Surrogate molecular markers for IGHV mutational status in chronic lymphocytic leukemia for predicting time to first treatment. Issue 8 (August 2015)

• Record Type: Journal Article
• Authors: Morabito, Fortunato; Cutrona, Giovanna; Mosca, Laura; D'Anca, Marianna; Matis, Serena; Gentile, Massimo; Vigna, Ernesto; Colombo, Monica; Recchia, Anna Grazia; Bossio, Sabrina; De Stefano, Laura; Maura, Francesco; Manzoni, Martina; Ilariucci, Fiorella; Consoli, Ugo; Vincelli, Iolanda; Musolino, Caterina; Cortelezzi, Agostino; Molica, Stefano; Ferrarini, Manlio; Neri, Antonino
• Is Part Of: Leukemia research. Volume 39:Issue 8(2015:Aug.)
• Page Start: 840
• Page End: 845
• Publication Date: 2015-08
• Subjects: Chronic lymphocytic leukemia -- IGHV -- ZAP-70 -- Flow-cytometry -- Gene expression profiling -- Progression free survival -- SNORA70F -- CRY1 -- MBOAT1 -- Prognostic markers; Leukemia -- Periodicals; Leukemia -- Periodicals; Leucémie -- Périodiques; Leukemia; Periodicals; Electronic journals; Electronic journals; 616.9941905
• DOI: 10.1016/j.leukres.2015.05.005
• Languages: English
• ISSNs: 0145-2126

Abstract

Highlights: Novel surrogate markers for ZAP-70 expression in CLL are proposed. Gene expression profiling identified genes with fold-change in expression ≥ZAP-70. Supervised analysis of these gene and IGHV mutation status was performed. CRY1 and MBOAT1 may surrogate the predictive value of IGHV mutational status. Abstract: ZAP-70 is a marker of clinical outcome in chronic lymphocytic leukemia (CLL), however its assessment suffers from a lack of standardization consensus. To identify novel markers able to surrogate IGHV mutational status, CD19(+)CD5(+)- B -lymphocytes from 216 patients enrolled in a prospective study (ClinicalTrial.gov Identifier:NCT00917540 ), underwent gene expression profiling. Samples were split into CLL-Training ( n = 102) and CLL-Validation ( n = 114) sets, and an independent supervised analysis for IGHV mutational status was performed considering all genes with gene expression equal or above that of ZAP-70. Thirty-one genes (23 up- and 8 down-regulated) and 23 genes (18 up- and 5 down-regulated) satisfied these criteria in the CLL-Training and CLL-Validation sets, respectively, and 20 common genes (15 up and 5 down) were found to be differentially regulated in both sets. Two (SNORA70F, NRIP1) of the down-regulated and 6 (SEPT10, ZNF667, TGFBR3, MBOAT1, LPL, CRY1) of the up-regulated genes were significantly associated with a reduced risk of disease progression in both sets. Forcing the afore-mentioned genes in a Cox multivariate model together with IGHV mutational status, only CRY1 (HR = 2.3, 95% CI: 1.1–4.9, P = .027) and MBOAT1 (HR = 2.1, 95% CI: 1.1–3.7, P = .018) retained their independent prognostic impact, supporting the hypothesis that these genes may potentially act as surrogates for predicting IGHV mutational status.