ABSTRACT
We analyzed the allelic distribution of 12 candidate polymorphisms in a large retrospective study of 486 patients with diffuse large B-cell lymphoma (DLBCL) treated at Oslo University Hospital with 1056 blood donors serving as controls. Variants in TNFα (rs1800629) (GG vs. AG/AA, p < 0.001) and LTA (rs909253) (AA vs. AG/GG, p = 0.02) and deletions in GSTM1 and GSTT1 (undeleted vs. deleted, p = 0.01 and p = 0.01, respectively) were associated with increased susceptibility of developing DLBCL. IL-10 (rs1800896) variants (GG vs. AG/AA, p = 0.03) were associated with decreased susceptibility. In line with several previous reports, patients carrying the TNFα (rs1800629) A allele treated in the pre-rituximab era had inferior outcome compared to patients carrying the homozygous GG genotype (p = 0.004, n = 33). However, patients receiving at least one dose of rituximab had equal outcome regardless of their TNFα genotype (HR = 0.94, p = 0.79, n = 307). Deletion in GSTM1 was associated with inferior outcome for patients with low International Prognostic Index (IPI) score (p = 0.04). Our findings support the suggestions that polymorphisms in genes encoding immunoregulatory proteins and enzymes that metabolize carcinogens and chemotherapeutic drugs influence DLBCL susceptibility and possibly treatment outcome. The influence of polymorphisms in immunoregulatory genes on outcome in DLBCL should be reevaluated in the rituximab era.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Genetic Predisposition to Disease , Lymphoma, Large B-Cell, Diffuse/drug therapy , Lymphoma, Large B-Cell, Diffuse/genetics , Polymorphism, Genetic , Adolescent , Adult , Aged , Alleles , Antibodies, Monoclonal, Murine-Derived/administration & dosage , Biomarkers , Case-Control Studies , Female , Follow-Up Studies , Genotype , Glutathione Transferase/genetics , Humans , Interleukin-10/genetics , Lymphoma, Large B-Cell, Diffuse/mortality , Lymphoma, Large B-Cell, Diffuse/pathology , Male , Middle Aged , Neoplasm Staging , Prognosis , Retrospective Studies , Risk Factors , Rituximab , Treatment Outcome , Tumor Necrosis Factor-alpha/genetics , Young AdultABSTRACT
We genotyped 224 patients with Hodgkin lymphoma (HL) and 1056 healthy controls and related the risk for HL and outcome of chemotherapy treatment to polymorphisms in genes encoding interleukins and metabolizing enzymes by capillary electrophoresis. Patients with the UGT1A1 TA tandem repeat TA6/6 genotype had a poorer overall survival (OS) (relative risk [RR] 3.63, p = 0.004), and patients above 40 years with the GSTA1 AA genotype had poorer event-free survival (EFS) (RR 4.38, p = 0.003) after chemotherapy. In patients above 40 years, the IL-10 rs1800890 T-allele was associated with lower risk for HL (TT genotype vs. AA, odds ratio [OR] 0.38 [95% confidence interval 0.21-0.69], p = 0.001; AT/TT combined genotypes vs. AA, OR 0.45 [0.27-0.74], p = 0.001). The GSTP1 rs1695 A-allele reduced the risk for HL (GG vs. AG, OR 0.64 [0.42-0.99], p = 0.04; GG vs. AG/AA combined genotypes, OR 0.70 [0.47-1.04], p = 0.07), and the GSTT1 deleted genotype increased the risk for HL (OR 3.17 [1.97-5.09], p < 0.001) regardless of age.
Subject(s)
Glucuronosyltransferase/genetics , Glutathione S-Transferase pi/genetics , Glutathione Transferase/genetics , Hodgkin Disease/genetics , Interleukin-10/genetics , Isoenzymes/genetics , Polymorphism, Single Nucleotide , Adolescent , Adult , Aged , Aged, 80 and over , Female , Genetic Predisposition to Disease , Genotype , Hodgkin Disease/mortality , Humans , Inactivation, Metabolic/genetics , Male , Middle Aged , Prognosis , Risk , Young AdultABSTRACT
The prognostic value of grading follicular lymphoma has been debated since the 1980s. There is consensus that World Health Organization (WHO) grades 1 and 2 are indolent, but not whether grades 3A or 3B are aggressive. We retrospectively reviewed the follicular lymphoma diagnoses according to the 2008 WHO classification in all diagnostic specimens from a population-based cohort of 505 patients with a median follow-up time of 10·0years (range, 4·6-16·0). After excluding 43 patients with concomitant diffuse large B-cell lymphoma, 345 remained with grade 1-2, 94 with grade 3A, and 23 with grade 3B follicular lymphoma. Grades 1-2 and 3A seemed equally indolent, with indistinguishable clinical courses, even in patients receiving anthracyclines. Compared with grades 1-3A and independently of clinical factors, grade 3B correlated with higher mortality (P=0·008), but outcome was improved after upfront anthracycline-containing therapy (P=0·015). In contrast to grade 1-3A patients, grade 3B patients experienced no relapses or deaths beyond 5years of follow-up. Furthermore, patients with grade 3B were predominantly male and seldom presented with bone-marrow involvement. We conclude that follicular lymphoma grade 1-3A is indolent and incurable with conventional therapy. Grade 3B appears to be an aggressive but curable disease.
