title: Whole-exome analysis reveals novel somatic genomic alterations associated with outcome in immunochemotherapy-treated diffuse large B-cell lymphoma.
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.
authors: Division of Hematology, Mayo Clinic, Rochester, MN, USA.
authors: A J
authors: AJ
authors: Novak
authors: Department of Health Sciences Research, Mayo Clinic, Jacksonville, FL, USA.
authors: Y W
authors: YW
authors: Asmann
authors: Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, MN, USA.
authors: M J
authors: MJ
authors: Maurer
authors: Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, MN, USA.
authors: C
authors: C
authors: Wang
authors: Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, MN, USA.
authors: S L
authors: SL
authors: Slager
authors: Division of Hematology, Mayo Clinic, Rochester, MN, USA.
authors: L S
authors: LS
authors: Hodge
authors: Division of Hematology, Mayo Clinic, Rochester, MN, USA.
authors: M
authors: M
authors: Manske
authors: Division of Hematology, Mayo Clinic, Rochester, MN, USA.
authors: T
authors: T
authors: Price-Troska
authors: Division of Hematology, Mayo Clinic, Rochester, MN, USA.
authors: Z-Z
authors: ZZ
authors: Yang
authors: Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, MN, USA.
authors: M T
authors: MT
authors: Zimmermann
authors: Division of Hematology, Mayo Clinic, Rochester, MN, USA.
authors: G S
authors: GS
authors: Nowakowski
authors: Division of Hematology, Mayo Clinic, Rochester, MN, USA.
authors: S M
authors: SM
authors: Ansell
authors: Division of Hematology, Mayo Clinic, Rochester, MN, USA.
authors: T E
authors: TE
authors: Witzig
authors: Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.
authors: E
authors: E
authors: McPhail
authors: Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.
authors: R
authors: R
authors: Ketterling
authors: Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.
authors: A L
authors: AL
authors: Feldman
authors: Departments of Pathology and Laboratory Medicine, Hematopathology Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors: A
authors: A
authors: Dogan
authors: Internal Medicine, University of Iowa, Iowa City, IA, USA.
authors: B K
authors: BK
authors: Link
authors: Division of Hematology, Mayo Clinic, Rochester, MN, USA.
authors: T M
authors: TM
authors: Habermann
authors: Division of Epidemiology, Mayo Clinic, Rochester, MN, USA.
authors: J R
authors: JR
authors: Cerhan
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D001692:Biological Transport; D003131:Combined Modality Therapy; D056915:DNA Copy Number Variations; D004252:DNA Mutational Analysis; D004317:Doxorubicin / Q000378:metabolism; D059472:Exome / Q000235:genetics*; D005260:Female; D056726:Genetic Association Studies; D015894:Genome, Human; D006801:Humans; D053208:Kaplan-Meier Estimate; D016403:Lymphoma, Large B-Cell, Diffuse / Q000235:genetics* / Q000401:mortality / Q000628:therapy; D008297:Male; D008875:Middle Aged; D027701:Organic Cation Transport Proteins / Q000235:genetics*; D017384:Sequence Deletion; D016896:Treatment Outcome
chemical_list: D027701:Organic Cation Transport Proteins; C467737:SLC22A16 protein, human; D004317:Doxorubicin