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Comprehensive molec...
Comprehensive molecular characterization of adenoid cystic carcinoma reveals tumor suppressors as novel drivers and prognostic biomarkers
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- Persson, Marta, 1979 (author)
- Gothenburg University,Göteborgs universitet,Sahlgrenska Centrum för Cancerforskning (SCCR),Sahlgrenska Center for Cancer Research (SCCR)
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- Andersson, Mattias K, 1979 (author)
- Gothenburg University,Göteborgs universitet,Sahlgrenska Centrum för Cancerforskning (SCCR),Sahlgrenska Center for Cancer Research (SCCR)
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Sahlin, P. E. (author)
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Mitani, Y. (author)
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Brandwein-Weber, M. S. (author)
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Frierson, H. F. (author)
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Moskaluk, C. (author)
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Fonseca, I. (author)
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Ferrarotto, R. (author)
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Boecker, W. (author)
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Loening, T. (author)
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El-Naggar, A. K. (author)
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- Stenman, Göran, 1953 (author)
- Gothenburg University,Göteborgs universitet,Sahlgrenska Centrum för Cancerforskning (SCCR),Sahlgrenska Center for Cancer Research (SCCR)
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(creator_code:org_t)
- 2023
- 2023
- English.
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In: Journal of Pathology. - 0022-3417. ; 261:3, s. 256-268
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Abstract
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- 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.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Cancer och onkologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Cancer and Oncology (hsv//eng)
Keyword
- tumor suppressor gene
- transcriptomic profiling
- TP73
- prognostic
- biomarker
- PARK2
- MYB
- genomic profiling
- adenoid cystic carcinoma
- 6q26
- deletion
- 1p deletion
Publication and Content Type
- ref (subject category)
- art (subject category)
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- By the author/editor
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Persson, Marta, ...
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Andersson, Matti ...
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Sahlin, P. E.
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Mitani, Y.
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Brandwein-Weber, ...
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Frierson, H. F.
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show more...
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Moskaluk, C.
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Fonseca, I.
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Ferrarotto, R.
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Boecker, W.
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Loening, T.
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El-Naggar, A. K.
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Stenman, Göran, ...
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show less...
- About the subject
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Clinical Medicin ...
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and Cancer and Oncol ...
- Articles in the publication
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Journal of Patho ...
- By the university
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University of Gothenburg