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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 ,
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
,
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 |
|---|---|
| ISSN: | 1541-7786 1557-3125 |
| Published: |
American Association for Cancer Research (AACR)
2024
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| Online Access: |
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| URI: | https://cronfa.swan.ac.uk/Record/cronfa65964 |
| first_indexed |
2024-04-05T14:40:40Z |
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| last_indexed |
2024-11-25T14:17:12Z |
| id |
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10.13039/100000002, GRANT #(s) R03CA176788; Health and Care Research Wales (HCRW), FUNDREF 10.13039/100012068, GRANT #(s) HF-14-10</funders><projectreference/><lastEdited>2024-10-17T15:26:18.5791259</lastEdited><Created>2024-04-04T11:34:53.8400549</Created><path><level id="1">Faculty of Medicine, Health and Life Sciences</level><level id="2">Swansea University Medical School - Biomedical Science</level></path><authors><author><firstname>Elena</firstname><surname>Meuser</surname><orcid>0000-0002-3308-8577</orcid><order>1</order></author><author><firstname>Kyle</firstname><surname>Chang</surname><orcid>0000-0001-5295-9676</orcid><order>2</order></author><author><firstname>Angharad</firstname><surname>Walters</surname><orcid>0009-0007-6056-1482</orcid><order>3</order></author><author><firstname>Joanna J.</firstname><surname>Hurley</surname><orcid>0009-0005-1422-0463</orcid><order>4</order></author><author><firstname>Hannah D.</firstname><surname>West</surname><orcid>0000-0002-6104-6534</orcid><order>5</order></author><author><firstname>Iain</firstname><surname>Perry</surname><orcid>0000-0001-8530-4086</orcid><order>6</order></author><author><firstname>Matthew</firstname><surname>Mort</surname><orcid>0000-0002-3986-0935</orcid><order>7</order></author><author><firstname>Laura</firstname><surname>Reyes-Uribe</surname><orcid>0000-0001-6091-6705</orcid><order>8</order></author><author><firstname>Rebekah</firstname><surname>Truscott</surname><orcid>0000-0002-2187-8571</orcid><order>9</order></author><author><firstname>Nick</firstname><surname>Jones</surname><orcid>0000-0003-4846-5117</orcid><order>10</order></author><author><firstname>Rachel</firstname><surname>Lawrence</surname><orcid>0000-0002-1023-5220</orcid><order>11</order></author><author><firstname>Gareth</firstname><surname>Jenkins</surname><orcid>0000-0002-5437-8389</orcid><order>12</order></author><author><firstname>Peter</firstname><surname>Giles</surname><orcid>0000-0003-3143-6854</orcid><order>13</order></author><author><firstname>Sunil</firstname><surname>Dolwani</surname><orcid>0000-0002-3113-5472</orcid><order>14</order></author><author><firstname>Bilal</firstname><surname>Al-Sarireh</surname><orcid>0000-0002-5974-187x</orcid><order>15</order></author><author><firstname>Neil</firstname><surname>Hawkes</surname><orcid>0009-0009-4573-3092</orcid><order>16</order></author><author><firstname>Emma</firstname><surname>Short</surname><orcid>0000-0001-5050-589x</orcid><order>17</order></author><author><firstname>Geraint T.</firstname><surname>Williams</surname><orcid>0000-0003-3768-9940</orcid><order>18</order></author><author><firstname>Melissa W.</firstname><surname>Taggart</surname><orcid>0000-0002-7803-9904</orcid><order>19</order></author><author><firstname>Kim</firstname><surname>Luetchford</surname><orcid>0000-0003-3601-508x</orcid><order>20</order></author><author><firstname>Patrick M.