Whole-exome analysis reveals novel somatic genomic alterations associated with outcome in immunochemotherapy-treated diffuse large B-cell lymphoma

A J Novak; Y W Asmann; M J Maurer; C Wang; S L Slager; L S Hodge; M Manske; T Price-Troska; Z-Z Yang; M T Zimmermann; G S Nowakowski; S M Ansell; T E Witzig; E McPhail; R Ketterling; A L Feldman; A Dogan; B K Link; T M Habermann; J R Cerhan

doi:10.1038/bcj.2015.69

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Whole-exome analysis reveals novel somatic genomic alterations associated with outcome in immunochemotherapy-treated diffuse large B-cell lymphoma

Journal article

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Whole-exome analysis reveals novel somatic genomic alterations associated with outcome in immunochemotherapy-treated diffuse large B-cell lymphoma

A J Novak, Y W Asmann, M J Maurer, C Wang, S L Slager, L S Hodge, M Manske, T Price-Troska, Z-Z Yang, M T Zimmermann, …

Blood cancer journal (New York), Vol.5(8), pp.e346-e346

08/28/2015

DOI: 10.1038/bcj.2015.69

PMCID: PMC4558593

PMID: 26314988

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Abstract

Lack of remission or early relapse remains a major clinical issue in diffuse large B-cell lymphoma (DLBCL), with 30% of patients failing standard of care. Although clinical factors and molecular signatures can partially predict DLBCL outcome, additional information is needed to identify high-risk patients, particularly biologic factors that might ultimately be amenable to intervention. Using whole-exome sequencing data from 51 newly diagnosed and immunochemotherapy-treated DLBCL patients, we evaluated the association of somatic genomic alterations with patient outcome, defined as failure to achieve event-free survival at 24 months after diagnosis (EFS24). We identified 16 genes with mutations, 374 with copy number gains and 151 with copy number losses that were associated with failure to achieve EFS24 (P<0.05). Except for FOXO1 and CIITA, known driver mutations did not correlate with EFS24. Gene losses were localized to 6q21-6q24.2, and gains to 3q13.12-3q29, 11q23.1-11q23.3 and 19q13.12-19q13.43. Globally, the number of gains was highly associated with poor outcome (P=7.4 × 10(-12)) and when combined with FOXO1 mutations identified 77% of cases that failed to achieve EFS24. One gene (SLC22A16) at 6q21, a doxorubicin transporter, was lost in 54% of EFS24 failures and our findings suggest it functions as a doxorubicin transporter in DLBCL cells.

Sequence Deletion

Genetic Association Studies

Humans

Middle Aged

Kaplan-Meier Estimate

Male

Treatment Outcome

Combined Modality Therapy

DNA Copy Number Variations

Lymphoma, Large B-Cell, Diffuse - mortality

Exome - genetics

Lymphoma, Large B-Cell, Diffuse - therapy

Biological Transport

DNA Mutational Analysis

Aged, 80 and over

Female

Aged

Doxorubicin - metabolism

Genome, Human

Organic Cation Transport Proteins - genetics

Lymphoma, Large B-Cell, Diffuse - genetics

Details

Title: Subtitle: Whole-exome analysis reveals novel somatic genomic alterations associated with outcome in immunochemotherapy-treated diffuse large B-cell lymphoma
Creators: A J Novak - Division of Hematology, Mayo Clinic, Rochester, MN, USA
Y W Asmann - Department of Health Sciences Research, Mayo Clinic, Jacksonville, FL, USA
M J Maurer - Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, MN, USA
C Wang - Mayo Clinic
S L Slager - Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, MN, USA
L S Hodge - Division of Hematology, Mayo Clinic, Rochester, MN, USA
M Manske - Division of Hematology, Mayo Clinic, Rochester, MN, USA
T Price-Troska - Division of Hematology, Mayo Clinic, Rochester, MN, USA
Z-Z Yang - Division of Hematology, Mayo Clinic, Rochester, MN, USA
M T Zimmermann - Medical College of Wisconsin
G S Nowakowski - Division of Hematology, Mayo Clinic, Rochester, MN, USA
S M Ansell - Division of Hematology, Mayo Clinic, Rochester, MN, USA
T E Witzig - Division of Hematology, Mayo Clinic, Rochester, MN, USA
E McPhail - Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA
R Ketterling - Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA
A L Feldman - Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA
A Dogan - Departments of Pathology and Laboratory Medicine, Hematopathology Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA
B K Link - Internal Medicine, University of Iowa, Iowa City, IA, USA
T M Habermann - Division of Hematology, Mayo Clinic, Rochester, MN, USA
J R Cerhan - Division of Epidemiology, Mayo Clinic, Rochester, MN, USA
Resource Type: Journal article
Publication Details: Blood cancer journal (New York), Vol.5(8), pp.e346-e346
DOI: 10.1038/bcj.2015.69
PMID: 26314988
PMCID: PMC4558593
NLM abbreviation: Blood Cancer J
ISSN: 2044-5385
eISSN: 2044-5385
Grant note: P50 CA097274 / NCI NIH HHS
Language: English
Date published: 08/28/2015
Academic Unit: Hematology, Oncology, and Blood & Marrow Transplantation; Epidemiology; Internal Medicine
Record Identifier: 9984094380802771

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