Hypoxia-inducible factor-1 α expression predicts superior survival in patients with diffuse large B-cell lymphoma treated with R-CHOP

Andrew M. Evens, Laurie H. Sehn, Pedro Farinha, Beverly P. Nelson, Adekunle Raji, Yi Lu, Adam Brakman, Vamsi Parimi, Jane N. Winter, Paul T. Schumacker, Randy D. Gascoyne, Leo I. Gordon

Research output: Contribution to journalArticlepeer-review

42 Scopus citations

Abstract

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-1α 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-1α 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-1α was expressed in 62% of germinal center and 59% of non-germinal center patients. With HIF-1α analyzed as a dependent variable, there were no survival differences in CHOP-treated patients. In the R-CHOP group, however, HIF-1α protein expression correlated with significantly improved progression-free survival (PFS) and overall survival (OS). Five-year PFS for HIF-1α-positive patients was 71% v 43% for HIF-1α-negative patients (P = .0187), whereas 5-year OS was 75% and 54%, respectively (P = .025). In multivariate analysis with International Prognostic Index criteria, HIF-1α remained a significant predictor for PFS (P = .026) and OS (P = .043). Compared with other biomarkers, HIF-1α correlated only with BCL6 (P = .004). In terms of gene expression, we found several common gene associations of HIF-1α 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-1α protein is an important independent favorable prognostic factor for survival in patients with DLBCL treated with R-CHOP.

Original languageEnglish (US)
Pages (from-to)1017-1024
Number of pages8
JournalJournal of Clinical Oncology
Volume28
Issue number6
DOIs
StatePublished - Feb 20 2010

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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