Comprehensive molecular characterization of adenoid cystic carcinoma reveals tumor suppressors as novel drivers and prognostic biomarkers
| Main Author: | |
|---|---|
| Publication Date: | 2023 |
| Other Authors: | , , , , , , , , , , , |
| Format: | Article |
| Language: | eng |
| Source: | Repositórios Científicos de Acesso Aberto de Portugal (RCAAP) |
| Download full: | http://hdl.handle.net/10451/60953 |
Summary: | © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. |
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Comprehensive molecular characterization of adenoid cystic carcinoma reveals tumor suppressors as novel drivers and prognostic biomarkers1p deletion6q26 deletionMYBPARK2TP73Adenoid cystic carcinomaGenomic profilingPrognostic biomarkerTranscriptomic profilingTumor suppressor gene© 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.Adenoid cystic carcinoma (ACC) is a MYB-driven head and neck malignancy with high rates of local recurrence and distant metastasis and poor long-term survival. New effective targeted therapies and clinically useful biomarkers for patient stratification are needed to improve ACC patient survival. Here, we present an integrated copy number and transcriptomic analysis of ACC to identify novel driver genes and prognostic biomarkers. A total of 598 ACCs were studied. Clinical follow-up was available from 366 patients, the largest cohort analyzed to date. Copy number losses of 1p36 (70/492; 14%) and of the tumor suppressor gene PARK2 (6q26) (85/343; 25%) were prognostic biomarkers; patients with concurrent losses (n = 20) had significantly shorter overall survival (OS) than those with one or no deletions (p < 0.0001). Deletion of 1p36 independently predicted short OS in multivariate analysis (p = 0.02). Two pro-apoptotic genes, TP73 and KIF1B, were identified as putative 1p36 tumor suppressor genes whose reduced expression was associated with poor survival and increased resistance to apoptosis. PARK2 expression was markedly reduced in tumors with 6q deletions, and PARK2 knockdown increased spherogenesis and decreased apoptosis, indicating that PARK2 is a tumor suppressor in ACC. Moreover, analysis of the global gene expression pattern in 30 ACCs revealed a transcriptomic signature associated with short OS, multiple copy number alterations including 1p36 deletions, and reduced expression of TP73. Taken together, the results indicate that TP73 and PARK2 are novel putative tumor suppressor genes and potential prognostic biomarkers in ACC. Our studies provide new important insights into the pathogenesis of ACC. The results have important implications for biomarker-driven stratification of patients in clinical trials. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.WileyRepositório da Universidade de LisboaPersson, MartaAndersson, Mattias K.Sahlin, Per‐ErikMitani, YoshitsuguBrandwein‐Weber, Margaret S.Frierson Jr, Henry F.Moskaluk, ChristopherFonseca, IsabelFerrarotto, RenataBoecker, WernerLoening, ThomasEl‐Naggar, Adel K.Stenman, Göran2023-11-28T14:39:56Z20232023-01-01T00:00:00Zinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articleapplication/pdfhttp://hdl.handle.net/10451/60953engJ Pathol. 2023 Nov;261(3):256-2680022-341710.1002/path.61721096-9896info:eu-repo/semantics/openAccessreponame:Repositórios Científicos de Acesso Aberto de Portugal (RCAAP)instname:FCCN, serviços digitais da FCT – Fundação para a Ciência e a Tecnologiainstacron:RCAAP2025-03-17T15:05:36Zoai:repositorio.ulisboa.pt:10451/60953Portal AgregadorONGhttps://www.rcaap.pt/oai/openaireinfo@rcaap.ptopendoar:https://opendoar.ac.uk/repository/71602025-05-29T03:33:38.425109Repositórios Científicos de Acesso Aberto de Portugal (RCAAP) - FCCN, serviços digitais da FCT – Fundação para a Ciência e a Tecnologiafalse |
| dc.title.none.fl_str_mv |
Comprehensive molecular characterization of adenoid cystic carcinoma reveals tumor suppressors as novel drivers and prognostic biomarkers |
| title |
