title: Surrogate molecular markers for IGHV mutational status in chronic lymphocytic leukemia for predicting time to first treatment.
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.
authors.affiliation: Hematology Unit, AO, Cosenza, Italy; Biotecnology Research Unit, Aprigliano, Cosenza, Italy. Electronic address: fortunato_morabito@tin.it.
authors.forename: Fortunato
authors.initials: F
authors.lastname: Morabito
authors.affiliation: SS di Diagnostica Molecolare IRCCS S. Martino-IST, Genova, Italy.
authors.forename: Giovanna
authors.initials: G
authors.lastname: Cutrona
authors.affiliation: Department of Clinical and Community Science, University of Milan, Milano, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Mosca
authors.affiliation: Department of Clinical and Community Science, University of Milan, Milano, Italy.
authors.forename: Marianna
authors.initials: M
authors.lastname: D'Anca
authors.affiliation: Scientific Division, IRCCS S. Martino-National Cancer Institute, Genova, Italy.
authors.forename: Serena
authors.initials: S
authors.lastname: Matis
authors.affiliation: Hematology Unit, AO, Cosenza, Italy.
authors.forename: Massimo
authors.initials: M
authors.lastname: Gentile
authors.affiliation: Hematology Unit, AO, Cosenza, Italy.
authors.forename: Ernesto
authors.initials: E
authors.lastname: Vigna
authors.affiliation: Scientific Division, IRCCS S. Martino-National Cancer Institute, Genova, Italy.
authors.forename: Monica
authors.initials: M
authors.lastname: Colombo
authors.affiliation: Biotecnology Research Unit, Aprigliano, Cosenza, Italy.
authors.forename: Anna Grazia
authors.initials: AG
authors.lastname: Recchia
authors.affiliation: Biotecnology Research Unit, Aprigliano, Cosenza, Italy.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Bossio
authors.affiliation: Biotecnology Research Unit, Aprigliano, Cosenza, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: De Stefano
authors.affiliation: Hematology Division, IRCCS Foundation Cà Granda, Policlinico Hospital, Milan, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Maura
authors.affiliation: Hematology Division, IRCCS Foundation Cà Granda, Policlinico Hospital, Milan, Italy.
authors.forename: Martina
authors.initials: M
authors.lastname: Manzoni
authors.affiliation: Hematology Unit, Maria Nuova Civil Hospital, Reggio Emilia, Italy.
authors.forename: Fiorella
authors.initials: F
authors.lastname: Ilariucci
authors.affiliation: Hematology-Oncology Unit, Garibaldi-Nesima Hospital, Catania, Italy.
authors.forename: Ugo
authors.initials: U
authors.lastname: Consoli
authors.affiliation: Hematology Unit, AO, Reggio Calabria, Italy.
authors.forename: Iolanda
authors.initials: I
authors.lastname: Vincelli
authors.affiliation: Hematology Unit, University of Messina, MessinaItaly.
authors.forename: Caterina
authors.initials: C
authors.lastname: Musolino
authors.affiliation: Department of Clinical and Community Science, University of Milan, Milano, Italy; Hematology Division, IRCCS Foundation Cà Granda, Policlinico Hospital, Milan, Italy.
authors.forename: Agostino
authors.initials: A
authors.lastname: Cortelezzi
authors.affiliation: Hematology Unit, AO, Catanzaro, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Molica
authors.affiliation: Scientific Division, IRCCS S. Martino-National Cancer Institute, Genova, Italy.
authors.forename: Manlio
authors.initials: M
authors.lastname: Ferrarini
authors.affiliation: Department of Clinical and Community Science, University of Milan, Milano, Italy; Hematology Division, IRCCS Foundation Cà Granda, Policlinico Hospital, Milan, Italy.
authors.forename: Antonino
authors.initials: A
authors.lastname: Neri
mesh_terms: D014408:Biomarkers, Tumor / Q000235:genetics*; D018450:Disease Progression; D005500:Follow-Up Studies; D020869:Gene Expression Profiling; D050438:Genes, Immunoglobulin Heavy Chain / Q000235:genetics*; D006801:Humans; D007135:Immunoglobulin Variable Region / Q000235:genetics; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000175:diagnosis* / Q000235:genetics / Q000628:therapy*; D009154:Mutation; D011237:Predictive Value of Tests; D011379:Prognosis; D061665:Time-to-Treatment; D059467:Transcriptome; D051746:ZAP-70 Protein-Tyrosine Kinase / Q000235:genetics
chemical_list: D014408:Biomarkers, Tumor; D007135:Immunoglobulin Variable Region; D051746:ZAP-70 Protein-Tyrosine Kinase; C497261:ZAP70 protein, human
keywords: CRY1; Chronic lymphocytic leukemia; Flow-cytometry; Gene expression profiling; IGHV; MBOAT1; Prognostic markers; Progression free survival; SNORA70F; ZAP-70