家族性腺瘤性息肉病 (FAP) 患者的种系 APC 突变可促进胃肠道息肉病，包括频繁形成胃底腺息肉 (FGP)。在这项研究中，我们研究了失调的 Wnt 信号传导如何促进 FGP 以及它们定位于胃体区域的原因。我们开发了 FGP 和 FAP 患者周围非息肉体活检和类器官的生物库，用于比较研究。息肉活检和息肉衍生的类器官表现出 Wnt 靶基因表达增强。具有本质上调的 Wnt 信号传导的息肉源性类器官对进一步诱导的耐受性较差，表明高 Wnt 限制了生长。靶向基因组测序表明，大多数胃息肉并不是由于 APC 杂合性缺失而产生的。对遗传小鼠模型的研究表明，杂合子 Apc 缺失会增加体部的上皮细胞增殖，但不会增加胃窦的上皮细胞增殖，而纯合子 Apc 缺失不会在体部维持，但会诱导胃窦的过度增殖。我们的研究结果表明，FAP 患者中的杂合 APC 突变可能足以驱动语料库区域息肉的形成，而随后进一步增强 Wnt 信号传导的杂合性丧失是不可接受的。这一发现表明，与胃窦中罕见的腺瘤性息肉相比，FAP 患者体内胃息肉的数量丰富但良性。

Germline APC mutation in familial adenomatous polyposis (FAP) patients promotes gastrointestinal polyposis, including the formation of frequent gastric fundic gland polyps (FGPs). In this study, we investigated how dysregulated Wnt signaling promotes FGPs and why they localize to the corpus region of the stomach. We developed a biobank of FGP and surrounding non-polyp corpus biopsies and organoids from FAP patients for comparative studies. Polyp biopsies and polyp-derived organoids exhibited enhanced Wnt target gene expression. Polyp-derived organoids with intrinsically upregulated Wnt signaling showed poor tolerance to further induction, suggesting that high Wnt restricts growth. Targeted genomic sequencing revealed that most gastric polyps did not arise via APC loss-of-heterozygosity. Studies in genetic mouse models demonstrated that heterozygous Apc loss increased epithelial cell proliferation in the corpus but not the antrum, while homozygous Apc loss was not maintained in the corpus yet induced hyperproliferation in antrum. Our findings suggest that heterozygous APC mutation in FAP patients may be sufficient to drive polyp formation in the corpus region while subsequent loss-of-heterozygosity to further enhance Wnt signaling is not tolerated. This finding contextualizes the abundant yet benign nature of gastric polyps in FAP patient corpus compared to the rare, yet adenomatous polyps in the antrum.