Risk of Non-Hodgkin Lymphoma Associated with Germline Variation in Genes that Regulate the Cell Cycle, Apoptosis, and Lymphocyte Development

Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Department of Health and Human Services, Rockville, MD 20852, USA.
Cancer Epidemiology Biomarkers & Prevention (Impact Factor: 4.13). 05/2009; 18(4):1259-70. DOI: 10.1158/1055-9965.EPI-08-1037
Source: PubMed


Chromosomal translocations are the hallmark genetic aberration in non-Hodgkin lymphoma (NHL), with specific translocations often selectively associated with specific NHL subtypes. Because many NHL-associated translocations involve cell cycle, apoptosis, and lymphocyte development regulatory genes, we evaluated NHL risk associated with common genetic variation in 20 candidate genes in these pathways. Genotyping of 203 tag single nucleotide polymorphisms (SNP) was conducted in 1,946 NHL cases and 1,808 controls pooled from 3 independent population-based case-control studies. We used logistic regression to compute odds ratios (OR) and 95% confidence intervals (CI) for NHL and four major NHL subtypes in relation to tag SNP genotypes and haplotypes. We observed the most striking associations for tag SNPs in the proapoptotic gene BCL2L11 (BIM) and BCL7A, which is involved in a rare NHL-associated translocation. Variants in BCL2L11 were strongly related to follicular lymphoma only, particularly rs3789068 (OR(AG), 1.41; 95% CI, 1.10-1.81; OR(GG), 1.65; 95% CI, 1.25-2.19; P(trend) = 0.0004). Variants in BCL7A were strongly related to diffuse large B-cell lymphoma only, particularly rs1880030 (OR(AG), 1.34; 95% CI, 1.08-1.68; OR(AA), 1.60; 95% CI, 1.22-2.08; P(trend) = 0.0004). The associations for both variants were similar in all three studies and supported by haplotype analyses. We also observed notable associations for variants in BCL6, CCND1, and MYC. Our results support the role of common genetic variation in cell cycle, apoptosis, and lymphocyte development regulatory genes in lymphomagenesis, and suggest that effects may vary by NHL subtype. Replication of our findings and further study to identify functional SNPs are warranted.

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    • "P9 , the other gene to be replicated , is a pro - apoptotic protease integral to the intrinsic apoptotic pathway , and is responsible for effector caspase activation and apoptosis execution following activation by Apaf - 1 bound to cytochrome c released from mitochondria ( Allan and Clarke , 2009 ) . The primers and probes used listed previously ( Morton et al . , 2009 ) . For controls , β2 - microglobulin was used in all cases . Each assay was analyzed by the comparative cycle threshold ( CT ) method . Results All the clinicopathological features of the studied samples were collected from pathology and medical records of patients . The variation in gene expression across 40 NHL and normal samples usi"
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