Priority Research Papers:
Comparative analysis of primary versus relapse/refractory DLBCL identifies shifts in mutation spectrum
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Danielle M. Greenawalt1,4, Winnie S. Liang2 Sakina Saif1, Justin Johnson1, Petar Todorov1, Austin Dulak1, Daniel Enriquez2, Rebecca Halperin2, Ambar Ahmed1, Vladislav Saveliev3, John Carpten2, David Craig2, J. Carl Barrett1, Brian Dougherty1, Michael Zinda1, Stephen Fawell1, Jonathan R. Dry1 and Kate Byth1
1 Oncology Innovative Medicines and Early Development, AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, MA, USA
2 Translational Genomics Research Institute, 445 N. Fifth Street, Phoenix AZ, USA
3 Center for Algorithmic Biotechnology, Institute of Translational Biomedicine, St. Petersburg State University, St. Petersburg, Russia
4 Current address: Translational Bioinformatics, Bristol-Myers Squibb Company, 331 Pennington Rocky Hill Rd. Hopewell, NJ
Jonathan Dry, email:
Danielle Greenawalt, email:
Keywords: DLBCL, R-CHOP, NGS, mutation, resistance
Received: December 21, 2016 Accepted: April 04, 2017 Published: June 15, 2017
Current understanding of the mutation spectrum of relapsed/refractory (RR) tumors is limited. We performed whole exome sequencing (WES) on 47 diffuse large B cell lymphoma (DLBCL) tumors that persisted after R-CHOP treatment, 8 matched to primary biopsies. We compared genomic alterations from the RR cohort against two treatment-naïve DLBCL cohorts (n=112). While the overall number and types of mutations did not differ significantly, we identified frequency changes in DLBCL driver genes. The overall frequency of MYD88 mutant samples increased (12% to 19%), but we noted a decrease in p.L265P (8% to 4%) and increase in p.S219C mutations (2% to 6%). CARD11 p.D230N, PIM1 p.K115N and CD79B p.Y196C mutations were not observed in the RR cohort, although these mutations were prominent in the primary DLBCL samples. We observed an increase in BCL2 mutations (21% to 38% of samples), BCL2 amplifications (3% to 6% of samples) and CREBBP mutations (31% to 42% of samples) in the RR cohort, supported by acquisition of mutations in these genes in relapsed compared to diagnostic biopsies from the same patient. These increases may reflect the genetic characteristics of R-CHOP RR tumors expected to be enriched for during clinical trial enrollment. These findings hold significance for a number of emerging targeted therapies aligned to genetic targets and biomarkers in DLBCL, reinforcing the importance of time-of-treatment biomarker screening during DLBCL therapy selection.
Danielle M. Greenawalt
Winnie S. Liang
J. Carl Barrett
Jonathan R. Dry
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