缺氧诱导因子-1α表达预测接受 R-CHOP 治疗的弥漫性大 B 细胞淋巴瘤患者的生存优势。
Hypoxia-inducible factor-1 {alpha} expression predicts superior survival in patients with diffuse large B-cell lymphoma treated with R-CHOP.
机构信息
DO, Division of Hematology/Oncology, 676 N St Clair St, Suite 850, Chicago, IL 60611, USA.
出版信息
J Clin Oncol. 2010 Feb 20;28(6):1017-24. doi: 10.1200/JCO.2009.24.1893. Epub 2010 Jan 4.
PURPOSE Hypoxia-inducible factor (HIF) controls the expression of genes in response to hypoxia, as well as a wide range of other cellular processes. We previously showed constitutive stabilization of HIF-1alpha in the majority of patients with diffuse large B-cell lymphoma (DLBCL). To our knowledge, the prognostic significance of HIF in lymphoma has never been investigated. PATIENTS AND METHODS We studied the immunohistochemical protein expression of HIF-1alpha on tissue microarrays from 153 patients with DLBCL treated in sequential cohorts with cyclophosphamide, doxorubicin, oncovin, and prednisone (CHOP) or rituximab-CHOP (R-CHOP) from 1999 to 2002. Results were correlated with patient outcome. Results Median follow-up for all patients was 80 months. Among all patients, HIF-1alpha was expressed in 62% of germinal center and 59% of non-germinal center patients. With HIF-1alpha analyzed as a dependent variable, there were no survival differences in CHOP-treated patients. In the R-CHOP group, however, HIF-1alpha protein expression correlated with significantly improved progression-free survival (PFS) and overall survival (OS). Five-year PFS for HIF-1alpha-positive patients was 71% v 43% for HIF-1alpha-negative patients (P = .0187), whereas 5-year OS was 75% and 54%, respectively (P = .025). In multivariate analysis with International Prognostic Index criteria, HIF-1alpha remained a significant predictor for PFS (P = .026) and OS (P = .043). Compared with other biomarkers, HIF-1alpha correlated only with BCL6 (P = .004). In terms of gene expression, we found several common gene associations of HIF-1alpha and the stromal-1 signature with genes predominantly involved in regulation of the extracellular matrix (eg, BGN, COL1A2, COL5A1, and PLOD2). CONCLUSION The expression of HIF-1alpha protein is an important independent favorable prognostic factor for survival in patients with DLBCL treated with R-CHOP.
目的
缺氧诱导因子（HIF）可控制基因在缺氧时的表达以及广泛的其他细胞过程。我们之前曾在大多数弥漫性大 B 细胞淋巴瘤（DLBCL）患者中显示出 HIF-1α的组成性稳定。据我们所知，HIF 在淋巴瘤中的预后意义从未被研究过。
患者和方法
我们研究了在 1999 年至 2002 年间，使用环磷酰胺、多柔比星、长春新碱和泼尼松（CHOP）或利妥昔单抗-CHOP（R-CHOP）连续治疗的 153 例 DLBCL 患者的组织微阵列上 HIF-1α的免疫组织化学蛋白表达。结果与患者的结局相关。
结果
所有患者的中位随访时间为 80 个月。在所有患者中，HIF-1α在生发中心患者中的表达率为 62%，在非生发中心患者中的表达率为 59%。在以 HIF-1α为因变量进行分析时，CHOP 治疗组患者的生存无差异。然而，在 R-CHOP 组中，HIF-1α蛋白的表达与无进展生存期（PFS）和总生存期（OS）的显著改善相关。HIF-1α阳性患者的 5 年 PFS 为 71%，而 HIF-1α阴性患者为 43%（P=.0187），5 年 OS 分别为 75%和 54%（P=.025）。在具有国际预后指数标准的多变量分析中，HIF-1α仍然是 PFS（P=.026）和 OS（P=.043）的重要预测因素。与其他生物标志物相比，HIF-1α仅与 BCL6 相关（P=.004）。在基因表达方面，我们发现 HIF-1α与基质-1 特征的几个共同基因关联，这些基因主要与细胞外基质的调节有关（例如，BGN、COL1A2、COL5A1 和 PLOD2）。
结论
在接受 R-CHOP 治疗的 DLBCL 患者中，HIF-1α蛋白的表达是一个重要的独立的预后良好的生存因素。
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