Gebert J F, Dupon C, Kadmon M, Hahn M, Herfarth C, von Knebel Doeberitz M, Schackert H K
Chirurgische Universitätsklinik, Sektion Molekulare Diagnostik & Therapie, Heidelberg, Germany.
Ann Surg. 1999 Mar;229(3):350-61. doi: 10.1097/00000658-199903000-00008.
Using an interdisciplinary clinical and molecular approach, the authors identified APC germline mutations in families with familial adenomatous polyposis (FAP). Correlation of mutation site with disease manifestation and the impact of molecular data on clinical proceedings were examined.
Germline mutations in the APC gene predispose to FAP. Established and proposed genotype-phenotype correlations as well as the influence of mutation site on surgical procedures have been reported. The predictive value of APC mutation analysis for disease manifestation and therapeutic decision making needs to be investigated further.
One hundred twenty-three kindreds of the local FAP registry were included in this study. CHRPE phenotype was defined as at least one large characteristic lesion or a total of four lesions in both eyes. APC mutations were identified by protein truncation test and automated DNA sequencing from patient lymphocyte DNA and RNA.
APC germline mutations were identified in 85/123 families with FAP. They were located between codons 213 and 1581 of the APC gene and displayed distinct genotype-phenotype correlations. CHRPE status facilitated mutation analysis by discriminating regions of interest within the APC coding region. Severe manifestations of desmoids were restricted to mutations between codons 1444 through 1581. Whereas 91% (75/82) of at-risk persons were excluded as mutation carriers, APC germline mutations were detected before clinical examination in 9% (7/82) of at-risk persons. One patient agreed to endoscopy only after mutation detection.
This study supports the feasibility of combined molecular and clinical screening of families with FAP and may provide a guideline for routine presymptomatic molecular diagnostics in a clinical laboratory.
作者采用跨学科临床和分子方法，在家族性腺瘤性息肉病（FAP）家族中鉴定出APC基因种系突变。研究了突变位点与疾病表现的相关性以及分子数据对临床诊疗过程的影响。
APC基因的种系突变易导致FAP。已有关于既定和提出的基因型-表型相关性以及突变位点对手术程序影响的报道。APC突变分析对疾病表现和治疗决策的预测价值有待进一步研究。
本研究纳入了当地FAP登记处的123个家族。CHRPE表型定义为双眼至少有一个大的特征性病变或共有四个病变。通过蛋白质截短试验以及对患者淋巴细胞DNA和RNA进行自动DNA测序来鉴定APC突变。
在123个FAP家族中的85个家族中鉴定出APC种系突变。它们位于APC基因的第213至1581密码子之间，并显示出不同的基因型-表型相关性。CHRPE状态通过区分APC编码区内的感兴趣区域促进了突变分析。硬纤维瘤的严重表现仅限于第1444至1581密码子之间的突变。虽然91%（75/82）的高危人群被排除为突变携带者，但在9%（7/82）的高危人群中，在临床检查之前就检测到了APC种系突变。一名患者仅在检测到突变后才同意进行内镜检查。
本研究支持对FAP家族进行分子和临床联合筛查的可行性，并可为临床实验室的常规症状前分子诊断提供指导。
