Faculty Collaboration Database

Whole-exome analysis reveals novel somatic genomic alterations associated with outcome in immunochemotherapy-treated diffuse large B-cell lymphoma. Blood Cancer J 2015 Aug 28;5(8):e346

Date

09/01/2015

Pubmed ID

26314988

Pubmed Central ID

PMC4558593

DOI

10.1038/bcj.2015.69

Scopus ID

2-s2.0-84975318451 (requires institutional sign-in at Scopus site)   52 Citations

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.

Author List

Novak AJ, Asmann YW, Maurer MJ, Wang C, Slager SL, Hodge LS, Manske M, Price-Troska T, Yang ZZ, Zimmermann MT, Nowakowski GS, Ansell SM, Witzig TE, McPhail E, Ketterling R, Feldman AL, Dogan A, Link BK, Habermann TM, Cerhan JR

Author

Michael T. Zimmermann PhD Director, Assistant Professor in the Clinical and Translational Science Institute department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Aged
Aged, 80 and over
Biological Transport
Combined Modality Therapy
DNA Copy Number Variations
DNA Mutational Analysis
Doxorubicin
Exome
Female
Genetic Association Studies
Genome, Human
Humans
Kaplan-Meier Estimate
Lymphoma, Large B-Cell, Diffuse
Male
Middle Aged
Organic Cation Transport Proteins
Sequence Deletion
Treatment Outcome