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Blood, 1 October 2008, Vol. 112, No. 7, pp. 2694-2702.
Prepublished online as a Blood First Edition Paper on July 16, 2008; DOI 10.1182/blood-2007-09-111658.
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Submitted September 10, 2007
Accepted June 8, 2008
Host immune gene polymorphisms in combination with clinical and demographic factors predicts late survival in diffuse large B-cell lymphoma patients in the pre-rituximab era
Thomas M Habermann, Sophia S Wang, Matthew J Maurer, Lindsay M Morton, Charles F Lynch, Stephen M Ansell, Patricia Hartge, Richard K Severson, Nathaniel Rothman, Scott Davis, Susan M Geyer, Wendy Cozen, Stephen J Chanock, and James R Cerhan*
Mayo Clinic College of Medicine, Rochester, MN, United States
Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, United States
Department of Epidemiology, University of Iowa, Iowa City, IA, United States
Department of Family Medicine, Wayne State University, Detroit, MI, United States
Division of Public Health Sciences, Fred Hutchinson Cancer Research Institute, Seattle, WA, United States
Department of Preventive Medicine, University of Southern California, Los Angeles, CA, United States
* Corresponding author; email: cerhan.james{at}mayo.edu.
To evaluate the hypothesis that host germline 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 immune genes in 365 DLBCL patients diagnosed from 1998-2000. We estimated hazard ratios (HR) and 95% confidence intervals 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 (range, 27-78 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=0.03) and SNPs in IL8RB (rs1126580; HRAG/GG=2.11, 1.28-3.50), IL1A (rs1800587; HRCT/TT=1.90, 1.26-2.87), TNF (rs1800629; HRAG/GG=1.44, 0.95-2.18), and IL4R (rs2107356; HRCC/CT=1.97, 1.01-3.83) were the strongest predictors of overall survival. A risk score that combined the latter four 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 germline variation in immune genes, particularly genes associated with a pro-inflammatory state, as predictors of late survival in DLBCL.
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