Hostname: page-component-7c8c6479df-27gpq Total loading time: 0 Render date: 2024-03-28T19:02:27.217Z Has data issue: false hasContentIssue false

3195 Genomic Analysis of Primary Plasma Cell Leukemia reveals Complex Cytogenetic Alterations and High Risk Mutational Patterns

Published online by Cambridge University Press:  26 March 2019

Carolina Schinke
Affiliation:
University of Arkansas Translational Research Institute
Eileen Boyle
Affiliation:
University of Arkansas Translational Research Institute
Cody Ashby
Affiliation:
University of Arkansas Translational Research Institute
Yan Wang
Affiliation:
University of Arkansas Translational Research Institute
Davies Christopher Wardell
Affiliation:
University of Arkansas Translational Research Institute
Sharmilan Thanendrarajan
Affiliation:
University of Arkansas Translational Research Institute
maurizio Zangari
Affiliation:
University of Arkansas Translational Research Institute
Frits van Rhee
Affiliation:
University of Arkansas Translational Research Institute
Gareth Morgan
Affiliation:
University of Arkansas Translational Research Institute
Brian Walker
Affiliation:
University of Arkansas Translational Research Institute
Rights & Permissions [Opens in a new window]

Abstract

Core share and HTML view are not available for this content. However, as you have access to this content, a full PDF is available via the ‘Save PDF’ action button.

OBJECTIVES/SPECIFIC AIMS: 1) Determine the mutational landscape, including translocation, mutations and mutational signatures as well as copy number variations of pPCL and identify significant differences to non pPCL MM. 2) Determine whether genetic changes pertinent to pPCL could be explored as therapeutic targets to improve the dismal prognosis of this patient population. METHODS/STUDY POPULATION: Samples from overall 19 pPCL patients that presented to the Myeloma Center, UAMS between 2000-2018 were used for this study. We performed gene expression profiling (GEP; Affymetrix U133 Plus 2.0) of matched circulating peripheral PCs and bone marrow (BM) PCs from 13 patients. Whole exome sequencing (WES) was performed on purified CD138+ PCs from BM aspirates from 19 pPCL patients with a median depth of 61x. CD34+ sorted cells, taken at the time of stem cell harvest from the same 19 patients, were used as controls. Translocations and mutations were called using Manta and Strelka and annotated as previously reported. Copy number was determined by Sequenza. RESULTS/ANTICIPATED RESULTS: 1) GEP from the BM and circulating peripheral PCs showed that the expression patterns of the two samples from each individual clustered together, indicating that circulating PCs and BM PCs in pPCL result from the same clone and are biologically clearly related. 2) The clinical characteristics from the patient cohort used for WES analysis were as follows: median age was 58 years (range 36–77), females accounted for 74% (14/19), an elevated creatinine level was found in 78% (14/18) and an elevated LDH level in 71% (10/14). All patients presented with an ISS stage of III. Median OS of the whole dataset was poor at 22 months, which is consistent with OS from previously reported pPCL cohorts. 3) Primary Immunoglobulin translocations were common and identified in 63% (12/19) of patients, including MAF translocations, which are known to carry high risk in 42% (8/19) of patients [t(14;16), 32% and t(14;20), 10%] followed by t(11;14) (16%) and t(4;14) (10%). Furthermore, 32% (6/19) of patients had at least one MYC translocation, which are known to play a crucial role in disease progression. 4) The mutational burden of pPCL consisted of a median of 98 non-silent mutations per sample, suggesting that the mutational landscape of pPCL is highly complex and harbors more coding mutations than non-pPCL MM. 5) Driver mutations, that previously have been described in non-pPCL MM showed a different prevalence and distribution in pPCL, including KRAS and TP53 with 47% (9/19) and 37% (7/19) affected patients respectively compared to 21% and 5% in non-PCL MM. PIK3CA (5%), PRDM1 (10%), EP300 (10%) and NF1 (10%) were also enriched in the pPCL group compared to previously reported cases in non-pPCL MM. 6) Biallelic inactivation of TP53 – a feature of Double Hit myeloma - was found in 6/19 (32%) samples, indicating a predominance of high risk genomic features compared to non-pPCL MM. Furthermore, analysis of mutational signatures in pPCL showed that aberrant APOBEC activity was highly prevalent only in patients with a MAF translocation, but not in other translocation groups. DISCUSSION/SIGNIFICANCE OF IMPACT: In conclusion we present one of the first WES datasets on pPCL with the largest patient cohort reported to date and show that pPCL is a highly complex disease. The aggressive disease behavior can, at least in part, be explained by a high prevalence of MAF and MYC translocations, TP53 and KRAS mutations as well as bi-allelic inactivation of TP53. It is of interest that only KRAS but not NRAS mutations are highly enriched in pPCL. From all highly prevalent genomic alterations in pPCL, only KRAS mutations offer a potential for already available therapeutically targeting with MEK inhibitors, which should be further explored.

Type
Basic/Translational Science/Team Science
Creative Commons
Creative Common License - CCCreative Common License - BYCreative Common License - NCCreative Common License - ND
This is an Open Access article, distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives licence (http://creativecommons.org/licenses/by-ncnd/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is unaltered and is properly cited. The written permission of Cambridge University Press must be obtained for commercial re-use or in order to create a derivative work.
Copyright
© The Association for Clinical and Translational Science 2019