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FOXP1 expression is a prognostic biomarker in follicular lymphoma treated with rituximab-containing regimens

Anja Mottok, Vindi Jurinovic, Pedro Farinha, Andreas Rosenwald, Ellen Leich, German Ott, Heike Horn, Wolfram Klapper, Michael Boesl, Wolfgang Hiddemann, Christian Steidl, Joseph M. Connors, Laurie H. Sehn, Randy D. Gascoyne, Eva Hoster, Oliver Weigert and Robert Kridel

Key points

  • High expression of FOXP1 predicts adverse failure-free survival in follicular lymphoma patients treated with immunochemotherapy.

  • FOXP1 high and low expressors differ in specific gene mutations and gene expression changes.

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 seven 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 a total of 763 tissue biopsies. For outcome correlation, a population-based training cohort of 142 FL patients treated with R-CVP, and a clinical trial validation cohort comprising 395 patients treated with CHOP +/- rituximab were used. We found FOXP1 to be significantly down-regulated 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 five-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 (HR 1.95, P=0.017), but not in patients treated with CHOP (HR 1.15, P=0.44). The impact of high FOXP1 expression on FFS in immunochemotherapy-treated patients was additional to the FLIPI. 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 centre or activated B cells. In summary, FOXP1 is a downstream phenotypic commonality of gene mutations and predicts outcome following rituximab-containing regimens.

  • Submitted August 4, 2017.
  • Accepted October 27, 2017.