Campbell F, Geraghty J M, Appleton M A, Williams E D, Williams G T
Department of Pathology, University of Wales College of Medicine, Cardiff, United Kingdom.
Hum Pathol. 1998 Dec;29(12):1531-5. doi: 10.1016/s0046-8177(98)90026-0.
Colorectal tumorigenesis in familial adenomatous polyposis (FAP) results from somatic mutation of either the normal APC allele or another growth control gene in epithelial cells bearing a germline APC defect. The rate at which tumors develop is therefore dependent on the somatic mutation frequency; it is not known whether this is normal or elevated in FAP. We aimed to quantify stem cell somatic mutation in FAP, comparing it with hereditary nonpolyposis colorectal cancer (HNPCC) and Crohn's disease (CD). Stem cell somatic mutation frequency was studied in 47 FAP patients, 5 HNPCC patients, and 13 CD patients, all younger than 49 years, by quantifying crypt-restricted loss of O-acetyltransferase activity in sections of morphologically normal colonic mucosa from individuals heterozygous for this monogenically inherited polymorphism. Median stem cell somatic mutation frequency was significantly higher in FAP than HNPCC (4.2 x 10(-4) v 1.4 x 10(-4), Mann-Whitney U, P < .02). The level in CD (4.0 x 10(-4)) was similar to FAP. Mutated crypts occurred in groups more frequently in FAP (22%) than HNPCC (12%) or CD (10%), suggesting an increase in stem cell division associated with crypt fission in FAP. We conclude that stem cell somatic mutation frequency is raised in non-neoplastic colorectal mucosa in FAP. This is probably related to increased stem cell proliferation and contributes to the high rate of tumor formation in this condition.
家族性腺瘤性息肉病（FAP）中的结直肠癌发生是由于携带种系APC缺陷的上皮细胞中正常APC等位基因或另一个生长控制基因发生体细胞突变所致。因此，肿瘤发生的速率取决于体细胞突变频率；目前尚不清楚在FAP中该频率是正常还是升高。我们旨在量化FAP中的干细胞体细胞突变，并将其与遗传性非息肉病性结直肠癌（HNPCC）和克罗恩病（CD）进行比较。通过量化来自该单基因遗传多态性杂合个体的形态学正常结肠黏膜切片中隐窝限制性O-乙酰转移酶活性的丧失，研究了47例FAP患者、5例HNPCC患者和13例CD患者（均小于49岁）的干细胞体细胞突变频率。FAP患者的干细胞体细胞突变频率中位数显著高于HNPCC（4.2×10⁻⁴对1.4×10⁻⁴，Mann-Whitney U检验，P＜0.02）。CD患者的水平（4.0×10⁻⁴）与FAP相似。FAP中突变隐窝成组出现的频率（22%）高于HNPCC（12%）或CD（10%），提示FAP中与隐窝裂变相关的干细胞分裂增加。我们得出结论，FAP中非肿瘤性结直肠黏膜中的干细胞体细胞突变频率升高。这可能与干细胞增殖增加有关，并导致这种情况下肿瘤形成的高发生率。
