Article

Inherited genetic variation and overall survival following follicular lymphoma

Division of Cancer Epidemiology and Genetics, Department of Health and Human Services, National Cancer Institute, National Institutes of Health, Rockville, Maryland, USA.
American Journal of Hematology (Impact Factor: 3.48). 07/2012; 87(7):724-6. DOI: 10.1002/ajh.23184
Source: PubMed

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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Available from: Matthew J. Maurer, Sep 19, 2014
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    ABSTRACT: Background Survival in follicular lymphoma (FL) is highly variable, even within prognostic groups defined by tumor grade and the Follicular Lymphoma International Prognostic Index. Studies suggest that germline single nucleotide polymorphisms (SNPs) may hold prognostic information but further investigation is needed.Methods We explored the association between SNPs and FL outcome using two approaches: 1) Two independent genome-wide association studies (GWAS) of ~300.000 SNPs followed by a meta-analysis encompassing 586 FL patients diagnosed in Denmark/Sweden 1999¿2002 and in the United States 2001¿2006; and 2) Investigation of 22 candidate-gene variants previously associated with FL outcome in the Danish/Swedish cohort (N¿=¿373). We estimated time to lymphoma-specific death (approach 1 and 2) and lymphoma progression (approach 2) with hazard ratios (HR) and 95% confidence intervals (CI) in a multivariable Cox regression model.ResultsIn the GWAS meta-analysis, using a random effects model, no variants were associated with lymphoma-specific death at a genome-wide significant level (p¿<¿5.0 x10¿8). The strongest association was observed for tightly linked SNPs on 17q24 near the ABCA10 and ABCA6 genes (rs10491178 HRrandom¿=¿3.17, 95% CI 2.09-4.79, prandom¿=¿5.24 x10¿8). The ABCA10 and ABCA6 genes belong to a family of genes encoding for ABC transporter proteins, implicated in multidrug resistance. In line with a previous study, rs2466571 in CD46 (HR¿=¿0.73, 95% CI 0.58-0.91, p¿=¿0.006) showed nominal association with lymphoma progression, as did two highly linked SNPs in IL8 (rs4073 HR¿=¿0.78, 95% CI 0.62-0.97, p¿=¿0.02; rs2227307 HR¿=¿0.75, 95% CI 0.60-0.94, p¿=¿0.01) previously associated with overall survival.Conclusions The results suggest a possible role for multidrug resistance in FL survival and add to the evidence that genetic variation in CD46 and IL8 may have prognostic implications in FL. Our findings need further confirmation in other independent populations or in a larger multicenter GWAS.
    BMC Medical Genetics 10/2014; 15(1):113. DOI:10.1186/s12881-014-0113-6 · 2.45 Impact Factor