Division of Cancer and Genetics, School of Medicine, Cardiff University, United Kingdom.
Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Mol Cancer Res. 2024 Jun 4;22(6):515-523. doi: 10.1158/1541-7786.MCR-23-0810.
The pathogenesis of duodenal tumors in the inherited tumor syndromes familial adenomatous polyposis (FAP) and MUTYH-associated polyposis (MAP) is poorly understood. This study aimed to identify genes that are significantly mutated in these tumors and to explore the effects of these mutations. Whole exome and whole transcriptome sequencing identified recurrent somatic coding variants of phosphatidylinositol N-acetylglucosaminyltransferase subunit A (PIGA) in 19/70 (27%) FAP and MAP duodenal adenomas, and further confirmed the established driver roles for APC and KRAS. PIGA catalyzes the first step in glycosylphosphatidylinositol (GPI) anchor biosynthesis. Flow cytometry of PIGA-mutant adenoma-derived and CRISPR-edited duodenal organoids confirmed loss of GPI anchors in duodenal epithelial cells and transcriptional profiling of duodenal adenomas revealed transcriptional signatures associated with loss of PIGA.
PIGA somatic mutation in duodenal tumors from patients with FAP and MAP and loss of membrane GPI-anchors may present new opportunities for understanding and intervention in duodenal tumorigenesis.
家族性腺瘤性息肉病（FAP）和 MUTYH 相关息肉病（MAP）等遗传性肿瘤综合征中十二指肠肿瘤的发病机制尚不清楚。本研究旨在鉴定这些肿瘤中显著突变的基因，并探讨这些突变的影响。全外显子组和全转录组测序在 70 个 FAP 和 MAP 十二指肠腺瘤中的 19 个（27%）中鉴定出磷酸肌醇 N-乙酰氨基葡萄糖基转移酶亚基 A（PIGA）的反复体细胞编码变异，进一步证实了 APC 和 KRAS 的既定驱动作用。PIGA 催化糖基磷脂酰肌醇（GPI）锚生物合成的第一步。来自 PIGA 突变腺瘤的衍生和 CRISPR 编辑的十二指肠类器官的流式细胞术证实了十二指肠上皮细胞中 GPI 锚的丢失，并且对十二指肠腺瘤的转录谱分析揭示了与 PIGA 缺失相关的转录特征。
FAP 和 MAP 患者的十二指肠肿瘤中的 PIGA 体细胞突变和膜 GPI-锚的丢失可能为理解和干预十二指肠肿瘤发生提供新的机会。
