Clinical and biological relevance of single-nucleotide polymorphisms and acquired somatic mutations of the BCL6 first intron in follicular lymphoma

Abstract

Genetic modifications of the BCL6 gene in lymphoma include translocations, deletions, and somatic mutations (SM) of the 5 0 noncoding region. Three single-nucleotide polymorphisms (SNPs) of the major mutation cluster region (MMC) have been reported, including two substitutions (397G/C, 502G/A) and one deletion (520DT). Clinical and biological relevance of these SNPs are unknown. Based on a case-control study, BCL6 SNPs frequencies were assessed in 97 t(14;18) follicular lymphomas (FL) and in 54 lymphomas with 3q27 rearrangement. Allele frequencies were similar in the FL and controls groups. The 397 G/C genotype was correlated to a higher-grade transformation risk (P ¼ 0.02). SM were observed in 39.1% of FL and were characterized by a clustering distribution (hot spots spanning position 420-435, 106-127, and 590-600). No correlation between genotypes or acquired mutational status and BCL6 expression was demonstrated. However, gel mobility-shift assays, using SNPs containing probes show results representative for protein/DNA complexes. This study demonstrates that the first BCL6 intron is a highly variable region as a consequence of both SNP and SM, which may contribute to biology and outcome of FL.

Gene Expression Profiling of Non-Hodgkin Lymphomas

“…In this study we have found upregulation of BCL6 gene expression that was in concordance with others who found that the levels of BCL6 gene expression and protein have been demonstrated to expect the clinical outcome of DLBCL (Lossos et al, 2001). The BCL6 findings from the pooled data set were consistent with our study (Zhang et al, 2005) but do not provide support for two other previous studies of follicular lymphoma (Jardin et al, 2005). Other study examined tumors with a variety of different BCL6 translocations and found no increase in total BCL6 mRNA levels in the NHL specimens harboring BCL6 gene translocation (Lossos et al, 2003).…”

Distinctive patterns of BCL6 molecular alterations and their functional consequences in different subgroups of diffuse large B-cell lymphoma

“…A preferential distribution of mutations in several regions has been reported. 37,38 We also observed clustering of mutations in three regions, but only one region (80-123) has been reported previously in DLBCLs. 29 Although one report 37 suggested that mutations in one cluster (420-443) were associated with increased protein expression, we did not find any correlation of BCL6 mRNA or protein expression with any of the intronic clusters, thus confirming other reports.…”

“…The first mutation cluster (80-123) has been reported by others. 37,38 In subgroup analysis, the presence of two major clusters was observed in the GCB subgroup (277-316 and 470-513), but clustering was not discernable in the other subgroups probably because of the lower number of cases with mutations. In agreement with previous studies, three single-nucleotide polymorphisms (SNPs) in the MMC were observed at positions 397 (C-G; 20%), 502 (A-G; 10%) and 520 (del T; 10%).…”

“…The GCB subgroup had high BCL6 protein and there was a trend toward higher BCL6 protein level in mutated cases (Figure 2). Previous studies have reported clustering of mutations in the MMC 35,36 and postulated the presence of two 37 or three 38 major clusters. We also observed a similar clustering pattern and defined three MMCs that had a mutational frequency X3-fold higher than the entire MMC region (1-1.5 Â 10 À2 /bp vs 5.4 Â 10 À3 /bp).…”

Subtype preference of the BCL6397G/C polymorphism in germinal-center and non-germinal-center subtypes of diffuse large B-cell lymphoma

“…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 ϭ .8). 7 In conclusion, we could not verify earlier findings by Lossos et al 5 or Jardin et al 7 concerning the associations between the BCL6 397G/C polymorphism and FL and transformed DLBCL. However, a highly significant difference in allele frequency (P Ͻ .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.…”