微卫星不稳定的结直肠癌中胸苷酸合成酶高表达：对化疗策略的影响

High thymidylate synthase expression in colorectal cancer with microsatellite instability: implications for chemotherapeutic strategies.

作者信息

Ricciardiello Luigi, Ceccarelli Claudio, Angiolini Graziella, Pariali Milena, Chieco Pasquale, Paterini Paola, Biasco Guido, Martinelli Giuseppe N, Roda Enrico, Bazzoli Franco

机构信息

Department of Internal Medicine and Gastroenterology, University of Bologna, Italy.

出版信息

Clin Cancer Res. 2005 Jun 1;11(11):4234-40. doi: 10.1158/1078-0432.CCR-05-0141.

DOI:10.1158/1078-0432.CCR-05-0141

PMID:15930362

Abstract

UNLABELLED

Colon cancers displaying microsatellite instability (MSI) are clinically less aggressive. Based on in vitro studies and recent clinical data, cancers displaying MSI do not respond to 5-fluorouracil (5-FU). The reasons why MSI tumors are clinically less aggressive and do not respond to 5-FU-based therapies have not been fully elucidated.

PURPOSE

We investigated biomolecular markers in an attempt to explain the different clinical behavior and chemotherapeutic responses of MSI and non-MSI colon cancers.

EXPERIMENTAL DESIGN

One hundred ninety-two sporadic colon cancers were tested for MSI with five mononucleotide markers and methylation of the hMLH1 promoter. Slides were stained for thymidylate synthase (TS), p53, MDM2, p21(WAF1/CIP1), beta-catenin, vascular endothelial growth factor, hMLH1, hMSH2, and hMSH6. Tumors were regarded as having wild-type, functional p53 (Fp53) if reduced expression of p53 and positive MDM2 and p21(WAF1/CIP1) expressions were found.

RESULTS

Of the cases, 12.5% were MSI-H (at least two markers mutated). Of MSI-H cases, 83.3% were characterized by a complete loss of at least one of the mismatch repair proteins, in particular loss of hMLH1 by promoter hypermethylation. MSI-H colon cancers showed higher expression of TS compared with MSS (no mutated markers)/MSI-L (one mutated marker) colon cancers (66.6% for MSI-H versus 14.8% MSS/MSI-L; P < 0.0001); 20.8% of MSI-H cases showed high expression of the vascular endothelial growth factor, compared with 45.8% MSS/MSI-L colon cancers (P = 0.0005); 45.8% MSI-H cases had Fp53 compared 11.9% MSS/MSI-L cases (P < 0.0001).

CONCLUSIONS

About 12% of colon cancers display MSI mostly due to lack of hMLH1 resulting from promoter hypermethylation. These tumors have high expression of TS and retain fully functional p53 system. Thus, these data suggest why sporadic hMLH1-defective colon cancers often do not respond to 5-FU.

摘要

未标记

显示微卫星不稳定性（MSI）的结肠癌在临床上侵袭性较低。基于体外研究和近期临床数据，显示MSI的癌症对5-氟尿嘧啶（5-FU）无反应。MSI肿瘤在临床上侵袭性较低且对基于5-FU的治疗无反应的原因尚未完全阐明。

目的

我们研究生物分子标志物，试图解释MSI和非MSI结肠癌不同的临床行为和化疗反应。

实验设计

用五个单核苷酸标志物和hMLH1启动子甲基化检测192例散发性结肠癌的MSI。玻片用胸苷酸合成酶（TS）、p53、MDM2、p21（WAF1/CIP1）、β-连环蛋白、血管内皮生长因子、hMLH1、hMSH2和hMSH6染色。如果发现p53表达降低且MDM2和p21（WAF1/CIP1）表达阳性，则肿瘤被视为具有野生型功能性p53（Fp53）。

结果

病例中，12.5%为MSI-H（至少两个标志物突变）。在MSI-H病例中，83.3%的特征是至少一种错配修复蛋白完全缺失，特别是由于启动子高甲基化导致hMLH1缺失。与MSS（无突变标志物）/MSI-L（一个突变标志物）结肠癌相比，MSI-H结肠癌TS表达更高（MSI-H为66.6%，MSS/MSI-L为14.8%；P<0.0001）；20.8%的MSI-H病例显示血管内皮生长因子高表达，而MSS/MSI-L结肠癌为45.8%（P = 0.0005）；45.8%的MSI-H病例有Fp53，而MSS/MSI-L病例为11.9%（P<0.0001）。