</firstname><surname>Lynch</surname><orcid>0000-0003-0125-3109</orcid><order>21</order></author><author><firstname>Diantha</firstname><surname>Terlouw</surname><orcid>0000-0002-8090-8806</orcid><order>22</order></author><author><firstname>Maartje</firstname><surname>Nielsen</surname><orcid>0000-0002-5351-1870</orcid><order>23</order></author><author><firstname>Sarah-Jane</firstname><surname>Walton</surname><orcid>0000-0002-3438-2268</orcid><order>24</order></author><author><firstname>Andrew</firstname><surname>Latchford</surname><orcid>0000-0002-8626-188x</orcid><order>25</order></author><author><firstname>Susan K.</firstname><surname>Clark</surname><orcid>0000-0002-6929-8082</orcid><order>26</order></author><author><firstname>Julian R.</firstname><surname>Sampson</surname><orcid>0000-0002-2902-2348</orcid><order>27</order></author><author><firstname>Eduardo</firstname><surname>Vilar</surname><orcid>0000-0001-6404-3761</orcid><order>28</order></author><author><firstname>Laura</firstname><surname>Thomas</surname><orcid>0000-0002-8621-5285</orcid><order>29</order></author></authors><documents><document><filename>65964__30336__af1c326f6aaf43c5bb1c01e47d468c75.pdf</filename><originalFilename>65964.VOR.pdf</originalFilename><uploaded>2024-05-13T15:21:42.2815395</uploaded><type>Output</type><contentLength>1962755</contentLength><contentType>application/pdf</contentType><version>Version of Record</version><cronfaStatus>true</cronfaStatus><documentNotes>Distributed under the terms of a Creative Commons CC-BY 4.0 Licence. Copyright 2024 The Authors.</documentNotes><copyrightCorrect>true</copyrightCorrect><language>eng</language><licence>http://creativecommons.org/licenses/by/4.0</licence></document></documents><OutputDurs/></rfc1807> |
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2024-10-17T15:26:18.5791259 v2 65964 2024-04-04 PIGA Mutations and Glycosylphosphatidylinositol Anchor Dysregulation in Polyposis-Associated Duodenal Tumorigenesis 7d630cc1fa34fdcd873711c80a874322 0000-0001-8530-4086 Iain Perry Iain Perry true false 0fce0f7ddbdbfeb968f4e2f1e3f86744 0000-0003-4846-5117 Nick Jones Nick Jones true false a44095d26187304e903da7ca778697b6 0000-0002-5437-8389 Gareth Jenkins Gareth Jenkins true false 6f80a1638d852bd88d37afe3aeb2fb62 0000-0002-8621-5285 Laura Thomas Laura Thomas true false 2024-04-04 MEDS 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. Journal Article Molecular Cancer Research 22 6 515 523 American Association for Cancer Research (AACR) 1541-7786 1557-3125 Duodenal tumors 1 6 2024 2024-06-01 10.1158/1541-7786.mcr-23-0810 COLLEGE NANME Medical School COLLEGE CODE MEDS Swansea University SU College/Department paid the OA fee 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 2024-10-17T15:26:18.5791259 2024-04-04T11:34:53.8400549 Faculty of Medicine, Health and Life Sciences Swansea University Medical School - Biomedical Science Elena Meuser 0000-0002-3308-8577 1 Kyle Chang 0000-0001-5295-9676 2 Angharad Walters 0009-0007-6056-1482 3 Joanna J. Hurley 0009-0005-1422-0463 4 Hannah D. West 0000-0002-6104-6534 5 Iain Perry 0000-0001-8530-4086 6 Matthew Mort 0000-0002-3986-0935 7 Laura Reyes-Uribe 0000-0001-6091-6705 8 Rebekah Truscott 0000-0002-2187-8571 9 Nick Jones 0000-0003-4846-5117 10 Rachel Lawrence 0000-0002-1023-5220 11 Gareth Jenkins 0000-0002-5437-8389 12 Peter Giles 0000-0003-3143-6854 13 Sunil Dolwani 0000-0002-3113-5472 14 Bilal Al-Sarireh 0000-0002-5974-187x 15 Neil Hawkes 0009-0009-4573-3092 16 Emma Short 0000-0001-5050-589x 17 Geraint T. Williams 0000-0003-3768-9940 18 Melissa W. Taggart 0000-0002-7803-9904 19 Kim Luetchford 0000-0003-3601-508x 20 Patrick M. Lynch 0000-0003-0125-3109 21 Diantha Terlouw 0000-0002-8090-8806 22 