PIGA mutations and glycosylphosphatidylinositol anchor dysregulation in polyposis-associated duodenal tumorigenesis

Meuser, Elena, Chang, Kyle, Walters, Angharad, Hurley, Joanna J., West, Hannah D. ORCID: https://orcid.org/0000-0002-6104-6534, Perry, Iain, Mort, Matthew, Reyes-Uribe, Laura, Truscott, Rebekah, Jones, Nicholas, Lawrence, Rachel, Jenkins, Gareth, Giles, Peter ORCID: https://orcid.org/0000-0003-3143-6854, Dolwani, Sunil ORCID: https://orcid.org/0000-0002-3113-5472, Al-Sarireh, Bilal, Hawkes, Neil, Short, Emma, Williams, Geraint T. ORCID: https://orcid.org/0000-0003-3768-9940, Taggart, Melissa W., Luetchford, Kim, Lynch, Patrick M., Terlouw, Diantha, Nielsen, Maartje, Walton, Sarah-Jane, Latchford, Andrew, Clark, Susan K., Sampson, Julian R. ORCID: https://orcid.org/0000-0002-2902-2348, Vilar, Eduardo and Thomas, Laura E. 2024. PIGA mutations and glycosylphosphatidylinositol anchor dysregulation in polyposis-associated duodenal tumorigenesis. Molecular Cancer Research 22 (6) , 515–523. 10.1158/1541-7786.MCR-23-0810

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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.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Medicine
Publisher:	American Association for Cancer Research
ISSN:	1541-7786
Date of First Compliant Deposit:	16 August 2024
Date of Acceptance:	26 March 2024
Last Modified:	19 Aug 2024 09:45
URI:	https://orca.cardiff.ac.uk/id/eprint/171443

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