Distinct biological subtypes and patterns of genome evolution in lymphoma revealed by circulating tumor DNA.

Abstract

Patients with diffuse large B cell lymphoma (DLBCL) exhibit marked diversity in tumor behavior and outcomes, yet the identification of poor-risk groups remains challenging. In addition, the biology underlying these differences is incompletely understood. We hypothesized that characterization of mutational heterogeneity and genomic evolution using circulating tumor DNA (ctDNA) profiling could reveal molecular determinants of adverse outcomes. To address this hypothesis, we applied cancer personalized profiling by deep sequencing (CAPP-Seq) analysis to tumor biopsies and cell-free DNA samples from 92 lymphoma patients and 24 healthy subjects. At diagnosis, the amount of ctDNA was found to strongly correlate with clinical indices and was independently predictive of patient outcomes. We demonstrate that ctDNA genotyping can classify transcriptionally defined tumor subtypes, including DLBCL cell of origin, directly from plasma. By simultaneously tracking multiple somatic mutations in ctDNA, our approach outperformed immunoglobulin sequencing and radiographic imaging for the detection of minimal residual disease and facilitated noninvasive identification of emergent resistance mutations to targeted therapies. In addition, we identified distinct patterns of clonal evolution distinguishing indolent follicular lymphomas from those that transformed into DLBCL, allowing for potential noninvasive prediction of histological transformation. Collectively, our results demonstrate that ctDNA analysis reveals biological factors that underlie lymphoma clinical outcomes and could facilitate individualized therapy.

• Authors: Florian Scherer, David M Kurtz, Aaron M Newman, Henning Stehr, Alexander F M Craig, Mohammad Shahrokh Esfahani, Alexander F Lovejoy, Jacob J Chabon, Daniel M Klass, Chih Long Liu, Li Zhou, Cynthia Glover, Brendan C Visser, George A Poultsides, Ranjana H Advani, Lauren S Maeda, Neel K Gupta, Ronald Levy, Robert S Ohgami, Christian A Kunder, Maximilian Diehn, Ash A Alizadeh
• Journal: Science translational medicine (Sci Transl Med) Vol. 8 Issue 364 Pg. 364ra155 (11 09 2016) ISSN: 1946-6242 [Electronic] United States
• PMID: 27831904 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2016, American Association for the Advancement of Science.

Chemical References

• Biomarkers, Tumor
• Circulating Tumor DNA
• Immunoglobulins

Topics

• Adult
• Aged
• Aged, 80 and over
• Algorithms
• Biomarkers, Tumor (blood)
• Biopsy
• Cell-Free System
• Circulating Tumor DNA (genetics)
• Female
• Genotype
• Humans
• Immunoglobulins (chemistry)
• Lymphoma, B-Cell (blood, genetics)
• Lymphoma, Large B-Cell, Diffuse (blood, genetics)
• Male
• Middle Aged
• Mutation
• Prognosis
• Recurrence
• Treatment Outcome