Host immune gene polymorphisms in combination with clinical and demographic factors predict late survival in diffuse large B-cell lymphoma patients in the pre-rituximab era.

To evaluate the hypothesis that host germ line variation in immune genes is associated with overall survival in diffuse large B-cell lymphoma (DLBCL), we genotyped 73 single nucleotide polymorphisms (SNPs) from 44 candidate genes in 365 DLBCL patients diagnosed from 1998 to 2000. We estimated hazard ratios (HRs) and 95% confidence intervals (CIs) for the association of SNPs with survival after adjusting for clinical factors. During follow-up, 96 (26%) patients died, and the median follow-up was 57 months for surviving patients. The observed survival of this cohort was consistent with population-based estimates conditioned on surviving 12 months. An IL10 haplotype (global P = .03) and SNPs in IL8RB (rs1126580; HR(AG/GG) = 2.11; CI, 1.28-3.50), IL1A (rs1800587; HR(CT/TT) = 1.90; CI, 1.26-2.87), TNF (rs1800629; HR(AG/GG) = 1.44; CI, 0.95-2.18), and IL4R (rs2107356; HR(CC/CT) = 1.97; CI, 1.01-3.83) were the strongest predictors of overall survival. A risk score that combined the latter 4 SNPs with clinical factors was strongly associated with survival in a Cox model (P = 6.0 x 10(-11)). Kaplan-Meier 5-year survival estimates for low, intermediate-low, intermediate-high, and high-risk patients were 94%, 79%, 60%, and 48%, respectively. These data support a role for germ line variation in immune genes, particularly genes associated with a proinflammatory state, as predictors of late survival in DLBCL.

[1]  G. Saglio,et al.  Molecular pathogenesis of diffuse large B-cell lymphoma , 2009 .

[2]  D. Weisenburger,et al.  Proposed classification of lymphoid neoplasms for epidemiologic research from the Pathology Working Group of the International Lymphoma Epidemiology Consortium (InterLymph). , 2007, Blood.

[3]  J. Cerhan,et al.  Prognostic significance of host immune gene polymorphisms in follicular lymphoma survival. , 2007, Blood.

[4]  N. Rothman,et al.  Polymorphisms in immune function genes and risk of non-Hodgkin lymphoma: findings from the New South Wales non-Hodgkin Lymphoma Study. , 2007, Carcinogenesis.

[5]  M. Pfreundschuh,et al.  The interleukin-10 gene promoter polymorphism −1087AG does not correlate with clinical outcome in non-Hodgkin's lymphoma , 2007, Genes and Immunity.

[6]  Nilanjan Chatterjee,et al.  Common genetic variants in proinflammatory and other immunoregulatory genes and risk for non-Hodgkin lymphoma. , 2006, Cancer research.

[7]  Randy D Gascoyne,et al.  Rituximab-CHOP versus CHOP alone or with maintenance rituximab in older patients with diffuse large B-cell lymphoma. , 2006, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[8]  Peter Boyle,et al.  Cytokine polymorphisms in the Th1/Th2 pathway and susceptibility to non-Hodgkin lymphoma. , 2006, Blood.

[9]  R. Millikan,et al.  Bladder cancer predisposition: a multigenic approach to DNA-repair and cell-cycle-control genes. , 2006, American journal of human genetics.

[10]  N. Crawford,et al.  Germ line polymorphism in metastatic progression. , 2006, Cancer research.

[11]  I. Soubeyran,et al.  Aggressive non-Hodgkin's lymphoma: Concomitant evaluation of interleukin-2, soluble interleukin-2 receptor, interleukin-4, interleukin-6, interleukin-10 and correlation with outcome , 2006, Leukemia & lymphoma.

[12]  R. Tibshirani,et al.  A tail strength measure for assessing the overall univariate significance in a dataset. , 2005, Biostatistics.

[13]  P. Gaulard,et al.  Long-term results of the R-CHOP study in the treatment of elderly patients with diffuse large B-cell lymphoma: a study by the Groupe d'Etude des Lymphomes de l'Adulte. , 2005, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[14]  R. Rosenquist,et al.  The interleukin-10 gene promoter polymorphism (-1082) does not correlate with clinical outcome in diffuse large B-cell lymphoma. , 2005, Blood.

[15]  Ash A. Alizadeh,et al.  Distinct IL-4-induced gene expression, proliferation, and intracellular signaling in germinal center B-cell-like and activated B-cell-like diffuse large-cell lymphomas. , 2005, Blood.

[16]  T. Golub,et al.  Molecular profiling of diffuse large B-cell lymphoma identifies robust subtypes including one characterized by host inflammatory response. , 2004, Blood.

[17]  R. Gascoyne.  Emerging prognostic factors in diffuse large B cell lymphoma , 2004, Current opinion in oncology.

[18]  J. D. De Larco,et al.  The Potential Role of Neutrophils in Promoting the Metastatic Phenotype of Tumors Releasing Interleukin-8 , 2004, Clinical Cancer Research.

