GENETIC ALTERATIONS DURING COLORECTAL-TUMOR DEVELOPMENT
GENETIC ALTERATIONS DURING COLORECTAL-TUMOR DEVELOPMENT
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DOI：
10.1056/nejm198809013190901
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发表时间：
1988-09-01
影响因子：
158.5
通讯作者：
BOS, JL
中科院分区：
文献类型：
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作者：
VOGELSTEIN, B;FEARON, ER;BOS, JL
由于大多数结直肠癌似乎起源于腺瘤，因此对结直肠肿瘤不同阶段的研究可能有助于阐明肿瘤进展中的基因改变。我们在172例代表肿瘤发展不同阶段的结直肠肿瘤标本中寻找4种遗传改变（ras基因突变和5、17和18号染色体等位基因缺失）。标本包括7例家族性腺瘤性息肉病患者的40个早期腺瘤，33例非家族性息肉病患者的40个腺瘤（19个无癌灶，21个有癌灶），89例患者的92个癌切除。我们发现ras基因突变发生在58%的大于1 cm的腺瘤和47%的癌中。然而，ras基因突变仅见于9%的小于1厘米的腺瘤。5号染色体上与家族性腺瘤性息肉病基因相关的序列在息肉病患者的腺瘤中没有丢失，但在其他患者的腺瘤和癌中分别丢失了29%至35%。18号染色体的特定区域在癌（73%）和晚期腺瘤（47%）中经常缺失，但在早期腺瘤中仅偶尔缺失（11%至13%）。染色体17p序列通常仅在癌中丢失（75%）。这四种分子改变以阻止肿瘤临床进展的方式积累。 这些结果与结直肠肿瘤发生的模型一致，其中癌症发展所需的步骤通常涉及癌基因的突变激活以及通常抑制肿瘤发生的几个基因的丢失。
Because most colorectal carcinomas apepar to arise from adenomas, studies of different stages of colorectal neoplasia may shed light on the genetic alterations involved in tumor progression. We looked for four genetic alterations (ras-gene mutations and allelic deletions of chromosomes 5, 17, and 18) in 172 colorectal-tumor specimens representing various stages of neoplastic development. The specimens consisted of 40 predominantly early-stage adenomas from 7 patiens with familial adenomatous polyposis, 40 adenomas (19 without associated foci of carcinoma and 21 with such foci) from 33 patients without familial polyposis, and 92 carcinomas resected from 89 patients. We found that ras-gene mutations occurred in 58 percent of adenomas larger than 1 cm and in 47 percent of carcinomas. However, ras mutations were found in only 9 percent of adenomas under 1 cm in size. Sequences on chromosome 5 that are linked to the gene for familial adenomatous polyposis were not lost in adenomas from the patients with polyposis but were lost in 29 to 35 percent of adenomas and carcinomas, respectively, from other patients. A specific region of chromosome 18 was deleted frequently in carcinomas (73 percent) and in advanced adenomas (47 percent) but only occasionally in earlier-stage adenomas (11 to 13 percent). Chromosome 17p sequences were usually lost only in carcinomas (75 percent). The four molecular alterations accumulated in a fashion that paralleled the clinical progression of tumors. These results are consistent with a model of colorectal tumorigenesis in which the steps required for the development of cancer often involve the mutational activation of an oncogene coupled with the loss of several genes that normally suppress tumorigenesis.