Laurent-Puig P, Blons H, Cugnenc P H
Laboratoire de Toxicologie Moléculaire, INSERM U490, Paris, France.
Eur J Cancer Prev. 1999 Dec;8 Suppl 1:S39-47.
Intensive screening for genetic alteration in colorectal cancer led to the identification of two types of colorectal tumours that are distinct by their carcinogenesis processes. The first group, named LOH (for loss of heterozygosity)-positive, is characterized by hyperploidy and allelic losses involving preferentially chromosome 18q and chromosome 17p. More than two-thirds of colorectal cancers belong to this group. The second group, called multiple microsatellite loci (MSI)-positive cancers, is characterized by genetic instability at microsatellite loci. Although colorectal cancer cells are characterized by specific microsatellite alterations, the same four different signalling pathways, WNT/Wingless pathway, K-ras pathway, transforming growth factor (TGF)beta pathway and p53 pathway, could be implicated in tumour progression. The WNT/Wingless pathway could be altered in two different ways according to whether the cancer cells belong to the group of LOH-positive or MSI-positive tumours. LOH-positive tumours activate the WNT/Wingless signalling pathway through an adenomatous polyposis coli (APC) mutation, whereas the MSI-positive tumours activate this pathway through a beta-catenin stabilizing mutation. Beta-catenin and APC mutations were observed as early as the adenomatous stage of colorectal neoplasia. In TGFbeta pathways LOH-positive tumours inactivated SMAD2 (similar to mother against decapentaplegic drosophilia) or SMAD4, whereas in MSI-positive tumours the TGFbeta type II receptor is frequently deleted. Alteration of these genes correlated closely with the progression of the adenoma to cancer. In the p53 pathway LOH-positive tumours showed frequent p53 mutation, whereas MSI-positive tumours demonstrated BAX (BCL-2-associated X protein)-inactivating mutation. These alterations contribute to the adenoma-carcinoma transition.
对结直肠癌基因改变进行的深入筛查，使得两种在致癌过程上存在差异的结直肠肿瘤得以被识别。第一组被命名为杂合性缺失（LOH）阳性，其特征为超倍体以及优先涉及18号染色体长臂和17号染色体短臂的等位基因缺失。超过三分之二的结直肠癌属于这一组。第二组被称为多个微卫星位点（MSI）阳性癌症，其特征是微卫星位点的基因不稳定。尽管结直肠癌细胞具有特定的微卫星改变，但相同的四种不同信号通路，即WNT/无翅通路、K-ras通路、转化生长因子（TGF）β通路和p53通路，可能与肿瘤进展有关。根据癌细胞属于LOH阳性还是MSI阳性肿瘤组，WNT/无翅通路可能会以两种不同方式发生改变。LOH阳性肿瘤通过腺瘤性息肉病 coli（APC）突变激活WNT/无翅信号通路，而MSI阳性肿瘤则通过β-连环蛋白稳定突变激活该通路。早在结直肠肿瘤的腺瘤阶段就观察到了β-连环蛋白和APC突变。在TGFβ通路中，LOH阳性肿瘤使SMAD2（类似于果蝇中与脱尾蛋白拮抗的母体蛋白）或SMAD4失活，而在MSI阳性肿瘤中，TGFβ II型受体经常缺失。这些基因的改变与腺瘤向癌症的进展密切相关。在p53通路中，LOH阳性肿瘤显示出频繁的p53突变，而MSI阳性肿瘤则表现出BAX（BCL-2相关X蛋白）失活突变。这些改变促成了腺瘤-癌转变。
