Low Drosha protein expression in cutaneous T-cell lymphoma is associated with worse disease outcome.
Journal
Journal of the European Academy of Dermatology and Venereology : JEADV
ISSN: 1468-3083
Titre abrégé: J Eur Acad Dermatol Venereol
Pays: England
ID NLM: 9216037
Informations de publication
Date de publication:
Sep 2019
Sep 2019
Historique:
received:
14
02
2019
accepted:
12
04
2019
pubmed:
6
5
2019
medline:
8
2
2020
entrez:
6
5
2019
Statut:
ppublish
Résumé
Dysregulation of microRNAs (miRNAs) key regulators may contribute to the pathogenesis of malignancies. miRNA machinery genes such Dicer and Drosha have been reported to be biomarkers in different cancer types. We aimed to evaluate Drosha and Dicer protein expression in cutaneous T-cell lymphoma (CTCL). We performed Drosha and Dicer immunohistochemistry in 45 patients with mycosis fungoides and subtypes. Drosha and Dicer expression scores were correlated with clinical parameters including disease-specific death (DSD), stage of disease and different laboratory data. Uni- and multivariate statistics were performed. On univariate analysis, elevated serum LDH and low Drosha expression were significantly associated with advanced stage (P = 0.032 and 0.0062, respectively) and lymphoma-specific death (LSD; P = 0.017 and P = 0.005, respectively). Moreover, elevated circulating CD4+/CD26- lymphocytes were significantly associated with advanced stage (P = 0.032) and DSD (P = 0.0098). On multivariate analysis, low Drosha expression remained in the logistic regression model as significant independent predictor for advanced disease stages [P = 0.013; odds ratio: 5 (confidence interval) CI 1.3-19.3]. Moreover, low Drosha expression (P = 0.026) and elevated LDH (P = 0.025) remained as significant independent predictors for DSD with odds ratios of 13.5 (CI 1.3-134.4 and 8.7 CI 1.3-57.2, respectively). Low Drosha expression is an independent predictor for advanced stage as well as LSD in CTCL patients indicating a tumour suppressor gene function of Drosha in this disorder.
Sections du résumé
BACKGROUND
BACKGROUND
Dysregulation of microRNAs (miRNAs) key regulators may contribute to the pathogenesis of malignancies. miRNA machinery genes such Dicer and Drosha have been reported to be biomarkers in different cancer types.
OBJECTIVES
OBJECTIVE
We aimed to evaluate Drosha and Dicer protein expression in cutaneous T-cell lymphoma (CTCL).
METHODS
METHODS
We performed Drosha and Dicer immunohistochemistry in 45 patients with mycosis fungoides and subtypes. Drosha and Dicer expression scores were correlated with clinical parameters including disease-specific death (DSD), stage of disease and different laboratory data. Uni- and multivariate statistics were performed.
RESULTS
RESULTS
On univariate analysis, elevated serum LDH and low Drosha expression were significantly associated with advanced stage (P = 0.032 and 0.0062, respectively) and lymphoma-specific death (LSD; P = 0.017 and P = 0.005, respectively). Moreover, elevated circulating CD4+/CD26- lymphocytes were significantly associated with advanced stage (P = 0.032) and DSD (P = 0.0098). On multivariate analysis, low Drosha expression remained in the logistic regression model as significant independent predictor for advanced disease stages [P = 0.013; odds ratio: 5 (confidence interval) CI 1.3-19.3]. Moreover, low Drosha expression (P = 0.026) and elevated LDH (P = 0.025) remained as significant independent predictors for DSD with odds ratios of 13.5 (CI 1.3-134.4 and 8.7 CI 1.3-57.2, respectively).
CONCLUSIONS
CONCLUSIONS
Low Drosha expression is an independent predictor for advanced stage as well as LSD in CTCL patients indicating a tumour suppressor gene function of Drosha in this disorder.
Substances chimiques
Biomarkers, Tumor
0
DICER1 protein, human
EC 3.1.26.3
DROSHA protein, human
EC 3.1.26.3
Ribonuclease III
EC 3.1.26.3
DEAD-box RNA Helicases
EC 3.6.4.13
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
1695-1699Informations de copyright
© 2019 European Academy of Dermatology and Venereology.
