Comprehensive molecular characterization of adenoid cystic carcinoma reveals tumor suppressors as novel drivers and prognostic biomarkers.
1p deletion
6q26 deletion
MYB
PARK2
TP73
adenoid cystic carcinoma
genomic profiling
prognostic biomarker
transcriptomic profiling
tumor suppressor gene
Journal
The Journal of pathology
ISSN: 1096-9896
Titre abrégé: J Pathol
Pays: England
ID NLM: 0204634
Informations de publication
Date de publication:
11 2023
11 2023
Historique:
revised:
19
06
2023
received:
15
12
2022
accepted:
28
06
2023
medline:
10
10
2023
pubmed:
11
8
2023
entrez:
11
8
2023
Statut:
ppublish
Résumé
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.
Substances chimiques
Biomarkers, Tumor
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
256-268Informations de copyright
© 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
Références
Stenman G, Licitra L, Said-Al-Naief N, et al. Adenoid cystic carcinoma. In World Health Organization Classification of Head and Neck Tumours, El-Naggar AK, Chan JKC, Grandis JR, et al. (eds). IARC Press: Lyon, 2017; 164-165.
Brill LB 2nd, Kanner WA, Fehr A, et al. Analysis of MYB expression and MYB-NFIB gene fusions in adenoid cystic carcinoma and other salivary neoplasms. Mod Pathol 2011; 24: 1169-1176.
Laurie SA, Ho AL, Fury MG, et al. Systemic therapy in the management of metastatic or locally recurrent adenoid cystic carcinoma of the salivary glands: a systematic review. Lancet Oncol 2011; 12: 815-824.
Carlson J, Licitra L, Locati L, et al. Salivary gland cancer: an update on present and emerging therapies. Am Soc Clin Oncol Educ Book 2013; 33: 257-263.
Coca-Pelaz A, Rodrigo JP, Bradley PJ, et al. Adenoid cystic carcinoma of the head and neck-an update. Oral Oncol 2015; 51: 652-661.
Xu B, Drill E, Ho A, et al. Predictors of outcome in adenoid cystic carcinoma of salivary glands: a clinicopathologic study with correlation between MYB fusion and protein expression. Am J Surg Pathol 2017; 41: 1422-1432.
Stenman G, Sandros J, Dahlenfors R, et al. 6q- and loss of the Y chromosome-two common deviations in malignant human salivary gland tumors. Cancer Genet Cytogenet 1986; 22: 283-293.
Nordkvist A, Mark J, Gustafsson H, et al. Non-random chromosome rearrangements in adenoid cystic carcinoma of the salivary glands. Genes Chromosomes Cancer 1994; 10: 115-121.
Persson M, Andrén Y, Mark J, et al. Recurrent fusion of MYB and NFIB transcription factor genes in carcinomas of the breast and head and neck. Proc Natl Acad Sci U S A 2009; 106: 18740-18744.
Mitani Y, Liu B, Rao PH, et al. Novel MYBL1 gene rearrangements with recurrent MYBL1-NFIB fusions in salivary adenoid cystic carcinomas lacking t(6;9) translocations. Clin Cancer Res 2016; 22: 725-733.
Brayer KJ, Frerich CA, Kang H, et al. Recurrent fusions in MYB and MYBL1 define a common, transcription factor-driven oncogenic pathway in salivary gland adenoid cystic carcinoma. Cancer Discov 2016; 6: 176-187.
Drier Y, Cotton MJ, Williamson KE, et al. An oncogenic MYB feedback loop drives alternate cell fates in adenoid cystic carcinoma. Nat Genet 2016; 48: 265-272.
Andersson MK, Afshari MK, Andrén Y, et al. Targeting the oncogenic transcriptional regulator MYB in adenoid cystic carcinoma by inhibition of IGF1R/AKT signaling. J Natl Cancer Inst 2017; 109: djx017.
Andersson MK, Mangiapane G, Nevado PT, et al. ATR is a MYB regulated gene and potential therapeutic target in adenoid cystic carcinoma. Oncogenesis 2020; 9: 5.
Andersson MK, Åman P, Stenman G. IGF2/IGF1R signaling as a therapeutic target in MYB-positive adenoid cystic carcinomas and other fusion gene-driven tumors. Cell 2019; 8: 913.
Ho AS, Kannan K, Roy DM, et al. The mutational landscape of adenoid cystic carcinoma. Nat Genet 2013; 45: 791-798.
