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.

中文翻译：

---

FOXP1 表达是用含利妥昔单抗方案治疗的滤泡性淋巴瘤的预后生物标志物

滤泡性淋巴瘤 (FL) 是一种临床和分子高度异质性的疾病，但预后主要依赖于临床工具。我们最近证明，整合 7 个基因的突变状态，包括 EZH2 和 MEF2B，可以改善风险分层。我们挖掘基因表达数据以发现在 EZH2 和 MEF2B 突变病例中差异表达的基因。我们专注于 FOXP1 并通过免疫组织化学 (IHC) 在 763 个组织活检中评估其蛋白质表达。对于结果相关性，一个由 142 名接受利妥昔单抗、环磷酰胺、长春新碱和泼尼松治疗的 FL 患者组成的基于人群的训练队列，以及一个由 395 名接受环磷酰胺、多柔比星、长春新碱和强的松 (CHOP) ± 利妥昔单抗治疗的患者组成的临床试验验证队列被使用。我们发现 FOXP1 在 EZH2 和 MEF2B 突变病例中均显着下调。通过 IHC，训练队列中的 76 个样本 (54%) 具有高 FOXP1 表达 (>10%)，这与 5 年无失败生存 (FFS) 率降低有关（55% 对 70%）。在验证队列中，在 248 名患者 (63%) 中观察到高 FOXP1 表达状态，并且与接受 R-CHOP 治疗的患者的 FFS 显着缩短相关（风险比 [HR]，1.95；P = .017），但在接受治疗的患者中没有CHOP（HR，1.15；P = .44）。FOXP1 高表达对免疫化疗治疗患者 FFS 的影响是滤泡性淋巴瘤国际预后指数的补充。FOXP1 的高表达与不同的分子特征相关，例如 TP53 突变、IRF4 的表达、和基因表达特征让人联想到暗区生发中心或激活的 B 细胞。总之，FOXP1 是基因突变的下游表型共性，可预测含利妥昔单抗方案后的结果。