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Translocation t(4;14) retains prognostic significance even in the setting of high-risk molecular signature

Leukemia volume 22, pages 459–461 (2008)Cite this article

A Corrigendum to this article was published on 13 February 2008

Recently, two powerful prognostic models were described in myeloma. The Intergroupe Francophone du Mye'lome (IFM) model uses genetic factors t(4;14) and/or 17p13 deletion by fluorescent in situ hybridization combined with β-2 microglobulin. The high-risk group in this model, defined by the presence of either t(4;14) or 17p13 depletion and β-2 microglobulin greater than 4 mg l−1, could dissect the survival of patients in each International Staging Study stage.1 As the International Staging Study did not fully consider genetic factors, this study in a large cohort of patients definitively validates the importance of genetic factors in multiple myeloma prognosis. The other model from the University of Arkansas School of Medical Sciences (UAMS) is based on the expression of 17 genes (17-gene model). The high-risk index based on this model is an extremely powerful prognostic factor with a hazard ratio in excess of 4.2 It can also further dissect patients with t(4;14) into two groups with significantly different survival. In this study, first we wanted to validate the prognostic significance of the 17-gene high-risk index in other independent (non-UAMS) data sets, and second examine the relationship between high-risk genetic features and the 17-gene high-risk molecular signature.

For the first objective, we analyzed a Mayo Clinic gene expression profile data set comprising 71 newly diagnosed multiple myeloma patients treated with high-dose melphalan and stem cell transplant (previously published and available in Gene Expression Omnibus, accession number GSE 6477),3 and for the second objective we analyzed the UAMS data set of 351 newly diagnosed patients treated with total therapy II from the UAMS (Gene Expression Omnibus accession GSE 2658).4 Both data sets were performed on Affymetrix platform. In the Mayo data set, gene expression profile was performed on malignant plasma cells enriched by positive immunomagnetic selection using CD138 (AutoMACS; Miltenyi-Biotec, Auburn, CA, USA). Bone marrow samples were obtained after informed consent according to the Declaration of Helsinki Principles. The study was approved by the Mayo Clinic Institutional Review Board. CD138 selection was also used to enrich for malignant plasma cells in the UAMS data set. Gene expression intensity values were generated using the Affymetrix MAS 5.0 software, median-centered and analyzed using GeneSpring GX 7.3.1 (Agilent Technologies, Palo Alto, CA, USA). The 17-gene high-risk score is calculated based on published methods.2 A gene expression profile based proliferation index (PI) was calculated as the median expression of the following genes: CCNB1, MKI67, L5, KIAA0186, CKS1B, TOP2A, UBE2C, ZWINT, 16E1BP, TRIP5, CCNA, p55CDC.5 Spiked expression of FGFR3 or WHSC1 defines cases with t(4;14).5 Low TP53 expression was used as a surrogate for 17p13 deletion, as a recent study showed that there is a close association between the cases with lowest TP53 expression and 17p13 deletion.6 The associations between prognostic factors were assessed using Fisher's exact test. The distribution for overall survival was estimated using the method of Kaplan and Meier. The log-rank test was used to test for differences in survival between groups. Overall survival was calculated from diagnosis to death. A P-value of <0.05 was considered significant.

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Authors and Affiliations

  1. Department of Hematology-Oncology, Comprehensive Cancer Center, Mayo Clinic, Scottsdale, AZ, USA

    W J Chng, P L Bergsagel & R Fonseca

  2. Genetics Branch, Center for Cancer Research, NCI, NIH, Bethesda, MD, USA

    W M Kuehl

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  1. W J Chng
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  2. W M Kuehl
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Correspondence to W J Chng.

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Chng, W., Kuehl, W., Bergsagel, P. et al. Translocation t(4;14) retains prognostic significance even in the setting of high-risk molecular signature. Leukemia 22, 459–461 (2008). https://doi.org/10.1038/sj.leu.2404934

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