Point Mutations in Exon 1B of APC Reveal Gastric Adenocarcinoma and Proximal Polyposis of the Stomach as a Familial Adenomatous Polyposis Variant
Point Mutations in Exon 1B of APC Reveal Gastric Adenocarcinoma and Proximal Polyposis of the Stomach as a Familial Adenomatous Polyposis Variant
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DOI：
10.1016/j.ajhg.2016.03.001
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发表时间：
2016-05-05
影响因子：
9.8
通讯作者：
Chenevix-Trench, Georgia
中科院分区：
文献类型：
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作者：
Li, Jun;Woods, Susan L.;Chenevix-Trench, Georgia
胃腺癌和胃近端息肉病（GAPPS）是一种常染色体显性遗传的癌症易感综合征，具有显著的胃腺癌风险，但不具有结肠直肠腺癌风险。我们将该基因定位于5q22，并在受影响个体的胃底腺息肉中发现了5q野生型等位基因的缺失。全外显子组和全基因组测序未能发现致病突变，但通过桑格测序，我们确定了APC启动子1B的点突变，在所有六个家庭中与疾病共分离。在荧光素酶测定中，突变降低了YY1转录因子的结合，并损害了APC启动子1B的活性。对携带者的血液和唾液的分析显示APC的等位基因不平衡，表明这些突变导致体内等位基因特异性表达降低。APC启动子1B的类似突变发生在罕见的家族性腺瘤性息肉病（FAP）家族中。启动子1A在GAPPS、散发性FGPs和正常胃中均发生甲基化，提示1B转录本在胃粘膜中比1A转录本更重要。这可能解释了为什么所有已知的受GAP影响的家族都携带启动子1B点突变，但只有罕见的受FAP影响的家族携带类似的突变，结肠细胞通常受到1A同种型表达的保护。胃息肉病和癌症先前已经在一些FAP受影响的个体中描述，这些个体在启动子1B周围有大的缺失。我们发现GAPPS是由相同启动子的点突变引起的，这表明具有影响启动子1B的突变的家族具有胃腺癌的风险，无论是否存在结直肠息肉。
Gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS) is an autosomal-dominant cancer-predisposition syndrome with a significant risk of gastric, but not colorectal, adenocarcinoma. We mapped the gene to 5q22 and found loss of the wild-type allele on 5q in fundic gland polyps from affected individuals. Whole-exome and -genome sequencing failed to find causal mutations but, through Sanger sequencing, we identified point mutations in APC promoter 1B that co-segregated with disease in all six families. The mutations reduced binding of the YY1 transcription factor and impaired activity of the APC promoter 1B in luciferase assays. Analysis of blood and saliva from carriers showed allelic imbalance of APC, suggesting that these mutations lead to decreased allele-specific expression in vivo. Similar mutations in APC promoter 1B occur in rare families with familial adenomatous polyposis (FAP). Promoter 1A is methylated in GAPPS and sporadic FGPs and in normal stomach, which suggests that 1B transcripts are more important than 1A in gastric mucosa. This might explain why all known GAPPS-affected families carry promoter 1B point mutations but only rare FAP-affected families carry similar mutations, the colonic cells usually being protected by the expression of the 1A isoform. Gastric polyposis and cancer have been previously described in some FAP-affected individuals with large deletions around promoter 1B. Our finding that GAPPS is caused by point mutations in the same promoter suggests that families with mutations affecting the promoter 1B are at risk of gastric adenocarcinoma, regardless of whether or not colorectal polyps are present.