Références
Olsen E, Vonderheid E, Pimpinelli N et al. Revisions to the staging and classification of mycosis fungoides and Sezary syndrome: a proposal of the International Society for Cutaneous Lymphomas (ISCL) and the cutaneous lymphoma task force of the European Organization of Research and Treatment of Cancer (EORTC). Blood 2007; 110: 1713-1722.
Shen X, Wang B, Li K et al. MicroRNA signatures in diagnosis and prognosis of cutaneous T-cell lymphoma. J Invest Dermatol. 2018; 138: 2024-2032.
Scarisbrick JJ, Prince HM, Vermeer MH et al. Cutaneous lymphoma international consortium study of outcome in advanced stages of mycosis fungoides and sézary syndrome: effect of specific prognostic markers on survival and development of a prognostic model. J Clin Oncol 2015; 33: 3766-3773.
Lindahl LM, Besenbacher S, Rittig AH et al. Prognostic miRNA classifier in early-stage mycosis fungoides: development and validation in a Danish nationwide study. Blood 2018; 131: 759-770.
Gambichler T, Mamali K, Patsinakidis N et al. Decreased expression of ten-eleven translocation 2 protein is associated with progressive disease and death in patients with mycosis fungoides. Br J Dermatol 2016; 174: 652-653.
Martinez-Escala ME, Choi J. Are MicroRNAs key to developing biomarkers for cutaneous T-cell lymphoma? J Invest Dermatol. 2018; 138: 1906-1908.
Palomero T, Couronné L, Khiabanian H et al. Recurrent mutations in epigenetic regulators, RHOA and FYN kinase in peripheral T cell lymphomas. Nat Genet 2014; 46: 166-170.
van Doorn R, Zoutman WH, Dijkman R et al. Epigenetic profiling of cutaneous T-cell lymphoma: promoter hypermethylation of multiple tumor suppressor genes including BCL7a, PTPRG, and p73. J Clin Oncol 2005; 23: 3886-3896.
Valencak J, Schmid K, Trautinger F et al. High expression of Dicer reveals a negative prognostic influence in certain subtypes of primary cutaneous T cell lymphomas. J Dermatol Sci 2011; 64: 185-190.
Grelier G, Voirin N, Ay AS et al. Prognostic value of Dicer expression in human breast cancers and association with the mesenchymal phenotype. Br J Cancer 2009; 101: 673-683.
Homo sapiens (1917 precursors, 2654 mature) [GRC MirBase] URL http://www.mirbase.org/cgi-bin/browse.pl?org=hsah38 (last accessed: 22 March 2018).
Sand M. MicroRNAs in Malignant Tumors of the Skin. First Steps of Tiny Players in the Skin to a New World of Genomic Medicine. Springer, Berlin, 2016.
Sand M, Gambichler T, Skrygan M et al. Expression levels of the microRNA processing enzymes Drosha and dicer in epithelial skin cancer. Cancer Invest 2010; 28: 649-653.
Liston A, Lu LF, O'Carroll D et al. Dicer-dependent microRNA pathway safeguards regulatory T cell function. J Exp Med 2008; 205: 1993-2004.
Danish HH, Liu S, Jhaveri J et al. Validation of cutaneous lymphoma international prognostic index (CLIPI) for mycosis fungoides and Sézary syndrome. Leuk Lymphoma 2016; 57: 2813-2819.
Gelmez MY, Coskunpinar E, Saracoglu B et al. Investigation of AID, Dicer, and Drosha expressions in patients with chronic lymphocytic leukemia. Immunol Invest 2017; 46: 433-446.
Huang JT, Wang J, Srivastava V et al. MicroRNA machinery genes as novel biomarkers for cancer. Front Oncol. 2014; 4: 113.
Lønvik K, Sørbye SW, Nilsen MN et al. Prognostic value of the MicroRNA regulators Dicer and Drosha in non-small-cell lung cancer: co-expression of Drosha and miR-126 predicts poor survival. BMC Clin Pathol. 2014; 14: 45.
Zhang Z, Zhang G, Kong C et al. Dicer, and Drosha are up-regulated along tumor progression and associated with poor prognosis in bladder carcinoma. Tumour Biol 2015; 36: 5071-5079.
Hata A, Kashima R. Dysregulation of microRNA biogenesis machinery in cancer. Crit Rev Biochem Mol Biol 2016; 51: 121-134.
Lu J, Getz G, Miska EA et al. MicroRNA expression profiles classify human cancers. Nature 2005; 435: 834-838.