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

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

doi:10.1158/1541-7786.MCR-23-0810

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

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 LuetchfordPatrick M. Lynch, Diantha Terlouw, Maartje Nielsen, Sarah Jane Walton, Andrew Latchford, Susan K. Clark, Julian R. Sampson, Eduardo Vilar, Laura E. Thomas^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

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.

Original language	English
Pages (from-to)	515-523
Number of pages	9
Journal	Molecular Cancer Research
Volume	22
Issue number	6
DOIs	https://doi.org/10.1158/1541-7786.MCR-23-0810
Publication status	Published - 4 Jun 2024
Externally published	Yes

Keywords

Adenomatous Polyposis Coli/genetics
Carcinogenesis/genetics
Duodenal Neoplasms/genetics
Female
Glycosylphosphatidylinositols/metabolism
Humans
Male
Membrane Proteins/genetics
Mutation

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10.1158/1541-7786.MCR-23-0810

Cite this

Meuser, E., Chang, K., Walters, A., Hurley, J. J., West, H. D., Perry, I., Mort, M., Reyes-Uribe, L., Truscott, R., Jones, N., Lawrence, R., Jenkins, G., Giles, P., Dolwani, S., Al-Sarireh, B., Hawkes, N., Short, E., Williams, G. T., Taggart, M. W., ... Thomas, L. E. (2024). PIGA Mutations and Glycosylphosphatidylinositol Anchor Dysregulation in Polyposis-Associated Duodenal Tumorigenesis. Molecular Cancer Research, 22(6), 515-523. https://doi.org/10.1158/1541-7786.MCR-23-0810

@article{193a722e2de24aad8b69d54c4a8a3dab,

title = "PIGA Mutations and Glycosylphosphatidylinositol Anchor Dysregulation in Polyposis-Associated Duodenal Tumorigenesis",

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 = "Adenomatous Polyposis Coli/genetics, Carcinogenesis/genetics, Duodenal Neoplasms/genetics, Female, Glycosylphosphatidylinositols/metabolism, Humans, Male, Membrane Proteins/genetics, Mutation",

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

note = "{\textcopyright}2024 The Authors; Published by the American Association for Cancer Research.",

year = "2024",

month = jun,

day = "4",

doi = "10.1158/1541-7786.MCR-23-0810",

language = "English",

volume = "22",

pages = "515--523",

journal = "Molecular Cancer Research",

issn = "1541-7786",

number = "6",

}

Meuser, E, Chang, K, Walters, A, Hurley, JJ, West, HD, Perry, I, Mort, M, Reyes-Uribe, L, Truscott, R, Jones, N, Lawrence, R, Jenkins, G, Giles, P, Dolwani, S, Al-Sarireh, B, Hawkes, N, Short, E, Williams, GT, Taggart, MW, Luetchford, K, Lynch, PM, Terlouw, D, Nielsen, M, Walton, SJ, Latchford, A, Clark, SK, Sampson, JR, Vilar, E & Thomas, LE 2024, 'PIGA Mutations and Glycosylphosphatidylinositol Anchor Dysregulation in Polyposis-Associated Duodenal Tumorigenesis', Molecular Cancer Research, vol. 22, no. 6, pp. 515-523. https://doi.org/10.1158/1541-7786.MCR-23-0810

TY - JOUR

T1 - PIGA Mutations and Glycosylphosphatidylinositol Anchor Dysregulation in Polyposis-Associated Duodenal Tumorigenesis

AU - Meuser, Elena

AU - Chang, Kyle

AU - Walters, Angharad

AU - Hurley, Joanna J.

AU - West, Hannah D.

AU - Perry, Iain

AU - Mort, Matthew

AU - Reyes-Uribe, Laura

AU - Truscott, Rebekah

AU - Jones, Nicholas

AU - Lawrence, Rachel

AU - Jenkins, Gareth

AU - Giles, Peter

AU - Dolwani, Sunil

AU - Al-Sarireh, Bilal

AU - Hawkes, Neil

AU - Short, Emma

AU - Williams, Geraint T.

AU - Taggart, Melissa W.

AU - Luetchford, Kim

AU - Lynch, Patrick M.

AU - Terlouw, Diantha

AU - Nielsen, Maartje

AU - Walton, Sarah Jane

AU - Latchford, Andrew

AU - Clark, Susan K.

AU - Sampson, Julian R.

AU - Vilar, Eduardo

AU - Thomas, Laura E.

PY - 2024/6/4

Y1 - 2024/6/4

N2 - 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.

AB - 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.

KW - Adenomatous Polyposis Coli/genetics

KW - Carcinogenesis/genetics

KW - Duodenal Neoplasms/genetics

KW - Female

KW - Glycosylphosphatidylinositols/metabolism

KW - Humans

KW - Male

KW - Membrane Proteins/genetics

KW - Mutation

UR - http://www.scopus.com/inward/record.url?scp=85195226815&partnerID=8YFLogxK

U2 - 10.1158/1541-7786.MCR-23-0810

DO - 10.1158/1541-7786.MCR-23-0810

M3 - Article

C2 - 38546397

AN - SCOPUS:85195226815

SN - 1541-7786

VL - 22

SP - 515

EP - 523

JO - Molecular Cancer Research

JF - Molecular Cancer Research

IS - 6

ER -

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

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Keywords

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