Brentnall T A, Crispin D A, Rabinovitch P S, Haggitt R C, Rubin C E, Stevens A C, Burmer G C
Division of Gastroenterology, University of Washington School of Medicine, Seattle.
Gastroenterology. 1994 Aug;107(2):369-78. doi: 10.1016/0016-5085(94)90161-9.
BACKGROUND/AIMS: In long-term extensive ulcerative colitis, aneuploidy occurs earlier and loss of heterozygosity for p53 (p53 LOH) later during histological progression towards carcinoma. This study determined the time of onset of p53 mutation in this progression.
We developed a rapid, sensitive screening assay for p53 mutations at codon 248. The geographic distribution of this p53 mutation was mapped in two fresh colectomy specimens with mutations of codon 248 (1 cancer, 1 dysplasia) and correlated with patterns of clonal expansion, histological progression, and allelic loss. Numerous samples from throughout both colons were analyzed (216 for histology, 142 for DNA content, 104 for mutation, and 41 for p53 LOH).
p53 mutation correlated highly with histological grade and was distributed more extensively than p53 LOH. Mutation, but not LOH, was also found in diploid, nondysplastic colonic mucosa adjacent to dysplastic areas.
These findings suggest that p53 mutation appears to be an early genetic event that precedes p53 LOH. The very close correlation of p53 mutation with aneuploidy (P > 0.0001) emphasizes the role of normal p53 at the G1 checkpoint to help prevent entry of genetically damaged cells into the cell cycle.
背景/目的：在长期广泛性溃疡性结肠炎中，非整倍体出现较早，而在向癌组织学进展过程中，p53基因杂合性缺失（p53 LOH）出现较晚。本研究确定了该进展过程中p53突变的起始时间。
我们开发了一种快速、灵敏的检测方法，用于筛查第248密码子处的p53突变。在两个第248密码子发生突变的新鲜结肠切除标本（1例癌组织，1例发育异常组织）中绘制该p53突变的地理分布图，并将其与克隆扩增模式、组织学进展及等位基因缺失情况相关联。对整个结肠的大量样本进行了分析（216份用于组织学分析，142份用于DNA含量分析，104份用于突变检测，41份用于p53 LOH检测）。
p53突变与组织学分级高度相关，且分布比p53 LOH更广泛。在发育异常区域相邻的二倍体、无发育异常的结肠黏膜中也发现了突变，但未发现LOH。
这些发现表明，p53突变似乎是p53 LOH之前的一个早期遗传事件。p53突变与非整倍体的密切相关性（P > 0.0001）强调了正常p53在G1期检查点的作用，有助于防止基因受损细胞进入细胞周期。