[19]  G. Salles,et al.  Interleukin-10 gene promoter polymorphisms influence the clinical outcome of diffuse large B-cell lymphoma. , 2004, Blood.

[20]  Adrian Wiestner,et al.  A gene expression-based method to diagnose clinically distinct subgroups of diffuse large B cell lymphoma , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[21]  Robert Tibshirani,et al.  HGAL is a novel interleukin-4-inducible gene that strongly predicts survival in diffuse large B-cell lymphoma. , 2003, Blood.

[22]  G. Salles,et al.  Human leukocyte antigens class II and tumor necrosis factor genetic polymorphisms are independent predictors of non-Hodgkin lymphoma outcome. , 2002, Blood.

[23]  Joseph L. Gastwirth,et al.  Trend Tests for Case-Control Studies of Genetic Markers: Power, Sample Size and Robustness , 2002, Human Heredity.

[24]  P. Pavlidis,et al.  Cutting Edge: STAT6 Serves as a Positive and Negative Regulator of Gene Expression in IL-4-Stimulated B Lymphocytes1 , 2002, The Journal of Immunology.

[25]  D. Schaid,et al.  Score tests for association between traits and haplotypes when linkage phase is ambiguous. , 2002, American journal of human genetics.

[26]  B. E. C. Oiffier,et al.  CHOP Chemotherapy plus Rituximab Compared with CHOP Alone in Elderly Patients with Diffuse Large-B-Cell Lymphoma , 2002 .

[27]  Alberto Mantovani,et al.  Inflammation and cancer: back to Virchow? , 2001, The Lancet.

[28]  P. Laippala,et al.  A rare allele combination of the interleukin-1 gene complex is associated with high interleukin-1 beta plasma levels in healthy individuals. , 2000, European cytokine network.

[29]  T. Lumley,et al.  Time‐Dependent ROC Curves for Censored Survival Data and a Diagnostic Marker , 2000, Biometrics.

[30]  K. Deichmann,et al.  Atopy and asthma: genetic variants of IL-4 and IL-13 signalling , 2000 .

[31]  R. Westendorp,et al.  Interleukin 10 secretion in relation to human IL-10 locus haplotypes. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[32]  G. Salles,et al.  Genetic polymorphisms in the tumor necrosis factor locus influence non-Hodgkin's lymphoma outcome. , 1998, Blood.

[33]  R. Kurzrock.  Cytokine deregulation in hematological malignancies: clinical and biological implications. , 1997, Clinical cancer research : an official journal of the American Association for Cancer Research.

[34]  G. Salles,et al.  Tumor necrosis factor ligand-receptor system can predict treatment outcome in lymphoma patients. , 1997, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[35]  M. Lazarus,et al.  An investigation of polymorphism in the interleukin-10 gene promoter. , 1997, European journal of immunogenetics : official journal of the British Society for Histocompatibility and Immunogenetics.

[36]  R. Kurzrock,et al.  Serum levels of interleukin-10 in patients with diffuse large cell lymphoma: lack of correlation with prognosis. , 1995, Blood.

[37]  R. Płoski,et al.  A genetic association between juvenile rheumatoid arthritis and a novel interleukin-1α polymorphism , 1995 .

[38]  P. Galieni,et al.  Clinical implications of cytokine and soluble receptor measurements in patients with newly‐diagnosed aggressive non‐Hodgkin's lymphoma , 1995, European journal of haematology.

[39]  J. Blay,et al.  Serum interleukin-10 in non-Hodgkin's lymphoma: a prognostic factor. , 1993, Blood.

[40]  Emili Montserrat,et al.  A predictive model for aggressive non-Hodgkin's lymphoma. , 1993, The New England journal of medicine.

[41]  D. Rubin,et al.  The central role of the propensity score in observational studies for causal effects , 1983 .

[42]  D. Weisenburger,et al.  Lymphoma incidence patterns by WHO subtype in the United States, 1992-2001. , 2006, Blood.

[43]  Theodore R Holford,et al.  Genetic variation in TNF and IL10 and risk of non-Hodgkin lymphoma: a report from the InterLymph Consortium. , 2006, The Lancet. Oncology.

[44]  Brian Staats,et al.  SNP500Cancer: a public resource for sequence validation and assay development for genetic variation in candidate genes , 2004, Nucleic Acids Res..

[45]  Meland,et al.  The use of molecular profiling to predict survival after chemotherapy for diffuse large-B-cell lymphoma. , 2002, The New England journal of medicine.

[46]  E. Berg,et al.  World Health Organization Classification of Tumours , 2002 .

[47]  Pierre Morel,et al.  CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large-B-cell lymphoma. , 2002, The New England journal of medicine.

[48]  R. Płoski,et al.  A genetic association between juvenile rheumatoid arthritis and a novel interleukin-1 alpha polymorphism. , 1995, Arthritis and rheumatism.

[49]  Y. Benjamini,et al.  Controlling the false discovery rate: a practical and powerful approach to multiple testing , 1995 .

[50]  David R. Cox,et al.  Regression models and life tables (with discussion , 1972 .