Stephens PJ, Davies HR, Mitani Y, et al. Whole exome sequencing of adenoid cystic carcinoma. J Clin Invest 2013; 123: 2965-2968.
Andersson MK, Stenman G. The landscape of gene fusions and somatic mutations in salivary gland neoplasms - implications for diagnosis and therapy. Oral Oncol 2016; 57: 63-69.
Rettig EM, Talbot CC Jr, Sausen M, et al. Whole-genome sequencing of salivary gland adenoid cystic carcinoma. Cancer Prev Res (Phila) 2016; 9: 265-274.
Ferrarotto R, Heymach JV. Taking it up a NOTCH: a novel subgroup of ACC is identified. Oncotarget 2017; 8: 81725-81726.
Liu B, Mitani Y, Rao X, et al. Spatio-temporal genomic heterogeneity, phylogeny, and metastatic evolution in salivary adenoid cystic carcinoma. J Natl Cancer Inst 2017; 109: djx033.
Skalova A, Stenman G, Simpson RHW, et al. The role of molecular testing in the differential diagnosis of salivary gland carcinomas. Am J Surg Pathol 2018; 42: e11-e27.
Ho AS, Ochoa A, Jayakumaran G, et al. Genetic hallmarks of recurrent/metastatic adenoid cystic carcinoma. J Clin Invest 2019; 129: 4276-4289.
Persson M, Andersson MK, Mitani Y, et al. Rearrangements, expression, and clinical significance of MYB and MYBL1 in adenoid cystic carcinoma: a multi-institutional study. Cancers (Basel) 2022; 14: 3691.
Persson M, Andren Y, Moskaluk CA, et al. Clinically significant copy number alterations and complex rearrangements of MYB and NFIB in head and neck adenoid cystic carcinoma. Genes Chromosomes Cancer 2012; 51: 805-817.
Szanto PA, Luna MA, Tortoledo ME, et al. Histologic grading of adenoid cystic carcinoma of the salivary glands. Cancer 1984; 54: 1062-1069.
Persson F, Winnes M, Andrén Y, et al. High-resolution array CGH analysis of salivary gland tumors reveals fusion and amplification of the FGFR1 and PLAG1 genes in ring chromosomes. Oncogene 2008; 27: 3072-3080.
Iafrate AJ, Feuk L, Rivera MN, et al. Detection of large-scale variation in the human genome. Nat Genet 2004; 36: 949-951.
Mermel CH, Schumacher SE, Hill B, et al. GISTIC2.0 facilitates sensitive and confident localization of the targets of focal somatic copy-number alteration in human cancers. Genome Biol 2011; 12: R41.
Ritchie ME, Phipson B, Wu D, et al. limma powers differential expression analyses for RNA-sequencing and microarray studies. Nucleic Acids Res 2015; 43: e47.
Mi H, Huang X, Muruganujan A, et al. PANTHER version 11: expanded annotation data from gene ontology and reactome pathways, and data analysis tool enhancements. Nucleic Acids Res 2017; 45: D183-D189.
Huang da W, Sherman BT, Lempicki RA. Bioinformatics enrichment tools: paths toward the comprehensive functional analysis of large gene lists. Nucleic Acids Res 2009; 37: 1-13.
Subramanian A, Tamayo P, Mootha VK, et al. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci U S A 2005; 102: 15545-15550.
Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods 2001; 25: 402-408.
Yusenko MV, Trentmann A, Andersson MK, et al. Monensin, a novel potent MYB inhibitor, suppresses proliferation of acute myeloid leukemia and adenoid cystic carcinoma cells. Cancer Lett 2020; 479: 61-70.
Rao PH, Roberts D, Zhao YJ, et al. Deletion of 1p32-p36 is the most frequent genetic change and poor prognostic marker in adenoid cystic carcinoma of the salivary glands. Clin Cancer Res 2008; 14: 5181-5187.
Šteiner P, Andreasen S, Grossmann P, et al. Prognostic significance of 1p36 locus deletion in adenoid cystic carcinoma of the salivary glands. Virchows Arch 2018; 473: 471-480.
Jost CA, Marin MC, Kaelin WG Jr. p73 is a simian [correction of human] p53-related protein that can induce apoptosis. Nature 1997; 389: 191-194.
