Laurent-Puig P, Agostini J, Maley K
Université Paris-Descartes, UMR-S775, Pôle de Biologie, Hôpital Européen Georges-Pompidou AP-HP, Paris, France.
Bull Cancer. 2010 Nov;97(11):1311-21. doi: 10.1684/bdc.2010.1216.
Recent progress in the field of molecular biology has allowed us to identify at least two different molecular mechanisms implicated in colorectal carcinogenesis (CRC): chromosomal instability (CIN) and genetic instability. Even though the two molecular mechanisms differ, their signalling pathways, implicated in malignant transformation of colonic epithelial cells, appear to be similar. The most frequent group of CRC, which represents 80% of sporadic CRC, is characterized by allelic losses on the short arm of chromosome 17 and 8 and on the long arm of chromosome 5, 18 and 22. These allelic losses are associated with mutations in TP53, APC, SMAD2 and SMAD4 genes. All of these alterations are grouped under the phenotype CIN. A genetic instability termed MSI (microsatellite instability), which results from a mismatch repair (MMR) deficiency, appears in 12-15% of CRC cases. The presence of MMR deficiency leads to the accumulation of mutations in genes controlling cell cycle and apoptosis (TGFBRII, BAX or CASPASE5). More recently, the existence of a third phenotype was suggested. The main alteration associated with this group of tumors is the hypermethylation of the promoter region of numerous genes, leading to their inactivation. An activating mutation of BRAF is frequently associated with this phenotype. As described above, CRC shows genetic heterogeneity, however the consequences in terms of signalling pathway alterations are similar. For example, the activation of Wnt signalling pathways can result from the inactivation of the APC gene in the CIN phenotype or from an activating mutation in the β-catenin gene in MSI tumors. The inactivation of TGFβ pathways is also present in both tumor types and is driven by SMAD4, and more rarely by a SMAD2 inactivating mutation in CIN tumors, or by the existence of a frame-shift mutation occurring in a polyG coding track of the TGFβ (transforming growth factor) receptor type II in MSI tumors. The RAS-MAP kinase pathway is activated by KRAS mutations in CIN tumors or by BRAF mutations in MSI tumors. The p53 pathway is inactivated by TP53 inactivation in CIN tumors or by BAX inactivating mutations in MSI tumors.
分子生物学领域的最新进展使我们能够确定至少两种与结直肠癌发生（CRC）相关的不同分子机制：染色体不稳定性（CIN）和基因不稳定。尽管这两种分子机制有所不同，但它们参与结肠上皮细胞恶性转化的信号通路似乎相似。最常见的CRC类型占散发性CRC的80%，其特征是17号和8号染色体短臂以及5号、18号和22号染色体长臂上的等位基因缺失。这些等位基因缺失与TP53、APC、SMAD2和SMAD4基因的突变有关。所有这些改变都归为CIN表型。一种由错配修复（MMR）缺陷导致的基因不稳定，称为微卫星不稳定性（MSI），出现在12% - 15%的CRC病例中。MMR缺陷的存在会导致控制细胞周期和凋亡的基因（TGFBRII、BAX或CASPASE5）中突变的积累。最近，有人提出存在第三种表型。与这组肿瘤相关的主要改变是许多基因启动子区域的高甲基化，导致它们失活。BRAF的激活突变经常与这种表型相关。如上所述，CRC表现出基因异质性，然而在信号通路改变方面的后果是相似的。例如，Wnt信号通路的激活可由CIN表型中APC基因的失活引起，或由MSI肿瘤中β - 连环蛋白基因的激活突变引起。TGFβ通路的失活在两种肿瘤类型中也都存在，在CIN肿瘤中由SMAD4驱动，在CIN肿瘤中较少由SMAD2失活突变驱动，或在MSI肿瘤中由II型TGFβ（转化生长因子）受体的多聚G编码序列中的移码突变引起。RAS - MAP激酶通路在CIN肿瘤中由KRAS突变激活，在MSI肿瘤中由BRAF突变激活。p53通路在CIN肿瘤中由TP53失活失活，在MSI肿瘤中由BAX失活突变失活。
