Chromosomal and microsatellite instability in colorectal cancer

CRC arises from the colorectal epithelium as a result of the accumulation of genetic alterations in defined oncogenes and tumour suppressor genes (TSG). Two major mechanisms of genomic instability have been identified in sporadic CRC progression. The first, known as chromosomal instability (CIN), results from a series of genetic changes that involve the activation of oncogenes such as K-ras and inactivation of TSG such as p53, DCC/Smad4, and APC. The second, known as microsatellite instability (MSI), results from inactivation of the DNA mismatch repair genes MLH1 and/or MSH2 by hypermethylation of their promoter, and secondary mutation of genes with coding microsatellites, such as transforming growth factor receptor II (TGF-RII) and BAX. Hereditary syndromes have germline mutations in specific genes (mutation in the tumour suppressor gene APC on chromosome 5q in FAP, mutated DNA mismatch repair genes in HNPCC). This pathway is based on information from [http://www.genome.jp/dbget-bin/www_bget?map05210 KEGG] The most common mutation in colon cancer is inactivation of APC. When APC does not have an inactivating mutation, frequently there are activating mutations in β-catenin. In order for cancer to develop, both alleles must be mutated. Mutations in APC or β-catenin must be followed by other mutations to become cancerous; however, in carriers of an APC inactivating mutations, the risk of colorectal cancer by age 40 is almost 100%. The impact of KRAS mutations is heavily dependent on the order of mutations. Primary KRAS mutations generally lead to a self-limiting hyperplastic or borderline lesion, but if they occur after a previous APC mutation it often progresses to cancer. KRAS mutation is predictive of a very poor response to panitumumab and cetuximab therapy in colorectal cancer. Currently, the most reliable way to predict whether a colorectal cancer patient will respond to one of the EGFR-inhibiting drugs is to test for certain “activating” mutations in the gene that encodes KRAS, which occurs in 30%–50% of colorectal cancers. Studies show patients whose tumors express the mutated version of the KRAS gene will not respond to cetuximab or panitumumab. Source: [https://en.wikipedia.org/wiki/KRAS#Colorectal_cancer Wikipedia] DCC can be considered a conditional tumor suppressor gene as well as a conditional oncogene. When DCC is present and not activated by netrin it is proapoptotic, and represses tumor formation. When DCC is present and netrin-activated it promotes cell survival, acting as an oncoprotein. One of the most frequent genetic abnormalities that occur in advanced colorectal cancer is loss of heterozygosity (LOH) of DCC in region 18q21. Source: [https://en.wikipedia.org/wiki/Deleted_in_Colorectal_Cancer Wikipedia] [https://www.ncbi.nlm.nih.gov/pubmed/25736321 de Miranda et al] suggest that TGFβ signaling remains active in some CRC cells with MSI mutations in the TGFBR2 gene, because the mutated gene still expresses a functional protein. Aberrant overexpression of cyclooxygenase-2 (COX-2) is thought to have an important role in development of CRC. The tumorigenic effects of COX-2 can be attributed to the production of PGE2; increased levels of PGE2 have been reported in colorectal adenomas as well as carcinomas. COX-2 and PGE2 regulate proliferation, survival, migration, and invasion in colorectal tumors. Source: [https://www.ncbi.nlm.nih.gov/pubmed/20420946 Pino et al]. Phosphorylation sites were added based on information from PhosphoSitePlus (R), www.phosphosite.org. Proteins on this pathway have targeted assays available via the [https://assays.cancer.gov/available_assays?wp_id=WP4216 CPTAC Assay Portal]

结直肠癌（CRC）起源于结直肠上皮细胞，是由于在特定的原癌基因和肿瘤抑制基因（TSG）中累积遗传变异所致。在散发性CRC的进展中，已识别出两种主要的基因组不稳定性机制。第一种被称为染色体不稳定性（CIN），是由于一系列涉及K-ras等原癌基因激活和p53、DCC/Smad4、APC等TSG失活的遗传变化。第二种被称为微卫星不稳定性（MSI），是由于DNA错配修复基因MLH1和/或MSH2的启动子发生高甲基化，导致其失活，以及编码微卫星基因（如转化生长因子受体II（TGF-RII）和BAX）的二次突变。遗传综合征具有特定基因的胚系突变（如FAP中5q染色体上肿瘤抑制基因APC的突变，HNPCC中DNA错配修复基因的突变）。此途径基于KEGG[http://www.genome.jp/dbget-bin/www_bget?map05210]的信息。结直肠癌中最常见的突变是APC的失活。当APC没有失活突变时，通常存在β-catenin的激活突变。为了癌症的发生，两个等位基因都必须发生突变。APC或β-catenin的突变必须随后发生其他突变才能成为癌症；然而，在APC失活突变携带者中，40岁前患结直肠癌的风险几乎达到100%。KRAS突变的影响高度依赖于突变顺序。初级KRAS突变通常导致自限性的增生或交界性病变，但如果它们发生在先前APC突变之后，往往进展为癌症。KRAS突变预示着结直肠癌对泛肽瘤单抗和西妥昔单抗治疗的极差反应。目前，预测结直肠癌患者是否对EGFR抑制药物之一有反应的最可靠方法是检测编码KRAS的基因中某些“激活”突变，这些突变在30%–50%的结直肠癌中发生。研究表明，肿瘤表达KRAS基因突变变异的患者不会对西妥昔单抗或泛肽瘤单抗产生反应。来源：[https://en.wikipedia.org/wiki/KRAS#Colorectal_cancer Wikipedia]。DCC可以被考虑为条件性肿瘤抑制基因以及条件性原癌基因。当DCC存在且未被netrin激活时，它具有促凋亡作用，并抑制肿瘤形成。当DCC存在且被netrin激活时，它促进细胞存活，作为原癌蛋白。在晚期结直肠癌中最常见的遗传异常之一是DCC在18q21区域中的杂合性丢失（LOH）。来源：[https://en.wikipedia.org/wiki/Deleted_in_Colorectal_Cancer Wikipedia]。[https://www.ncbi.nlm.nih.gov/pubmed/25736321 de Miranda等]提出，由于突变的基因仍然表达功能蛋白，因此TGFβ信号通路在某些MSI突变TGFBR2基因的CRC细胞中保持活跃。异常过表达环氧化酶-2（COX-2）被认为在CRC的发展中起着重要作用。COX-2的致瘤效应可以归因于PGE2的产生；据报道，PGE2的水平在结直肠腺瘤以及腺癌中均升高。COX-2和PGE2调节结直肠肿瘤的增殖、存活、迁移和侵袭。来源：[https://www.ncbi.nlm.nih.gov/pubmed/20420946 Pino等]。基于PhosphoSitePlus（R），www.phosphosite.org的信息，添加了磷酸化位点。该途径上的蛋白质有靶向检测方法，可通过[https://assays.cancer.gov/available_assays?wp_id=WP4216 CPTAC检测门户]获取。