Inherited genetic variation and overall survival following follicular lymphoma.
ABSTRACT Follicular lymphoma (FL) has variable progression and survival, and improved identification of patients at high risk for progression would aid in identifying patients most likely to benefit from alternative therapy.In a sample of 244 FL cases identified during a population-based case-control study of non-Hodgkin lymphoma (NHL), we examined 6,679 tag SNPs in 488 gene regions for associations with overall FL survival. Over a median follow-up of 89 months with 65 deaths in this preliminary study, we identified 5 gene regions (BMP7, GALNT12,DUSP2, GADD45B, and ADAM17) that were associated with overall survival from FL. Results did not meet the criteria for statistical significance after adjustment for multiple hypothesis testing. These results,which support a role for host factors in determining the variable progression of FL, serve as an initial examination that can inform future studies of genetic variation and FL survival. However, they require replication in independent populations, as well as assessment in rituximab-treated patients.
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ABSTRACT: There is growing evidence linking genetic variations to non-Hodgkin lymphoma (NHL) etiology. To complement ongoing agnostic approaches for identifying susceptibility genes, we evaluated 488 candidate gene regions and their relation to risk for NHL and NHL subtypes. We genotyped 6,679 tag single nucleotide polymorphisms (SNPs) in 947 cases and 826 population-based controls from a multicenter U.S. case-control study. Gene-level summary of associations were obtained by computing the minimum P value ("minP test") on the basis of 10,000 permutations. We used logistic regression to evaluate the association between genotypes and haplotypes with NHL. For NHL subtypes, we conducted polytomous multivariate unconditional logistic regression (adjusted for sex, race, age). We calculated P-trends under the codominant model for each SNP. Fourteen gene regions were associated with NHL (P < 0.01). The most significant SNP associated with NHL maps to the SYK gene (rs2991216, P-trend = 0.00005). The three most significant gene regions were on chromosome 6p21.3 (RING1/RXRB; AIF1; BAT4). Accordingly, SNPs in RING1/RXRB (rs2855429), AIF1 (rs2857597), and BAT4 (rs3115667) were associated with NHL (P-trends ≤ 0.0002) and both diffuse large B-cell and follicular lymphomas (P-trends < 0.05). Our results suggest potential importance for SYK on chromosome 9 with NHL etiology. Our results further implicate 6p21.3 gene variants, supporting the need for full characterization of this chromosomal region in relation to lymphomagenesis. Gene variants on chromosome 9 may represent a new region of interesting for NHL etiology. The independence of the reported variants in 6p21.3 from implicated variants (TNF/HLA) supports the need to confirm causal variants in this region.Cancer Epidemiology Biomarkers & Prevention 01/2011; 20(1):42-9. · 4.56 Impact Factor
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ABSTRACT: The natural history of follicular lymphoma is believed not to have changed over the last 30 years. Median survivals have ranged from 7 to 10 years, and the disease is considered incurable. However, multiple new treatment options have been developed in the last decade, and their impact on survival of follicular lymphoma remains unknown. In the current analysis, we identified all previously untreated, advanced-stage, follicular lymphoma patients treated with the following three sequential treatment approaches: cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) chemotherapy +/- nonspecific immunostimulants (Southwest Oncology Group [SWOG] 7426 and 7713: 1974 to 1983); prednisone, methotrexate, doxorubicin, cyclophosphamide, and etoposide (ProMACE) plus mechlorethamine, vincristine, procarbazine, and prednisone (MOPP) +/- interferon (SWOG 8809: 1988 to 1994); and CHOP followed by monoclonal antibody (MoAb) therapy (SWOG 9800 and 9911: 1998 to 2000). We assessed the patients' progression-free survival (PFS) and overall survival (OS). The MoAb trials included CHOP followed by rituximab (SWOG 9800) and CHOP followed by (131)I-tositumomab (SWOG 9911). The PFS curves for the CHOP and ProMACE-MOPP studies are overlapping, with 4-year PFS estimates of 46% and 48%, respectively. However, the PFS rate of the CHOP + MoAb studies is significantly improved at 61% (P = .005). The OS curves show improvement with each succeeding study. The 4-year estimate of OS is 69% for the CHOP regimens, 79% for the ProMACE-MOPP study, and 91% for the CHOP + MoAb regimens (P < .001). These conclusions were retained after adjusting for differences in prognostic factors between the study groups. The results of this study suggest that OS for patients with follicular lymphoma has improved over time and that the choice of initial therapy may matter.Journal of Clinical Oncology 12/2005; 23(33):8447-52. · 18.04 Impact Factor
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ABSTRACT: To examine outcome of treatment for patients with recurrent follicular lymphoma. Two hundred twelve newly diagnosed follicular lymphoma patients were studied. One hundred seventy-nine were initially treated successfully. Recurrent or progressive lymphoma developed in 116. Treatment was given according to disease stage and current protocols, mostly with single alkylating agents. A policy of repeated lymph node and bone marrow biopsy was pursued. The overall median survival duration was 9 years, with a median follow-up duration of 12 years. Following recurrence, the median survival duration was 4 1/2 years. Only eight of 116 patients with recurrent disease died of causes unrelated to lymphoma. The overall response rate to first re-treatment was 78% and showed slight decline with successive recurrences, reaching 48% after the fourth treatment. The median duration of second remission was 13 months, (v 31 months for first remission), with the only significant predictive factor being quality of remission. Multivariate analysis showed only age at recurrence and number of prior treatments to correlate with survival after first recurrence. Survival after second remission was only correlated with age and quality of response: Kaplan-Meier estimates gave 53% of patients reaching second complete remission alive 10 years later, compared with 28% in partial remission. Age and previous and continuing responsiveness of follicular lymphoma to therapy are the principal determinants of survival following recurrence. Improvement in survival with new treatments will be demonstrated most readily in older patients, while more intensive approaches should be tested in younger patients in whom remission is achieved with difficulty.Journal of Clinical Oncology 02/1995; 13(1):140-7. · 18.04 Impact Factor