Crabtree M D, Tomlinson I P, Talbot I C, Phillips R K
Molecular and Population Genetics Laboratory, Imperial Cancer Research Fund, 44 Lincoln's Inn Fields, London WC2A 3PX, UK.
Gut. 2001 Oct;49(4):540-3. doi: 10.1136/gut.49.4.540.
As large scale genetic analysis becomes increasingly efficient, attention is turning to problems arising from inaccurate measurement of the phenotype. We have investigated the underlying basis of variation in disease severity in the large intestine of familial adenomatous polyposis (FAP) patients. The development of objective and reproducible measures may have future use in genetic studies, such as analysis of modifier genes.
We examined the ratio of adenomas to crypts from microscopic slides taken from all parts of the colon of 44 resected FAP specimens. These findings were compared with a carefully reported macroscopic polyp count. Age dependency of adenoma counts (in the period around colectomy) was also analysed.
The adenoma:crypt ratio strongly correlated with reported macroscopic polyp count (r=0.82, p<0.001) with no significant residual variation. Polyp density measured using the adenoma: crypt ratio did not vary significantly within an individual colon. Apparent visible variation in polyp density within any colon was not found at the microscopic level. There was no detectable age related increase in macroscopic adenoma count between siblings over the age range at which colectomies were performed.
The severity of colonic polyposis in FAP can be determined accurately by counting the adenoma:crypt ratio in sections derived from stored tissue blocks. Variation between patients-dependent on APC genotype and, probably, modifier genes-is manifest at both the microscopic and macroscopic levels. Thus variation in disease severity is more likely to result from different rates of tumour initiation than from differences in progression of microadenomas to macroscopic tumours. The absence of a detectable relationship between adenoma number and age (over the range studied) suggests that most tumours may be initiated relatively early in the patient's life, perhaps at a time of particular susceptibility.
随着大规模基因分析变得越来越高效，人们的注意力正转向因表型测量不准确而产生的问题。我们研究了家族性腺瘤性息肉病（FAP）患者大肠疾病严重程度变异的潜在基础。客观且可重复测量方法的开发可能在未来的基因研究中有用，比如对修饰基因的分析。
我们检查了从44个切除的FAP标本的结肠各部位所取显微切片上腺瘤与隐窝的比例。将这些结果与详细报告的宏观息肉计数进行比较。还分析了（在结肠切除术前后这段时间内）腺瘤计数的年龄依赖性。
腺瘤与隐窝的比例与报告的宏观息肉计数密切相关（r = 0.82，p < 0.001），且无显著的残余变异。使用腺瘤与隐窝比例测量的息肉密度在单个结肠内无显著变化。在显微镜水平未发现任何结肠内息肉密度有明显可见的变化。在进行结肠切除术的年龄范围内，兄弟姐妹之间宏观腺瘤计数未发现与年龄相关的可检测到的增加。
FAP患者结肠息肉病的严重程度可通过计算来自储存组织块切片中的腺瘤与隐窝比例准确确定。患者之间的变异——取决于APC基因型以及可能的修饰基因——在微观和宏观层面均有体现。因此，疾病严重程度的变异更可能是由不同的肿瘤起始率导致的，而非微腺瘤进展为宏观肿瘤过程中的差异。腺瘤数量与年龄之间（在所研究的范围内）未发现可检测到的关系，这表明大多数肿瘤可能在患者生命相对早期发生，也许是在特别易患的时期。
