Variability in the severity of colonic disease in familial adenomatous polyposis results from differences in tumour initiation rather than progression and depends relatively little on patient age

Introduction-As large scale genetic analysis becomes increasingly efficient , attention is turning to problems arising from inaccurate measurement of t he phenotype. We have investigated the underlying basis of variation in dis ease 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. Methods-We examined the ratio of adenomas to crypts from microscopic slides taken from all parts of the colon of 44 resected FAP specimens. These find ings were compared with a carefully reported macroscopic polyp count. Age d ependency of adenoma counts (in the period around colectomy) was also analy sed. Results-The adenoma:crypt ratio strongly correlated with reported macroscop ic polyp count (r=0.82, p <0.001) with no significant residual variation. P olyp density measured using the adenoma: crypt ratio did not vary significa ntly within an individual colon. Apparent visible variation in polyp densit y within any colon was not found at the microscopic level. There was no det ectable age related increase in macroscopic adenoma count between siblings over the age range at which colectomies were performed. Discussion-The severity of colonic polyposis in FAP can be determined accur ately by counting the adenoma:crypt ratio in sections derived from stored t issue blocks. Variation between patients-dependent on APC genotype and, pro bably, modifier genes-is manifest at both the microscopic and macroscopic l evels. Thus variation in disease severity is more likely to result from dif ferent rates of tumour initiation than from differences in progression of m icroadenomas to macroscopic tumours. The absence of a detectable relationsh ip between adenoma number and age (over the range studied) suggests that mo st tumours may be initiated relatively early in the patient's life, perhaps at a time of particular susceptibility.