RAG1 and BRCA2 polymorphisms in non-Hodgkin lymphoma

To the editor:

A recent Blood paper by Hill et al¹  suggested a link between the risk of developing non-Hodgkin lymphoma (NHL) and polymorphic variations in several genes involved in DNA strand break induction and DNA repair pathways. We examined 2 of these polymorphisms where Hill et al reported statistically significant associations, in the Recombination-activating 1 (RAG1) gene (K820R; odds ratio [OR] = 2.7 [AA vs GG], 95% confidence interval [CI], 1.4-5.0) and the Breast cancer 2 (BRCA2) gene (N372H; OR = 1.5 [AA vs CC], 95% CI, 1.0-2.1), in a United Kingdom case-control study of lymphoma.

Local ethical approval was obtained for this research. Informed consent was obtained in accordance with the Declaration of Helsinki.

A total of 741 white patients with NHL and 806 white control participants randomly selected from population registers were recruited as part of a lymphoma case-control study conducted in parts of north and southwest England.²  Our study participants consented to give a blood sample, and represented 67% of patients with incident NHL aged 16 to 69 years in the study area and 66% of the control participants who were contacted successfully. We genotyped the participants' DNA while blinded to case-control status using TaqMan SNP genotyping assays (Applied Biosystems, Warrington, United Kingdom) and ABI PRISM 7000 software (Applied Biosystems). To assess the reliability of the Taqman assays, 20 samples were randomly selected for direct DNA sequencing: concordance with TaqMan was 100% for both polymorphisms. Among our control population, RAG1 K820R and BRCA2 N372H were in Hardy-Weinberg equilibrium, and the distributions of variants were consistent with those reported by Hill et al and the cancer genome anatomy project SNP500 cancer database.³  Unmatched statistical analyses to estimate ORs and 95% CIs were conducted using unconditional logistic regression adjusting for age and sex,⁴  and the likelihood ratio test was used to test for interactions.

We observed a modest but nonsignificant decrease in risk of NHL with BRCA2 N372H AC and CC variants compared with the AA variant, and no evidence of any association between NHL and the RAG1 K820R polymorphism (Table 1). Risks for B-cell lymphoma, and the 2 major diagnostic subgroups of diffuse large B-cell lymphoma and follicular lymphoma (data not shown), were similar to those for total NHL for both variants, while risk estimates were elevated for T-cell lymphoma, but were not significant (Table 1). Risks were generally similar among men and women, and varied little by age (data not shown). However, for T-cell lymphoma, men who carried at least 1 copy of the BRCA2 N372H C allele had a significantly increased risk (OR = 2.30, 95% CI, 1.08-4.87 based on 23 patients and 194 control participants with the C allele compared with 11 patients and 208 control participants), while women were at decreased risk (OR = 0.43, 95% CI, 0.17-1.06 based on 7 patients and 176 control participants with the C allele compared with 17 patients and 179 control participants) (test for interaction: χ² = 8.42, P = .004).

Our data suggest that there is little association between NHL and either of these 2 polymorphisms. However, we cannot exclude the possibility of an association, and further investigation is required using larger datasets to elucidate the role of these polymorphisms in determining the risk of developing NHL.