title: Analysis of FOXO1 mutations in diffuse large B-cell lymphoma.
abstract: Diffuse large B-cell lymphoma (DLBCL) accounts for 30% to 40% of newly diagnosed lymphomas and has an overall cure rate of approximately 60%. Previously, we observed FOXO1 mutations in non-Hodgkin lymphoma patient samples. To explore the effects of FOXO1 mutations, we assessed FOXO1 status in 279 DLBCL patient samples and 22 DLBCL-derived cell lines. FOXO1 mutations were found in 8.6% (24/279) of DLBCL cases: 92.3% (24/26) of mutations were in the first exon, 46.2% (12/26) were recurrent mutations affecting the N-terminal region, and another 38.5% (10/26) affected the Forkhead DNA binding domain. Recurrent mutations in the N-terminal region resulted in diminished T24 phosphorylation, loss of interaction with 14-3-3, and nuclear retention. FOXO1 mutation was associated with decreased overall survival in patients treated with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (P = .037), independent of cell of origin (COO) and the revised International Prognostic Index (R-IPI). This association was particularly evident (P = .003) in patients in the low-risk R-IPI categories. The independent relationship of mutations in FOXO1 to survival, transcending the prognostic influence of the R-IPI and COO, indicates that FOXO1 mutation is a novel prognostic factor that plays an important role in DLBCL pathogenesis.
authors: Canada's Michael Smith Genome Sciences Centre, British Columbia Cancer Agency, Vancouver, Canada.
authors: Diane L
authors: DL
authors: Trinh
authors: David W
authors: DW
authors: Scott
authors: Ryan D
authors: RD
authors: Morin
authors: Maria
authors: M
authors: Mendez-Lago
authors: Jianghong
authors: J
authors: An
authors: Steven J M
authors: SJ
authors: Jones
authors: Andrew J
authors: AJ
authors: Mungall
authors: Yongjun
authors: Y
authors: Zhao
authors: Jacqueline
authors: J
authors: Schein
authors: Christian
authors: C
authors: Steidl
authors: Joseph M
authors: JM
authors: Connors
authors: Randy D
authors: RD
authors: Gascoyne
authors: Marco A
authors: MA
authors: Marra
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D045744:Cell Line, Tumor; D004252:DNA Mutational Analysis; D005260:Female; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000737:chemistry / Q000235:genetics* / Q000502:physiology; D020022:Genetic Predisposition to Disease; D057809:HEK293 Cells; D006801:Humans; D016403:Lymphoma, Large B-Cell, Diffuse / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D008958:Models, Molecular; D009154:Mutation / Q000502:physiology; D011379:Prognosis; D055815:Young Adult
chemical_list: C085126:FOXO1 protein, human; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors