Williams G T, Geraghty J M, Campbell F, Appleton M A, Williams E D
Department of Pathology, University of Wales College of Medicine, Heath Park, Cardiff, UK.
Br J Cancer. 1995 May;71(5):1077-80. doi: 10.1038/bjc.1995.208.
Hereditary non-polyposis colorectal cancer (HNPCC) has recently been linked to germline defects of DNA repair genes. Colorectal tumours in HNPCC frequently show DNA microsatellite instability, but it is not certain whether this mutator phenotype occurs throughout the morphologically normal colonic mucosa. We have previously used the mPAS histochemical technique in human colorectal mucosa to identify a polymorphism for O-acetyltransferase activity that shows monogenic inheritance and to show that crypt-restricted loss of O-acetyltransferase activity in heterozygotes is due to somatic mutation. We have now used this histochemical technique to measure the somatic mutation frequency in the uninvolved colon of 12 heterozygous patients with HNPCC, 15 with ileocaecal Crohn's disease and 16 with sporadic colorectal cancer (CRC). HNPCC patients showed a significant increase in mutation frequency with age (Mann-Whitney U, P = 0.02). In HNPCC patients aged < 49 years the mean stem cell mutation frequency was significantly lower than in the slightly younger group of patients with Crohn's disease (0.8 +/- 0.9 x 10(-4) vs 3.5 +/- 3.3 x 10(-4), P < 0.01), probably reflecting an increased mutation rate relating to chronic mucosal damage in Crohn's disease. Although not statistically significant, the stem cell mutation frequency was slightly less in HNPCC patients > 50 years than in sporadic CRC cases (4.9 +/- 3.4 x 10(-4) vs 5.9 +/- 3.6 x 10(-4), P > 0.5). We conclude that germline defects in HNPCC do not result in a generalised increase in liability to mutation in normal colonic mucosa but that a second, somatic, event is required. We postulate that this second event occurs in crypt stem cells at low frequency, giving rise to scattered individual crypts composed of mutation-prone cells. The cells in these crypts are then at high risk of acquiring the mutations that lead to adenomas, and to rapid progression to carcinoma.
遗传性非息肉病性结直肠癌（HNPCC）最近被认为与DNA修复基因的种系缺陷有关。HNPCC患者的结直肠肿瘤常表现出DNA微卫星不稳定性，但这种突变表型是否在形态学正常的结肠黏膜中普遍存在尚不确定。我们之前曾使用mPAS组织化学技术研究人类结直肠黏膜中O - 乙酰转移酶活性的多态性，该多态性呈单基因遗传，并表明杂合子中O - 乙酰转移酶活性的隐窝局限性缺失是由体细胞突变引起的。我们现在使用这种组织化学技术来测量12例HNPCC杂合子患者、15例回盲部克罗恩病患者和16例散发性结直肠癌（CRC）患者未受累结肠的体细胞突变频率。HNPCC患者的突变频率随年龄显著增加（Mann - Whitney U检验，P = 0.02）。在年龄小于49岁的HNPCC患者中，平均干细胞突变频率显著低于稍年轻的克罗恩病患者组（0.8±0.9×10⁻⁴ 对3.5±3.3×10⁻⁴，P < 0.01），这可能反映了克罗恩病中与慢性黏膜损伤相关的突变率增加。虽然无统计学意义，但年龄大于50岁的HNPCC患者的干细胞突变频率略低于散发性CRC病例（4.9±3.4×10⁻⁴ 对5.9±3.6×10⁻⁴，P > 0.5）。我们得出结论，HNPCC中的种系缺陷不会导致正常结肠黏膜中突变易感性普遍增加，而是需要第二个体细胞事件。我们推测这个第二个事件在隐窝干细胞中以低频率发生，产生由易突变细胞组成的散在单个隐窝。这些隐窝中的细胞随后极有可能获得导致腺瘤的突变，并迅速进展为癌。
