Mantle cell lymphoma (MCL) is clinically heterogeneous; some patients demonstrate an indolent course over several years, while others experience early progression and short survival. In order to better refine prognostic markers, Kienle and colleagues analyzed archival MCL samples obtained at the time of diagnosis by real-time quantitative reverse transcriptase PCR, targeting 20 genes previously associated with MCL pathogenesis and prognosis. Although lymph node (n=65) and peripheral blood (n=13) samples were similar for overall tumor cell content, differing gene expression profiles were noted between these compartments, and correlative analyses were restricted to the lymph node cohort. CCND1, the gene encoding the hallmark MCL cyclin D1 protein, was verified to produce either a short or long variant transcript based upon differences in length of the untranslated region. Those patients with the short form (n=9) had higher CCND1 expression levels, higher proliferative rates, and a median survival of only 8.4 months, versus 45.1 month median survival for patients with the long variant. Immunostaining with Ki-67, a marker of proliferation, also stratified patients into low- and high-risk groups. Those with more than 40 percent positive cells had a median survival of 17 months, versus 52.5 months for those with a lower percent positivity. Increased CCND1 expression levels and the short variant CCND1 correlated positively with Ki-67 index, whereas low expression of ataxia telangiectasia gene (ATM), retinoblastoma gene (RB1) and an antiapoptosis gene (MCL1), among others, had a negative correlation. In a multivariate analysis of clinical and molecular parameters with decreased patient survival, significant positive correlations were found for Ki-67 protein expression, the presence of B symptoms, and gene expression of MYC, MDM2, EZH, and CCND1.
In Brief
MCL is among the most challenging subtypes of lymphoma, with no curative standard therapeutic approach yet identified. There is, however, reason for optimism that improved outcomes may be realized through novel agents now in clinical trials and by individualization of therapy based upon molecular and phenotypic biomarkers. The present report verifies and extends earlier correlative work that defined markers of proliferation and apoptosis and, as noted by the authors, implicates the relevance of "gene dosage" for proliferation — promoting genes, proliferation inhibitors, and regulators of apoptosis. Although complex to orchestrate within prospective clinical trials, biomarker and bioinformatic analyses hold considerable promise for individualization of treatment and improved outcomes. Close collaboration between clinical and laboratory scientists in the design and conduct of therapeutic trials, and in prioritizing clinical studies of novel targeted therapies, will be critical to this process.
Competing Interests
Dr. Williams serves on the Executive Committee of the Lymphoma Research Foundation Mantle Cell Lymphoma Consortium and on the European Mantle Cell Lymphoma Network Scientific Advisory Board.
