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- Persson, Marta, 1979, et al.
(författare)
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Comprehensive molecular characterization of adenoid cystic carcinoma reveals tumor suppressors as novel drivers and prognostic biomarkers
- 2023
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Ingår i: Journal of Pathology. - 0022-3417. ; 261:3, s. 256-268
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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- Persson, Marta, 1979, et al.
(författare)
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Rearrangements, Expression, and Clinical Significance of MYB and MYBL1 in Adenoid Cystic Carcinoma: A Multi-Institutional Study
- 2022
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Ingår i: Cancers. - : MDPI AG. - 2072-6694. ; 14:15
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Tidskriftsartikel (refereegranskat)abstract
- Simple Summary Adenoid cystic carcinoma (ACC) is an aggressive glandular cancer with poor prognosis that preferentially occurs in the head and neck. The MYB and MYBL1 oncogenes are main oncogenic drivers, but the true frequency and clinical significance of these alterations are unclear. Here, we have used tissue microarrays to study these genes in a multi-institutional study of close to 400 ACCs, the largest study to date. We found alterations of MYB/MYBL1 in 78% of the cases and overexpression of the MYB/MYBL1 proteins in 93% of the cases. Importantly, we show that patients with loss of one part of the MYB gene and its neighboring sequences on chromosome 6 have a significantly shorter overall survival compared to those without loss. Our study provides new knowledge about the frequency and clinical significance of MYB/MYBL1 alterations and identifies genes with tumor suppressive functions on chromosome 6 that contribute to poor prognosis in ACC. Adenoid cystic carcinoma (ACC) is an aggressive head and neck malignancy characterized by a t (6;9) translocation resulting in an MYB-NFIB gene fusion or, more rarely, an MYBL1 fusion. The true frequency and clinical significance of these alterations are still unclear. Here, we have used tissue microarrays and analyzed 391 ACCs and 647 non-ACC salivary neoplasms to study the prevalence, expression, and clinical significance of MYB/MYBL1 alterations by FISH and immunohistochemistry. Alterations of MYB or MYBL1 were found in 78% of the cases, of which 62% had MYB alterations and 16% had MYBL1 rearrangements. Overexpression of MYB/MYBL1 oncoproteins was detected in 93% of the cases. MYB split signal, seen in 39% of the cases, was specific for ACC and not encountered in non-ACC salivary tumors. Loss of the 3 '-part of MYB was enriched in grade 3 tumors and was a significant independent prognostic biomarker for overall survival in multivariate analyses. We hypothesize that loss of the 3 '-part of MYB results from an unbalanced t(6;9) leading to an MYB-NFIB fusion with concomitant loss of the segment distal to the MYB breakpoint in 6q23.3. Our study provides new knowledge about the prevalence and clinical significance of MYB/MYBL1 alterations and indicates the presence of genes with tumor suppressive functions in 6q23.3-qter that contribute to poor prognosis and short overall survival in ACC.
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