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PIGA Mutations and Glycosylphosphatidylinositol Anchor Dysregulation in Polyposis-Associated Duodenal Tumorigenesis
,
Kyle Chang ,
Angharad Walters ,
Joanna J. Hurley ,
Hannah D. West ,
Iain Perry ,
Matthew Mort ,
Laura Reyes-Uribe ,
Rebekah Truscott ,
Nick 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 Thomas
Molecular Cancer Research, Volume: 22, Issue: 6, Pages: 515 - 523
Swansea University Authors:
Iain Perry , Nick Jones , Gareth Jenkins , Laura Thomas
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DOI (Published version): 10.1158/1541-7786.mcr-23-0810
Abstract
The pathogenesis of duodenal tumors in the inherited tumor syndromes familial adenomatous polyposis (FAP) and MUTYHassociated 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 e...
| Published in: | Molecular Cancer Research |
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| ISSN: | 1541-7786 1557-3125 |
| Published: |
American Association for Cancer Research (AACR)
2024
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| Online Access: |
Check full text
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| URI: | https://cronfa.swan.ac.uk/Record/cronfa65964 |
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| Abstract: |
The pathogenesis of duodenal tumors in the inherited tumor syndromes familial adenomatous polyposis (FAP) and MUTYHassociated 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. |
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| Keywords: |
Duodenal tumors |
| College: |
Faculty of Medicine, Health and Life Sciences |
| Funders: |
Swansea University, HHS, National Institutes of Health (NIH), FUNDREF 10.13039/100000002, GRANT #(s) CA016672; HHS , National Institutes of Health (NIH), FUNDREF 10.13039/100000002, GRANT #(s) R25T CA057730; HHS, National Institutes of Health (NIH), FUNDREF
10.13039/100000002, GRANT #(s) R03CA176788; Health and Care Research Wales (HCRW), FUNDREF 10.13039/100012068, GRANT #(s) HF-14-10 |
| Issue: |
6 |
| Start Page: |
515 |
| End Page: |
523 |