Comprehensive molecular characterization of adenoid cystic carcinoma reveals tumor suppressors as novel drivers and prognostic biomarkers |
| spellingShingle |
Comprehensive molecular characterization of adenoid cystic carcinoma reveals tumor suppressors as novel drivers and prognostic biomarkers Persson, Marta 1p deletion 6q26 deletion MYB PARK2 TP73 Adenoid cystic carcinoma Genomic profiling Prognostic biomarker Transcriptomic profiling Tumor suppressor gene |
| title_short |
Comprehensive molecular characterization of adenoid cystic carcinoma reveals tumor suppressors as novel drivers and prognostic biomarkers |
| title_full |
Comprehensive molecular characterization of adenoid cystic carcinoma reveals tumor suppressors as novel drivers and prognostic biomarkers |
| title_fullStr |
Comprehensive molecular characterization of adenoid cystic carcinoma reveals tumor suppressors as novel drivers and prognostic biomarkers |
| title_full_unstemmed |
Comprehensive molecular characterization of adenoid cystic carcinoma reveals tumor suppressors as novel drivers and prognostic biomarkers |
| title_sort |
Comprehensive molecular characterization of adenoid cystic carcinoma reveals tumor suppressors as novel drivers and prognostic biomarkers |
| author |
Persson, Marta |
| author_facet |
Persson, Marta Andersson, Mattias K. Sahlin, Per‐Erik Mitani, Yoshitsugu Brandwein‐Weber, Margaret S. Frierson Jr, Henry F. Moskaluk, Christopher Fonseca, Isabel Ferrarotto, Renata Boecker, Werner Loening, Thomas El‐Naggar, Adel K. Stenman, Göran |
| author_role |
author |
| author2 |
Andersson, Mattias K. Sahlin, Per‐Erik Mitani, Yoshitsugu Brandwein‐Weber, Margaret S. Frierson Jr, Henry F. Moskaluk, Christopher Fonseca, Isabel Ferrarotto, Renata Boecker, Werner Loening, Thomas El‐Naggar, Adel K. Stenman, Göran |
| author2_role |
author author author author author author author author author author author author |
| dc.contributor.none.fl_str_mv |
Repositório da Universidade de Lisboa |
| dc.contributor.author.fl_str_mv |
Persson, Marta Andersson, Mattias K. Sahlin, Per‐Erik Mitani, Yoshitsugu Brandwein‐Weber, Margaret S. Frierson Jr, Henry F. Moskaluk, Christopher Fonseca, Isabel Ferrarotto, Renata Boecker, Werner Loening, Thomas El‐Naggar, Adel K. Stenman, Göran |
| dc.subject.por.fl_str_mv |
1p deletion 6q26 deletion MYB PARK2 TP73 Adenoid cystic carcinoma Genomic profiling Prognostic biomarker Transcriptomic profiling Tumor suppressor gene |
| topic |
1p deletion 6q26 deletion MYB PARK2 TP73 Adenoid cystic carcinoma Genomic profiling Prognostic biomarker Transcriptomic profiling Tumor suppressor gene |
| description |
© 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. |
| publishDate |
2023 |
| dc.date.none.fl_str_mv |
2023-11-28T14:39:56Z 2023 2023-01-01T00:00:00Z |
| dc.type.status.fl_str_mv |
info:eu-repo/semantics/publishedVersion |
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info:eu-repo/semantics/article |
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article |
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publishedVersion |
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http://hdl.handle.net/10451/60953 |
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http://hdl.handle.net/10451/60953 |
| dc.language.iso.fl_str_mv |
eng |
| language |
eng |
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J Pathol. 2023 Nov;261(3):256-268 0022-3417 10.1002/path.6172 1096-9896 |
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info:eu-repo/semantics/openAccess |
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openAccess |
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application/pdf |
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Wiley |
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Wiley |
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reponame:Repositórios Científicos de Acesso Aberto de Portugal (RCAAP) instname:FCCN, serviços digitais da FCT – Fundação para a Ciência e a Tecnologia instacron:RCAAP |
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