Friedl W, Caspari R, Sengteller M, Uhlhaas S, Lamberti C, Jungck M, Kadmon M, Wolf M, Fahnenstich J, Gebert J, Möslein G, Mangold E, Propping P
Institute of Human Genetics, University of Bonn, Germany.
Gut. 2001 Apr;48(4):515-21. doi: 10.1136/gut.48.4.515.
In familial adenomatous polyposis (FAP), correlations between site of mutation in the adenomatous polyposis coli (APC) gene and severity of colonic polyposis or extracolonic manifestations are well known. While mutation analysis is important for predictive diagnosis in persons at risk, its relevance for clinical management of individual patients is open to question.
We examined 680 unrelated FAP families for germline mutations in the APC gene. Clinical information was obtained from 1256 patients.
APC mutations were detected in 48% (327/680) of families. Age at diagnosis of FAP based on bowel symptoms and age at diagnosis of colorectal cancer in untreated patients were used as indicators of the severity of the natural course of the disease. A germline mutation was detected in 230 of 404 patients who were diagnosed after onset of bowel symptoms (rectal bleeding, abdominal pain, diarrhoea). When these patients were grouped according to the different sites of mutations, mean values for age at onset of disease differed significantly: patients carrying APC mutations at codon 1309 showed a disease onset 10 years earlier (mean age 20 years) compared with patients with mutations between codons 168 and 1580 (except codon 1309) (mean age 30 years), whereas patients with mutations at the 5' end of codon 168 or the 3' end of codon 1580 were diagnosed at a mean age of 52 years. Within each group of patients however large phenotypic variation was observed, even among patients with identical germline mutations. A higher incidence of desmoids was found in patients with mutations between codons 1445 and 1580 compared with mutations at other sites, while no correlation between site of mutation and presence of duodenal adenomas was observed.
As age at manifestation and course of the disease may be rather variable, even in carriers of identical germline mutations, therapeutic decisions should be based on colonoscopic findings in individual patients rather than on the site of mutation. However, in patients with mutations within codons 1445-1580, it may be advisable to postpone elective colectomy because desmoids may arise through surgical intervention.
在家族性腺瘤性息肉病（FAP）中，腺瘤性息肉病 coli（APC）基因的突变位点与结肠息肉病的严重程度或结肠外表现之间的相关性是众所周知的。虽然突变分析对于有风险人群的预测性诊断很重要，但其对个体患者临床管理的相关性仍存在疑问。
我们对680个无亲缘关系的FAP家族进行了APC基因的种系突变检测。从1256例患者中获取了临床信息。
在48%（327/680）的家族中检测到APC突变。基于肠道症状诊断FAP的年龄以及未治疗患者诊断结直肠癌的年龄被用作疾病自然病程严重程度的指标。在404例出现肠道症状（直肠出血、腹痛、腹泻）后被诊断的患者中，有230例检测到种系突变。当这些患者根据不同的突变位点进行分组时，疾病发病年龄的平均值差异显著：与密码子168至1580之间（除密码子1309外）发生突变的患者（平均年龄30岁）相比，密码子1309处发生APC突变的患者疾病发病早10年（平均年龄20岁），而密码子168的5'端或密码子1580的3'端发生突变的患者诊断时的平均年龄为52岁。然而，在每组患者中，即使是具有相同种系突变的患者之间也观察到了较大的表型变异。与其他位点的突变相比，密码子1445至1580之间发生突变的患者中硬纤维瘤的发生率更高，而未观察到突变位点与十二指肠腺瘤的存在之间存在相关性。
由于疾病的表现年龄和病程可能差异很大，即使是相同种系突变的携带者，治疗决策也应基于个体患者的结肠镜检查结果，而不是突变位点。然而，对于密码子1445 - 1580之间发生突变的患者，推迟择期结肠切除术可能是明智的，因为手术干预可能会引发硬纤维瘤。
