Work

Five gene probes carry most of the discriminatory power of the 70-gene risk model in multiple myeloma

Year: 2014

Type: article

Abstract: The prognostic value of gene expression profiling (GEP) in multiple myeloma (MM) has been reported by several groups. 1 , 2 , 3 , 4 We have previously published a 70-gene classifier (GEP70) that identifies patients with high risk for short progression-free survival (PFS) and overall survival (OS). 1 The GEP70 model was developed from data on patients enrolled in Total Therapy 2 (TT2). 1 Its discriminatory power has been validated in several published data sets in the transplant, non-transplant and relapse settings (reviewed in Johnson et al. 5 ). We applied the GEP70 model to 56 previously treated patients with available baseline GEP information who were enrolled in Total Therapy 6 (TT6), a tandem transplant trial the details of which are provided in Supplementary Methods . The gene expression profiles have been deposited at the NCBI GEO data repository ( http://www.ncbi.nlm.nih.gov/geo/ ) under GEO accession number GSE57317 . Sample procurement and processing for GEP, as well as calculations of the GEP70 risk score, have been reported previously. 1 The estimated 1-year survival was 62% for the high-risk group and 97% for the low-risk group by GEP70 ( Supplementary Figure S1A , P <0.0001). To investigate whether this striking difference in outcomes was driven by a few genes, all 70 probe sets of the GEP70 risk model were ranked by their P- values, based on univariate Cox regression analysis for OS in TT6 ( Supplementary Table S1 ). The five probe sets with the smallest P -values ( ENO1 , FABP5 , TRIP13 , TAGLN2 and RFC4 ) were combined to create a continuous score, using methodology similar to that used to develop the GEP70 model. 1 Because each of the five probe sets had a positive association with short OS in TT6, the GEP5 score was simply the mean of log2 transformed expression levels of the five probe sets. An optimal cutoff for the new risk score (hereafter referred to as GEP5) was then established with the running log-rank test, so that patients with scores higher than the cutoff were deemed to have high-risk MM and others to have low-risk ( Figure 1a ), with an estimated OS at 1 year of 60% and 95%, respectively (1-year PFS 50% and 91%, respectively). Figure 1 GEP5 distinguishes a high- and a low-risk group with significantly different OS and PFS in the TT6 discovery set, the TT3A training set, and the TT3B and HOVON65/GMMG-HD4 validation sets. Left panels show overall survival, right panels progression-free survival. ( a ) TT6 discovery set; ( b ) TT3A training set; ( c ) TT3B validation set; ( d ) HOVON65/GMMG-HD4 validation set ( P <0.0001, all panels). Full size image

Source: Leukemia

DOI: 10.1038/leu.2014.232