Subtype preference of the BCL6_397G/C polymorphism in germinal-center and non-germinal-center subtypes of diffuse large B-cell lymphoma

The BCL6 gene encodes a POZ/Zink finger sequence-specific transcription inhibitor important for T- and B-cell maturation, cell-cycle control, apoptosis, and inflammation. Recent studies indicate that high BCL6 expression correlates with good prognosis for diffuse large B-cell lymphoma (DLBCL) patients.^1,2  Moreover, mutations and polymorphisms, such as the BCL6_397G/C polymorphism, in the 5′ regulatory region of the BCL6 gene have been suggested to increase BCL6 expression and to be involved in lymphoma progression and transformation from follicular lymphoma (FL) to diffuse large B-cell lymphoma,^3-5  whereas no correlation was evident for de novo DLBCL.⁶  DLBCL can now be classified into 2 major subgroups: one derived from germinal-center B cells, the GC subtype, often with a high expression of BCL6, and one derived from B cells, often with a lower expression of BCL6, the non-GC subtype.^1,2 

To investigate the impact of the BCL6_397G/C polymorphism, we screened 120 de novo DLBCLs from Uppsala and Umeå University Hospitals regarding their BCL6_397G/C genotype and compared the allele and genotype frequencies with samples from 230 healthy donors. Subclassification into GC and non-GC DLBCL according to Hans et al¹  was available for all 120 tumors.

In the present material, the frequency of the BCL6_397C allele did not differ significantly in our DLBCL patients compared with the control group, which is in accordance with previous data.⁶  Furthermore, we did not find any difference in overall survival between patients with the BCL6_397GG genotype and BCL6_397GC/CC genotypes. No significant difference was indicated between the 2 groups concerning sex, clinical stage, or age.

Interestingly, the allele frequencies of BCL6_397G/C polymorphism were significantly different between GC DLBCL and non-GC DLBCL (P < .001; Table 1) as well as between GC DLBCL and healthy controls (P = .005). The genotype frequencies were also shown to differ between GC DLBCL and non-GC DLBCL (BCL6_397GG vs BCL6_397GC/CC; P = .001), with a preference for the C allele in the GC group and for the G allele in the non-GC group. We also found a significant difference between GC DLBCL and controls concerning the genotype frequencies (P = .02; Table 1). A tendency to a difference was indicated between non-GC DLBCL and controls with a higher frequency for the G allele in the DLBCL patients (P = .07). Furthermore, 95 patients diagnosed with FL were screened for the BCL6_397G/C polymorphism. No significant difference was found concerning allele or genotype frequencies between FL and controls, which is in contrast to the result by Lossos et al.⁵  The previously reported higher risk of transformation for FL patients with the C allele could not be verified (P = .8).⁷ 

In conclusion, we could not verify earlier findings by Lossos et al⁵  or Jardin et al⁷  concerning the associations between the BCL6_397G/C polymorphism and FL and transformed DLBCL. However, a highly significant difference in allele frequency (P < .001) of the BCL6_397G/C polymorphism was evident between GC-DLBCL and non-GC DLBCL, with a preference for the C allele in the GC group and a preference for the G allele in the non-GC group. Jardin et al⁷  have suggested that the BCL6_397G/C polymorphism may influence the binding of an unknown transcription factor. A possible indirect effect by linkage disequilibrium with another gene was also suggested. Our finding adds to the concept that the GC and non-GC groups of DLBCL are molecularly distinct and probably 2 different types of lymphoma.