Faculty, Staff and Student Publications
Publication Date
6-4-2024
Journal
Molecular Cancer Research
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.
Keywords
Female, Humans, Male, Adenomatous Polyposis Coli, Carcinogenesis, Duodenal Neoplasms, Glycosylphosphatidylinositols, Membrane Proteins, Mutation
DOI
10.1158/1541-7786.MCR-23-0810
PMID
38546397
PMCID
PMC11148540
PubMedCentral® Posted Date
3-28-2024
PubMedCentral® Full Text Version
Post-print
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Published Open-Access
yes
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