Somatic APC mosalicism:: A frequent cause of familial adenomatous polyposis (FAP)
Somatic APC mosalicism:: A frequent cause of familial adenomatous polyposis (FAP)
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DOI：
10.1002/humu.20549
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发表时间：
2007-10-01
期刊：
影响因子：
3.9
通讯作者：
Friedl, Waltraut
中科院分区：
文献类型：
--
作者：
Aretz, Stefan;Stienen, Dietlinde;Friedl, Waltraut
体细胞突变嵌合体对分子和临床诊断都是一个挑战，并可能导致与预测的基因型-表型相关性的偏差。在对1248例家族性腺瘤性息肉病(FAP)患者进行APC突变筛查的过程中，我们确定了75例假定或确认为新基因突变的患者。预筛选方法(蛋白质截断试验[PTT]，DHPLC)提示8例(11%)存在体细胞嵌合体。对相应片段的测序显示了非常弱的突变信号，表明存在低水平的无义突变或移码突变。所有突变通过快照分析得到确认和量化：8例患者的白细胞DNA中，嵌合体比例在5.5%到77%之间，而从各自患者的腺瘤中提取的DNA中的突变比例一直较高。这8个被确认为马赛克的突变位于A-PC基因的216-1464密码子内。根据已知的基因-表型相关性，该区域突变的患者表现为典型或严重，然而，8名患者中有6名患者表现为减弱或不典型的息肉表型。我们的数据表明，在一小部分FAP患者中，由于弱信号或仅限于血液以外组织的体细胞嵌合体，可能无法检测到致病的APC突变。快照分析被证明是确认低水平突变和评估嵌合体程度的一种简单、快速和可靠的方法。FAP中与预期表型的一些偏差可以用体细胞嵌合体的存在来解释。
Somatic mutational mosaicism presents a challenge for both molecular and clinical diagnostics and may contribute to deviations from predicted genotype-phenotype correlations. During APC mutation screening in 1,248 unrelated patients with familial adenomatous polyposis (FAP), we identified 75 cases with an assumed or confirmed de novo mutation. Prescreening methods (protein truncation test [PTT], DHPLC) indicated the presence of somatic mosaicism in eight cases (11%). Sequencing of the corresponding fragments revealed very weak mutation signals, pointing to the presence of either nonsense or frameshift mutations at low level. All mutations were confirmed and quantified by SNaPshot analysis: in leukocyte DNA from the eight patients, the percentage of mosaicism varied between 5.5% and 77%, while the proportion of the mutation in DNA extracted from adenomas of the respective patient was consistently higher. The eight mutations identified as mosaic are localized within codons 216-1464 of the A-PC gene. According to the known genotype-phenotype correlation, patients with mutations in this region exhibit typical or severe FAR However, six of the eight patients presented with an attenuated or atypical polyposis phenotype. Our data demonstrate that in a fraction of FAP patients the causative APC mutation may not be detected due to weak signals or somatic mosaicism that is restricted to tissues other than blood. SNaPshot analysis was proven to be an easy, rapid, and reliable method of confirming low,level mutations and evaluating the degree of mosaicism. Some of the deviations from the expected phenotype in FAP can be explained by the presence of somatic mosaicism.