Vogelstein B, Fearon E R, Hamilton S R, Kern S E, Preisinger A C, Leppert M, Nakamura Y, White R, Smits A M, Bos J L
Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD.
N Engl J Med. 1988 Sep 1;319(9):525-32. doi: 10.1056/NEJM198809013190901.
Because most colorectal carcinomas appear 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 patients 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.
由于大多数结直肠癌似乎起源于腺瘤，因此对结直肠肿瘤形成不同阶段的研究可能会揭示肿瘤进展过程中涉及的基因改变。我们在172份代表肿瘤发生不同阶段的结直肠肿瘤标本中寻找四种基因改变（ras基因突变以及5号、17号和18号染色体的等位基因缺失）。这些标本包括来自7例家族性腺瘤性息肉病患者的40份主要为早期腺瘤、来自33例无家族性息肉病患者的40份腺瘤（19份无相关癌灶，21份有相关癌灶）以及从89例患者切除的92份癌组织。我们发现，大于1 cm的腺瘤中有58%发生ras基因突变，癌组织中有47%发生该突变。然而，在直径小于1 cm的腺瘤中仅9%发现有ras基因突变。与家族性腺瘤性息肉病基因相关的5号染色体序列在息肉病患者的腺瘤中未丢失，但在其他患者的腺瘤和癌组织中分别有29%至35%发生丢失。18号染色体的一个特定区域在癌组织（73%）和晚期腺瘤（47%）中频繁缺失，但在早期腺瘤中仅偶尔缺失（11%至13%）。17号染色体短臂序列通常仅在癌组织中丢失（75%）。这四种分子改变的积累方式与肿瘤的临床进展平行。这些结果与结直肠癌发生模型一致，即癌症发生所需的步骤通常涉及癌基因的突变激活以及几个正常情况下抑制肿瘤发生的基因的丢失。