Maartje Nielsen 0000-0002-5351-1870 23 Sarah-Jane Walton 0000-0002-3438-2268 24 Andrew Latchford 0000-0002-8626-188x 25 Susan K. Clark 0000-0002-6929-8082 26 Julian R. Sampson 0000-0002-2902-2348 27 Eduardo Vilar 0000-0001-6404-3761 28 Laura Thomas 0000-0002-8621-5285 29 65964__30336__af1c326f6aaf43c5bb1c01e47d468c75.pdf 65964.VOR.pdf 2024-05-13T15:21:42.2815395 Output 1962755 application/pdf Version of Record true Distributed under the terms of a Creative Commons CC-BY 4.0 Licence. Copyright 2024 The Authors. true eng http://creativecommons.org/licenses/by/4.0 |
| title |
PIGA Mutations and Glycosylphosphatidylinositol Anchor Dysregulation in Polyposis-Associated Duodenal Tumorigenesis |
| spellingShingle |
PIGA Mutations and Glycosylphosphatidylinositol Anchor Dysregulation in Polyposis-Associated Duodenal Tumorigenesis Iain Perry Nick Jones Gareth Jenkins Laura Thomas |
| title_short |
PIGA Mutations and Glycosylphosphatidylinositol Anchor Dysregulation in Polyposis-Associated Duodenal Tumorigenesis |
| title_full |
PIGA Mutations and Glycosylphosphatidylinositol Anchor Dysregulation in Polyposis-Associated Duodenal Tumorigenesis |
| title_fullStr |
PIGA Mutations and Glycosylphosphatidylinositol Anchor Dysregulation in Polyposis-Associated Duodenal Tumorigenesis |
| title_full_unstemmed |
PIGA Mutations and Glycosylphosphatidylinositol Anchor Dysregulation in Polyposis-Associated Duodenal Tumorigenesis |
| title_sort |
PIGA Mutations and Glycosylphosphatidylinositol Anchor Dysregulation in Polyposis-Associated Duodenal Tumorigenesis |
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7d630cc1fa34fdcd873711c80a874322 0fce0f7ddbdbfeb968f4e2f1e3f86744 a44095d26187304e903da7ca778697b6 6f80a1638d852bd88d37afe3aeb2fb62 |
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7d630cc1fa34fdcd873711c80a874322_***_Iain Perry 0fce0f7ddbdbfeb968f4e2f1e3f86744_***_Nick Jones a44095d26187304e903da7ca778697b6_***_Gareth Jenkins 6f80a1638d852bd88d37afe3aeb2fb62_***_Laura Thomas |
| author |
Iain Perry Nick Jones Gareth Jenkins Laura Thomas |
| author2 |
Elena Meuser 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 |
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Journal article |
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Molecular Cancer Research |
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22 |
| container_issue |
6 |
| container_start_page |
515 |
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2024 |
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Swansea University |
| issn |
1541-7786 1557-3125 |
| doi_str_mv |
10.1158/1541-7786.mcr-23-0810 |
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American Association for Cancer Research (AACR) |
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Faculty of Medicine, Health and Life Sciences |
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facultyofmedicinehealthandlifesciences |
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Faculty of Medicine, Health and Life Sciences |
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Faculty of Medicine, Health and Life Sciences |
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Swansea University Medical School - Biomedical Science{{{_:::_}}}Faculty of Medicine, Health and Life Sciences{{{_:::_}}}Swansea University Medical School - Biomedical Science |
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| description |
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. |
| published_date |
2024-06-01T14:38:30Z |
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1821416683623940096 |
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11.048216 |