Distinct biological subtypes and patterns of genome evolution in lymphoma revealed by circulating tumor DNA.
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.
Division of Oncology, Department of Medicine, Stanford University, Stanford, CA 94305, USA.
Florian
F
Scherer
Division of Oncology, Department of Medicine, Stanford University, Stanford, CA 94305, USA.|Department of Bioengineering, Stanford University, Stanford, CA 94305, USA.|Division of Hematology, Department of Medicine, Stanford University, Stanford, CA 94305, USA.
David M
DM
Kurtz
Division of Oncology, Department of Medicine, Stanford University, Stanford, CA 94305, USA.|Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, CA 94305, USA.
Aaron M
AM
Newman
Stanford Cancer Institute, Stanford University, Stanford, CA 94305, USA.
Henning
H
Stehr
Division of Oncology, Department of Medicine, Stanford University, Stanford, CA 94305, USA.
Alexander F M
AF
Craig
Division of Oncology, Department of Medicine, Stanford University, Stanford, CA 94305, USA.
Mohammad Shahrokh
MS
Esfahani
Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, CA 94305, USA.|Stanford Cancer Institute, Stanford University, Stanford, CA 94305, USA.|Department of Radiation Oncology, Stanford University, Stanford, CA 94305, USA.
Alexander F
AF
Lovejoy
Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, CA 94305, USA.
Jacob J
JJ
Chabon
Division of Oncology, Department of Medicine, Stanford University, Stanford, CA 94305, USA.|Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, CA 94305, USA.|Stanford Cancer Institute, Stanford University, Stanford, CA 94305, USA.
Daniel M
DM
Klass
Division of Oncology, Department of Medicine, Stanford University, Stanford, CA 94305, USA.|Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, CA 94305, USA.
Chih Long
CL
Liu
Stanford Cancer Institute, Stanford University, Stanford, CA 94305, USA.
Li
L
Zhou
Division of Oncology, Department of Medicine, Stanford University, Stanford, CA 94305, USA.
Cynthia
C
Glover
Division of Surgical Oncology, Department of Surgery, Stanford University, Stanford, CA 94305, USA.
Brendan C
BC
Visser
Division of Surgical Oncology, Department of Surgery, Stanford University, Stanford, CA 94305, USA.
George A
GA
Poultsides
Division of Oncology, Department of Medicine, Stanford University, Stanford, CA 94305, USA.
Ranjana H
RH
Advani
Division of Oncology, Department of Medicine, Stanford University, Stanford, CA 94305, USA.|Division of Hematology, Department of Medicine, Stanford University, Stanford, CA 94305, USA.
Lauren S
LS
Maeda
Division of Oncology, Department of Medicine, Stanford University, Stanford, CA 94305, USA.|Division of Hematology, Department of Medicine, Stanford University, Stanford, CA 94305, USA.
Neel K
NK
Gupta
Division of Oncology, Department of Medicine, Stanford University, Stanford, CA 94305, USA.
Ronald
R
Levy
Department of Pathology, Stanford University, Stanford, CA 94305, USA.
Robert S
RS
Ohgami
Department of Pathology, Stanford University, Stanford, CA 94305, USA.
Christian A
CA
Kunder
Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, CA 94305, USA. arasha@stanford.edu diehn@stanford.edu.|Stanford Cancer Institute, Stanford University, Stanford, CA 94305, USA.|Department of Radiation Oncology, Stanford University, Stanford, CA 94305, USA.
Maximilian
M
Diehn
Division of Oncology, Department of Medicine, Stanford University, Stanford, CA 94305, USA. arasha@stanford.edu diehn@stanford.edu.|Division of Hematology, Department of Medicine, Stanford University, Stanford, CA 94305, USA.|Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, CA 94305, USA.|Stanford Cancer Institute, Stanford University, Stanford, CA 94305, USA.
Ash A
AA
Alizadeh
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000465:Algorithms; D014408:Biomarkers, Tumor / Q000097:blood; D001706:Biopsy; D002474:Cell-Free System; D000074141:Circulating Tumor DNA / Q000235:genetics*; D005260:Female; D005838:Genotype; D006801:Humans; D007136:Immunoglobulins / Q000737:chemistry; D016393:Lymphoma, B-Cell / Q000097:blood / Q000235:genetics*; D016403:Lymphoma, Large B-Cell, Diffuse / Q000097:blood / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D011379:Prognosis; D012008:Recurrence; D016896:Treatment Outcome
D014408:Biomarkers, Tumor; D000074141:Circulating Tumor DNA; D007136:Immunoglobulins