and their distribution can be summarized as follows: (a) K-ras mutations were more commonly detected in colon than in rectum; (b) the number of mutations detected was significantly higher in colon than in rectal tumors; and (c) a mutational pattern restricted to the APC gene was more common in rectal than in colon tumors. This molecular characterization can be translated into a clinical setting to improve diagnosis and to direct a rationale pharmacological treatment.