The varied distribution and impact of RAS codon and other key DNA alterations across the translocation cyclin D subgroups in multiple myeloma

// Caleb K. Stein 1 , Charlotte Pawlyn 2 , Shweta Chavan 1 , Leo Rasche 1 , Niels Weinhold 1 , Adam Corken 1 , Amy Buros 1 , Pieter Sonneveld 3 , Graham H. Jackson 4 , Ola Landgren 5 , Tariq Mughal 6, 7 , Jie He 6 , Bart Barlogie 1 , P. Leif Bergsagel 8 , Faith E. Davies 1 , Brian A. Walker 1 , Gareth J. Morgan 1 1 The Myeloma Institute, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA 2 The Institute of Cancer Research, London, UK 3 Eramus University, Rotterdam, NL 4 Department of Haematology, Newcastle University, Newcastle-upon-Tyne, UK 5 Memorial Sloan Kettering Cancer Center, New York, New York, USA 6 FoundationOne Medicine, Cambridge, Massachusetts, USA 7 Tufts Medical Center, Boston, Massachusetts, USA 8 Mayo Clinic, Scottsdale, Arizona, USA Correspondence to: Caleb K. Stein, email: CKStein@uams.edu Keywords: multiple myeloma, gene expression profiling, mutational analysis, translocation cyclin D (TC) Received: January 13, 2017      Accepted: February 15, 2017      Published: February 24, 2017 ABSTRACT We examined a set of 805 cases that underwent DNA sequencing using the FoundationOne Heme (F1H) targeted sequencing panel and gene expression profiling. Known and likely variant calls from the mutational data were analyzed for significant associations with gene expression defined translocation cyclin D (TC) molecular subgroups. The spectrum of KRAS, NRAS, and BRAF codon mutations varied across subgroups with NRAS mutations at Q61 codon being common in hyperdiploid (HRD) and t(11;14) myeloma while being rare in MMSET and MAF. In addition, the presence of RAS-RAF mutations was inversely associated with NFκB pathway activation in all subgroups excluding MAF. In the MMSET subgroup, cases with low FGFR3 expression frequently had RAS-RAF mutations. Conditional inference tree analysis determined that mutation and homozygous deletion of TP53, CDKN2C, and RB1 were key prognostic factors associated with adverse outcome in a non-relapse clinical setting. In conclusion, this study highlights the heterogeneity in the distribution and clinical outcomes of RAS codon and other mutations in multiple myeloma dependent upon primary molecular subgroup.