Differences Between Follicular Lymphoma With and Without Translocation t(14;18)

Follicular lymphoma (FL) is genetically characterized by the presence of the t(14;18)(q32;q21) chromosomal translocation in approximately 90% of cases. In contrast to FL carrying the t(14;18), their t(14;18)-negative counterparts are less well studied regarding their immunohistochemical, genetic, molecular and clinical features. Within a previously published series of 184 FL grade 1-3A with available gene expression data, we identified 17 FL lacking the t(14;18). Comparative genomic hybridization and high resolution SNP array profiling demonstrated that gains/amplifications of the BCL2 gene locus in 18q were restricted to the t(14;18)-positive FL subgroup. A comparison of gene expression profiles revealed an enrichment of germinal center B-cell associated signatures in t(14;18)-positive FL, whereas activated B-cell like, NFƒÛB, proliferation and bystander cell signatures were enriched in t(14;18)-negative FL. These findings were confirmed by immunohistochemistry in an independent validation series of 84 FL, in which 32% of t(14;18)-negative FL showed weak or absent CD10 expression and 91% an increased Ki67 proliferation rate. Although overall survival did not differ between FL with and without t(14;18), our findings suggest distinct molecular features of t(14;18)-negative FL. Fresh-frozen tumor-biopsy specimens were obtained from 184 untreated patients who had received a diagnosis of follicular lymphoma. RNA was extracted from the biopsy specimens and was examined for gene expression with the use of Affymetrix U133A and U133B microarrays.

滤泡淋巴瘤（Follicular lymphoma, FL）的遗传学特征为约90%的病例存在t(14;18)(q32;q21)染色体易位。与携带t(14;18)易位的滤泡淋巴瘤相比，t(14;18)阴性的滤泡淋巴瘤在免疫组化、遗传学、分子生物学及临床特征方面的研究尚不充分。在一项既往发表的、纳入184例1~3A级滤泡淋巴瘤且具备可用基因表达数据的研究队列中，我们鉴定出17例不存在t(14;18)易位的滤泡淋巴瘤。比较基因组杂交及高分辨率单核苷酸多态性（SNP）阵列谱分析显示，18号染色体长臂（18q）上的BCL2基因位点拷贝数获得/扩增仅见于t(14;18)阳性的滤泡淋巴瘤亚组。基因表达谱比较分析结果显示，t(14;18)阳性滤泡淋巴瘤中富集生发中心B细胞相关特征标签，而t(14;18)阴性滤泡淋巴瘤则富集活化B细胞样、核因子κB（NF-κB）、增殖及旁观者细胞特征标签。上述研究结果在另一独立的84例滤泡淋巴瘤验证队列中通过免疫组化得到了证实：该队列中32%的t(14;18)阴性滤泡淋巴瘤表现为CD10表达微弱或缺失，91%的病例Ki67增殖指数升高。尽管伴与不伴t(14;18)易位的滤泡淋巴瘤患者总生存期无显著差异，但本研究结果提示t(14;18)阴性滤泡淋巴瘤具有独特的分子特征。本研究的新鲜冷冻肿瘤活检标本取自184例初诊滤泡淋巴瘤患者，从活检标本中提取RNA，并采用Affymetrix U133A及U133B微阵列进行基因表达检测。