title: Mantle-cell lymphoma genotypes identified with CGH to BAC microarrays define a leukemic subgroup of disease and predict patient outcome.
abstract: To identify recurrent genomic changes in mantle cell lymphoma (MCL), we used high-resolution comparative genomic hybridization (CGH) to bacterial artificial chromosome (BAC) microarrays in 68 patients and 9 MCL-derived cell lines. Array CGH defined an MCL genomic signature distinct from other B-cell lymphomas, including deletions of 1p21 and 11q22.3-ATM gene with coincident 10p12-BMI1 gene amplification and 10p14 deletion, along with a previously unidentified loss within 9q21-q22. Specific genomic alterations were associated with different subgroups of disease. Notably, 11 patients with leukemic MCL showed a different genomic profile than nodal cases, including 8p21.3 deletion at tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) receptor gene cluster (55% versus 19%; P = .01) and gain of 8q24.1 at MYC locus (46% versus 14%; P = .015). Additionally, leukemic MCL exhibited frequent IGVH mutation (64% versus 21%; P = .009) with preferential VH4-39 use (36% versus 4%; P = .005) and followed a more indolent clinical course. Blastoid variants, increased number of genomic gains, and deletions of P16/INK4a and TP53 genes correlated with poorer outcomes, while 1p21 loss was associated with prolonged survival (P = .02). In multivariate analysis, deletion of 9q21-q22 was the strongest predictor for inferior survival (hazard ratio [HR], 6; confidence interval [CI], 2.3 to 15.7). Our study highlights the genomic profile as a predictor for clinical outcome and suggests that "genome scanning" of chromosomes 1p21, 9q21-q22, 9p21.3-P16/INK4a, and 17p13.1-TP53 may be clinically useful in MCL.
authors.affiliation: Department of Hematology and Medical Oncology, Hospital Clínico, University of Valencia, Spain.
authors.forename: Fanny
authors.initials: F
authors.lastname: Rubio-Moscardo
authors.forename: Joan
authors.initials: J
authors.lastname: Climent
authors.forename: Reiner
authors.initials: R
authors.lastname: Siebert
authors.forename: Miguel A
authors.initials: MA
authors.lastname: Piris
authors.forename: Jose I
authors.initials: JI
authors.lastname: Martín-Subero
authors.forename: Inga
authors.initials: I
authors.lastname: Nieländer
authors.forename: Javier
authors.initials: J
authors.lastname: Garcia-Conde
authors.forename: Martin J S
authors.initials: MJ
authors.lastname: Dyer
authors.forename: Maria Jose
authors.initials: MJ
authors.lastname: Terol
authors.forename: Daniel
authors.initials: D
authors.lastname: Pinkel
authors.forename: Jose A
authors.initials: JA
authors.lastname: Martinez-Climent
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D022202:Chromosomes, Artificial, Bacterial; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods*; D023281:Genomics / Q000379:methods; D005838:Genotype; D006801:Humans; D007938:Leukemia / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D020522:Lymphoma, Mantle-Cell / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D008297:Male; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D017384:Sequence Deletion; D015996:Survival Rate; D016896:Treatment Outcome