Karbowski M, Lee YJ, Gaume B, et al. Spatial and temporal association of Bax with mitochondrial fission sites, Drp1, and Mfn2 during apoptosis. J Cell Biol 2002; 159: 931-938.
Schlisio S, Kenchappa RS, Vredeveld LC, et al. The kinesin KIF1Bbeta acts downstream from EglN3 to induce apoptosis and is a potential 1p36 tumor suppressor. Genes Dev 2008; 22: 884-893.
Stiewe T, Pützer BM. p73 in apoptosis. Apoptosis 2001; 6: 447-452.
Kaghad M, Bonnet H, Yang A, et al. Monoallelically expressed gene related to p53 at 1p36, a region frequently deleted in neuroblastoma and other human cancers. Cell 1997; 90: 809-819.
Chen ZX, Wallis K, Fell SM, et al. RNA helicase a is a downstream mediator of KIF1Bβ tumor-suppressor function in neuroblastoma. Cancer Discov 2014; 4: 434-451.
Climent J, Perez-Losada J, Quigley DA, et al. Deletion of the PER3 gene on chromosome 1p36 in recurrent ER-positive breast cancer. J Clin Oncol 2010; 28: 3770-3778.
Henrich KO, Schwab M, Westermann F. 1p36 tumor suppression-a matter of dosage? Cancer Res 2012; 72: 6079-6088.
Cesari R, Martin ES, Calin GA, et al. Parkin, a gene implicated in autosomal recessive juvenile parkinsonism, is a candidate tumor suppressor gene on chromosome 6q25-q27. Proc Natl Acad Sci U S A 2003; 100: 5956-5961.
Hu HH, Kannengiesser C, Lesage S, et al. PARKIN inactivation links Parkinson's disease to melanoma. J Natl Cancer Inst 2016; 108: djv340.
Veeriah S, Taylor BS, Meng S, et al. Somatic mutations of the Parkinson's disease-associated gene PARK2 in glioblastoma and other human malignancies. Nat Genet 2010; 42: 77-82.
Hampe C, Ardila-Osorio H, Fournier M, et al. Biochemical analysis of Parkinson's disease-causing variants of Parkin, an E3 ubiquitin-protein ligase with monoubiquitylation capacity. Hum Mol Genet 2006; 15: 2059-2075.
Shimura H, Hattori N, Kubo S, et al. Familial Parkinson disease gene product, parkin, is a ubiquitin-protein ligase. Nat Genet 2000; 25: 302-305.
Gong Y, Zack TI, Morris LG, et al. Pan-cancer genetic analysis identifies PARK2 as a master regulator of G1/S cyclins. Nat Genet 2014; 46: 588-594.
Gong Y, Schumacher SE, Wu WH, et al. Pan-cancer analysis links PARK2 to BCL-XL-dependent control of apoptosis. Neoplasia 2017; 19: 75-83.
Gupta A, Anjomani-Virmouni S, Koundouros N, et al. PARK2 depletion connects energy and oxidative stress to PI3K/Akt activation via PTEN S-Nitrosylation. Mol Cell 2017; 65: 1013.e7.
Lin DC, Xu L, Chen Y, et al. Genomic and functional analysis of the E3 ligase PARK2 in glioma. Cancer Res 2015; 75: 1815-1827.
Veeriah S, Morris L, Solit D, et al. The familial Parkinson disease gene PARK2 is a multisite tumor suppressor on chromosome 6q25.2-27 that regulates cyclin E. Cell Cycle 2010; 9: 1451-1452.
Xiong D, Wang Y, Kupert E, et al. A recurrent mutation in PARK2 is associated with familial lung cancer. Am J Hum Genet 2015; 96: 301-308.
Ferrarotto R, Mitani Y, McGrail DJ, et al. Proteogenomic analysis of salivary adenoid cystic carcinomas defines molecular subtypes and identifies therapeutic targets. Clin Cancer Res 2021; 27: 852-864.
Frerich CA, Brayer KJ, Painter BM, et al. Transcriptomes define distinct subgroups of salivary gland adenoid cystic carcinoma with different driver mutations and outcomes. Oncotarget 2018; 9: 7341-7358.
Phuchareon J, Ohta Y, Woo JM, et al. Genetic profiling reveals cross-contamination and misidentification of 6 adenoid cystic carcinoma cell lines: ACC2, ACC3, ACCM, ACCNS, ACCS and CAC2. PloS One 2009; 4: e6040.