PIGA Mutations and Glycosylphosphatidylinositol Anchor Dysregulation in Polyposis-Associated Duodenal Tumorigenesis.

IF 4.1 2区医学 Q2 CELL BIOLOGY Molecular Cancer Research Pub Date : 2024-06-04 DOI:10.1158/1541-7786.MCR-23-0810

Elena Meuser, Kyle Chang, Angharad Walters, Joanna J Hurley, Hannah D West, Iain Perry, Matthew Mort, Laura Reyes-Uribe, Rebekah Truscott, Nicholas Jones, Rachel Lawrence, Gareth Jenkins, Peter Giles, Sunil Dolwani, Bilal Al-Sarireh, Neil Hawkes, Emma Short, Geraint T Williams, Melissa W Taggart, Kim Luetchford, Patrick M Lynch, Diantha Terlouw, Maartje Nielsen, Sarah-Jane Walton, Andrew Latchford, Susan K Clark, Julian R Sampson, Eduardo Vilar, Laura E Thomas

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Abstract

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.

Implications: 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.

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息肉病相关十二指肠肿瘤发生过程中的 PIGA 基因突变和糖基磷脂酰肌醇锚失调。

人们对家族性腺瘤性息肉病（FAP）和MUTYH相关性息肉病（MAP）遗传性肿瘤综合征十二指肠肿瘤的发病机制知之甚少。本研究旨在确定这些肿瘤中发生重大突变的基因，并探讨这些突变的影响。全外显子组和全转录组测序在 19/70 例（27%）FAP 和 MAP 十二指肠腺瘤中发现了 PIGA 的复发性体细胞编码变异，并进一步证实了 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。PIGA突变腺瘤衍生和CRISPR编辑十二指肠器官组织的流式细胞术证实了十二指肠上皮细胞中GPI锚的缺失，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。影响：FAP和MAP患者十二指肠肿瘤中的PIGA体细胞突变以及膜GPI锚的缺失可能为了解和干预十二指肠肿瘤发生提供了新的机会。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Molecular Cancer Research 医学-细胞生物学

CiteScore

9.90

自引率

0.00%

发文量

280

审稿时长

4-8 weeks

期刊介绍： Molecular Cancer Research publishes articles describing novel basic cancer research discoveries of broad interest to the field. Studies must be of demonstrated significance, and the journal prioritizes analyses performed at the molecular and cellular level that reveal novel mechanistic insight into pathways and processes linked to cancer risk, development, and/or progression. Areas of emphasis include all cancer-associated pathways (including cell-cycle regulation; cell death; chromatin regulation; DNA damage and repair; gene and RNA regulation; genomics; oncogenes and tumor suppressors; signal transduction; and tumor microenvironment), in addition to studies describing new molecular mechanisms and interactions that support cancer phenotypes. For full consideration, primary research submissions must provide significant novel insight into existing pathway functions or address new hypotheses associated with cancer-relevant biologic questions.