The APC variants I1307K and E1317Q are associated with colorectal tumors, but not always with a family history
The APC variants I1307K and E1317Q are associated with colorectal tumors, but not always with a family history
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DOI：
10.1073/pnas.95.18.10722
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发表时间：
1998-09-01
影响因子：
11.1
通讯作者：
Tomlinson, IPM
中科院分区：
文献类型：
--
作者：
Frayling, IM;Beck, NE;Tomlinson, IPM
经典家族性腺瘤性息肉病(FAP)是一种高显性常染色体显性遗传病，易患数百或数千例结直肠腺瘤和结直肠癌，其原因是APC基因的截短突变。FAP的一种变体是减少性腺瘤性息肉病结肠，它是由APC基因5‘和3’区域的胚系突变引起的。弱化腺瘤性结肠息肉病患者有“多个”结直肠腺瘤(通常少于100个)，没有典型的FAP的华丽表型。另一组患有多发性腺瘤的患者没有APC基因突变，他们的表型可能是由于基因组中其他一个或多个基因座的变异造成的。然而，最近，APC的一个错义变体(I1307K)被描述为在阿什肯纳兹姆增加了结直肠肿瘤(包括多发性腺瘤)的风险。我们对164例多发性结直肠腺瘤和/或癌患者进行了研究，并分析了APC基因1263-1377(外显子15G)的胚系变异。检测到三名携带I1307K等位基因的患者，每个患者都有德系血统。4名患者具有APC的胚系E1317Q错义变体，这在对照组中不存在；其中一名患者患有数量异常多的结肠直肠化生性息肉。越来越多的证据表明，存在APC基因的胚系变异，这些变异易导致多发性结直肠腺瘤和癌的发展，但没有经典FAP的华丽表型，可能对普通人群的结直肠癌风险具有重要意义。
Classical familial adenomatous polyposis (FAP) is a high-penetrance autosomal dominant disease that predisposes to hundreds or thousands of colorectal adenomas and carcinoma and that results from truncating mutations in the APC gene. A variant of FAP is attenuated adenomatous polyposis coli, which results from germ-line mutations in the 5' and 3' regions of the APC gene. Attenuated adenomatous polyposis coli patients have "multiple" colorectal adenomas (typically fewer than 100) without the florid phenotype of classical FAP. Another group of patients with multiple adenomas has no mutations in the APC gene, and their phenotype probably results from variation at a locus, or loci, elsewhere in the genome. Recently, however, a missense variant of APC (I1307K) was described that confers an increased risk of colorectal tumors, including multiple adenomas, in Ashkenazim. We have studied a set of 164 patients with multiple colorectal adenomas and/or carcinoma and analyzed codons 1263-1377 (exon 15G) of the APC gene for germ-line variants. Three patients with the I1307K allele were detected, each of Ashkenazi descent. Four patients had a germ-line E1317Q missense variant of APC that was not present in controls; one of these individuals had an unusually large number of metaplastic polyps of the colorectum. There is increasing evidence that there exist germ-line variants of the APC gene that predispose to the development of multiple colorectal adenomas and carcinoma, but without the florid phenotype of classical FAP, and possibly with importance for colorectal cancer risk in the general population.