Genetic pathways in the evolution of morphologically distinct colorectal neoplasms.
Genetic pathways in the evolution of morphologically distinct colorectal neoplasms.
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发表时间：
2001-03
期刊：
影响因子：
11.2
通讯作者：
M. Yashiro;J. Carethers;L. Laghi;Koji Saito;P. Slezak;E. Jaramillo;C. Rubio;Koichi Koizumi;K. Hirakawa;C. Boland
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作者：
M. Yashiro;J. Carethers;L. Laghi;Koji Saito;P. Slezak;E. Jaramillo;C. Rubio;Koichi Koizumi;K. Hirakawa;C. Boland
结直肠腺瘤在形态上可分为外生型和扁平型。息肉样癌和新生癌（即，没有任何腺瘤成分）可能分别是外生性腺瘤和扁平腺瘤遗传进展的结果。在这项研究中，我们检查了94个形态学不同的肿瘤标本中的K-RAS突变，并分析了与肿瘤抑制基因APC，p53，DCC/SMAD 4，hMSH 2和hMLH 1紧密连锁的10个微卫星位点。K-RAS突变与外生性腺瘤[11/21（52%）]显著相关，与扁平腺瘤[2/13（15%），P < 0.03]和息肉样癌[17/25（68%）]显著相关，与新发癌[7/25（28%），P < 0.01]显著相关。两个息肉样癌病例分别显示了三个和四个不同的K-RAS突变，表明多个克隆扩张区域。原发性癌症与染色体3 p杂合性缺失（洛）显著相关，而多形癌与之相比[6/18（33%）vs 1/20（5%，P < 0.03]，而染色体2 p、5 q、17 p和18 q的洛和微卫星不稳定性的患病率在两组之间没有差异。在所有癌症中，染色体17 p和18 q的洛缺失分别占47%和51%。然而，17 p和18 q的洛缺失分别发生在0和16%的良性病变，这表明它们在恶性转化中的作用。外生型和扁平型病斑在染色体17 p和18 q处的洛缺失无差异。这些研究结果表明：（a）突变型K-RAS与结肠肿瘤的外生性生长有关，（b）一些从头发生的结直肠癌在其进化过程中丢失了染色体3 p，这在息肉样癌中没有观察到。（B）一些从头发生的结直肠癌在其进化过程中丢失了染色体3 p，这在息肉样癌中没有观察到。如前所述，无论形态如何，所有癌症中有一半在良性病变的恶性转化处或附近丢失染色体17 p和18 q。结直肠癌的形成可能有一个以上的遗传途径，这与形态学特征相关。
Colorectal adenomas can be morphologically classified as exophytic or flat. Polypoid cancers and cancers arising de novo (ie., without any adenomatous component) might be the results of genetic progression from exophytic and flat adenomas, respectively. In this study, we examined 94 morphologically distinct neoplastic specimens for mutations in K-RAS and analyzed 10 microsatellite loci tightly linked to the tumor suppressor genes APC, p53, DCC/SMAD4, hMSH2, and hMLH1. K-RAS mutations were significantly associated with exophytic adenomas [11 of 21 (52%)] compared to flat adenomas [2 of 13(15%), P < 0.03] and polypoid cancers [17 of 25 (68%)] compared to cancers arising de novo [7 of 25 (28%), P < 0.01]. Two polypoid cancer cases demonstrated three and four different K-RAS mutations, respectively, suggesting multiple areas of clonal expansion. Cancers arising de novo were significantly associated with loss of heterozygosity (LOH) at chromosome 3p compared to pol ypoid cancers [6 of 18(33%) versus 1 of 20(5%), P < 0.03], whereas the prevalence of LOH at chromosomes 2p, 5q, 17p, and 18q and microsatellite instability were not different between the groups. For all cancers, LOH at chromosomes 17p and 18q occurred in 47 and 51%, respectively. However, LOH at 17p and 18q occurred in 0 and 16% of benign lesions, respectively, suggesting their role in malignant transformation. There was no difference in LOH at chromosomes 17p and 18q between exophytic and flat lesions. These findings suggest that (a) mutant K-RAS is associated with the exophytic growth of colonic neoplasms, and that (b) some colorectal cancers arising de novo lose chromosome 3p during their evolution, which is not seen in polypoid cancers. Half of all cancers lose chromosomes 17p and 18q at or near the malignant transition of benign lesions as reported previously, irrespective of morphology. There may be more than one genetic avenue for colorectal cancer formation, and this correlates with the morphological characteristics.