Genetic variation in the BCL2 pathway and risk of non-hodgkin lymphoma

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Background: Non-Hodgkin Lymphoma (NHL) is a malignancy of lymphocytes, and BCL2 family members are known regulators of programmed cell death in these cells. t(14;18)(q32;q21) is the most commonly observed chromosomal translocation in NHL, and this somatic event juxtaposes the anti-apoptotic gene BCL2 to the immunoglobulin heavy chain locus. However, little is known about the role of germline genetic variation in BCL2 and related genes with risk of NHL.

Methods: We genotyped 152 single nucleotide polymorphisms (SNPs) within 20 candidate BCL2-family member genes in a clinic-based study of 458 Caucasian NHL cases and 484 frequency matched Caucasian controls seen at the Mayo Clinic from 2002-2005. Tagging SNPs were selected from HapMap for the following candidate genes: BCL2; BCL2LA1; BCL2L1, 2, 10, 11, 12, 13, 14; BAD; BAX; BAG1, 3, 4, 5; BIK; BAK1; BNIP2, 3; and HRK. The most prevalent homozygous genotype was used as the reference group, and each SNP was modeled individually as having a log-additive effect in a logistic regression model adjusted for age and sex. For gene analyses, we evaluated the association of haplotypes from each gene with risk of NHL using the score test implemented from HAPLO.SCORE. We also jointly tested the main effects for all independent (r²<0.25) SNPs from a gene using a multivariate logistic regression (MLR) model and a likelihood ratio test.

Results. The mean age at diagnosis was 60.0 years for cases and 58% were male; among controls, the mean age at enrollment was 61.6 years and 55% were male. In the MLR gene analyses, both BCL2L11 (also know as BIM) (p=0.0028) and BCL2L2 (also known as BCLW) (p=0.049) were significant at p<0.05; BCL2L11 was also significant in the haplotype analysis based on 4 SNPs and 7 haplotypes (p=0.0046). For BCL2L11, 2 of the 4 tagSNPs were significant at p<0.05 (rs12613243 and rs6746608), while for BCL2L2, 1 of the 3 tagSNPs was significant (rs7042474). The protein encoded by BCL2L11 contains a BCL-2 homology domain 3 (BH3) that has been shown to interact with BCL2, BCL2L1/BCL-X(L), and MCL2, and to act as an apoptotic activator. Expression of BCL2L2 in cells has been shown to contribute to reduced cell apoptosis under cytotoxic conditions.

Conclusions. Two genes from the BCL2 family, BCL2L11 and BCL2L2, were associated with risk of NHL and warrant replication. Consideration of upstream regulators of BCL2, as well as downstream targets may identify additional genes that contribute to NHL risk.