Specific secondary genetic alterations in mantle cell lymphoma provide prognostic information independent of the gene expression-based proliferation signature

Abstract

Purpose: To compare the genetic relationship between cyclin D1-positive and cyclin D1-negative mantle cell lymphomas (MCLs) and to determine whether specific genetic alterations may add prognostic information to survival prediction based on the proliferation signature of MCLs.

Patients and methods: Seventy-one cyclin D1-positive and six cyclin D1-negative MCLs previously characterized by gene expression profiling were examined by comparative genomic hybridization (CGH).

Results: Cyclin D1-negative MCLs were genetically characterized by gains of 3q, 8q, and 15q, and losses of 1p, 8p23-pter, 9p21-pter, 11q21-q23, and 13q that were also the most common alterations in conventional MCLs. Parallel analysis of CGH aberrations and locus-specific gene expression profiles in cyclin D1-positive patients showed that chromosomal imbalances had a substantial impact on the expression levels of the genes located in the altered regions. The analysis of prognostic factors revealed that the proliferation signature, the number of chromosomal aberrations, gains of 3q, and losses of 8p, 9p, and 9q predicted survival of MCL patients. A multivariate analysis showed that the gene expression-based proliferation signature was the strongest predictor for shorter survival. However, 3q gains and 9q losses provided prognostic information that was independent of the proliferative activity.

Conclusion: Cyclin D1-positive and -negative MCLs share the same secondary genetic aberrations, supporting the concept that they correspond to the same genetic entity. The integration of genetic information on chromosome 3q and 9q alterations into a proliferation signature-based model may improve the ability to predict survival in patients with MCL.

Fig 1

Ideogram of the distribution of gains and losses of genetic material detected by comparative genomic hybridization in (A) cyclin D1–positive mantle cell lymphoma (MCL) and (B) cyclin D1–negative MCL. Red bars on the left side correspond to genetic losses; green bars on the right side indicate genetic gains. Bold bars indicate amplifications.

Fig. 2

Influence of chromosomal alterations on locus-specific gene expression levels. (A) 3q, (B) 8p, (C) 9q, and (D) 13q. Genes are ordered according to their chromosomal position (Genes On Sequence Map, Homo sapiens built 33). For genes with more than one microarray element on the Lymphochip, the average expression from different clones was calculated. Genes with significant differences (P < .05) are highlighted in red. Amp, amplification.

Fig. 3

Impact of genomic imbalances on survival of mantle cell lymphoma (MCL) patients. Kaplan-Meier survival estimates of MCL patients (A) with genomic gains of 3q27-qter (P = .039) and (B) losses of 9q22–q32 (P = .039) in comparison with their stratification into two survival groups based on the gene expression–based proliferation predictor model alone. n, number of patients; D, dead patients.