FOXP1 expression is a prognostic biomarker in follicular lymphoma treated with rituximab and chemotherapy

Blood. 2018 Jan 11;131(2):226-235. doi: 10.1182/blood-2017-08-799080. Epub 2017 Nov 9.

Abstract

Follicular lymphoma (FL) is a clinically and molecularly highly heterogeneous disease, yet prognostication relies predominantly on clinical tools. We recently demonstrated that integration of mutation status of 7 genes, including EZH2 and MEF2B, improves risk stratification. We mined gene expression data to uncover genes that are differentially expressed in EZH2- and MEF2B-mutated cases. We focused on FOXP1 and assessed its protein expression by immunohistochemistry (IHC) in 763 tissue biopsies. For outcome correlation, a population-based training cohort of 142 patients with FL treated with rituximab, cyclophosphamide, vincristine, and prednisone, and a clinical trial validation cohort comprising 395 patients treated with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) ± rituximab were used. We found FOXP1 to be significantly downregulated in both EZH2- and MEF2B-mutated cases. By IHC, 76 specimens in the training cohort (54%) had high FOXP1 expression (>10%), which was associated with reduced 5-year failure-free survival (FFS) rates (55% vs 70%). In the validation cohort, high FOXP1 expression status was observed in 248 patients (63%) and correlated with significantly shorter FFS in patients treated with R-CHOP (hazard ratio [HR], 1.95; P = .017) but not in patients treated with CHOP (HR, 1.15; P = .44). The impact of high FOXP1 expression on FFS in immunochemotherapy-treated patients was additional to the Follicular Lymphoma International Prognostic Index. High FOXP1 expression was associated with distinct molecular features such as TP53 mutations, expression of IRF4, and gene expression signatures reminiscent of dark zone germinal center or activated B cells. In summary, FOXP1 is a downstream phenotypic commonality of gene mutations and predicts outcome following rituximab-containing regimens.

Publication types

  • Clinical Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents, Immunological / therapeutic use*
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use
  • Cyclophosphamide / therapeutic use
  • Doxorubicin / therapeutic use
  • Enhancer of Zeste Homolog 2 Protein / genetics
  • Forkhead Transcription Factors / analysis
  • Forkhead Transcription Factors / genetics*
  • Gene Expression Regulation, Neoplastic*
  • Humans
  • Lymphoma, Follicular / drug therapy*
  • Lymphoma, Follicular / genetics
  • Lymphoma, Follicular / pathology
  • MEF2 Transcription Factors / genetics
  • Middle Aged
  • Mutation
  • Prednisolone / therapeutic use
  • Prednisone / therapeutic use
  • Prognosis
  • Repressor Proteins / analysis
  • Repressor Proteins / genetics*
  • Rituximab / therapeutic use*
  • Treatment Outcome
  • Vincristine / therapeutic use

Substances

  • Antineoplastic Agents, Immunological
  • FOXP1 protein, human
  • Forkhead Transcription Factors
  • MEF2 Transcription Factors
  • MEF2B protein, human
  • R-CVP protocol
  • Repressor Proteins
  • Rituximab
  • Vincristine
  • Doxorubicin
  • Cyclophosphamide
  • Prednisolone
  • EZH2 protein, human
  • Enhancer of Zeste Homolog 2 Protein
  • Prednisone

Supplementary concepts

  • VAP-cyclo protocol