Abstract
Follicular lymphoma (FL) is a heterogeneous disease whose pathogenesis remains partially unknown. Around 20% of FL patients experience early progression or treatment-refractory disease and 2–3% of patients per year experience histological transformation (HT) into a more aggressive lymphoma (tFL). Here, we evaluate the immunoglobulin heavy chain variable (IGHV) gene usage and mutational status in 187 FL cases to assess its impact on clinical outcome and histological transformation. The IGHV gene repertoire was remarkably biased in FL. The IGHV4-34 (14%), IGHV3-23 (14%), IGHV3-48 (10%), IGHV3-30 (9%) and IGHV3-21 (7%) genes accounted for more than half of the whole cohort. IGHV3-48 was overrepresented in cases of tFL (19%) compared with non-transformed FL at 5 years (5%, P = 0.05). Patients with the IGHV3-48 gene were significantly more likely to have had HT after 10 years than those who used other genes (71% vs. 25%, P < 0.05), irrespective of the therapy they received. Moreover, IGHV3-30 was also overrepresented in cases of FL (9%) and tFL (13%) compared with diffuse large B-cell lymphoma in which it was nearly absent. In conclusion, our results indicate a role for antigen selection in the development of FL, while the use of IGHV3-48 could help predict histological transformation.
Highlights
Follicular lymphoma (FL) is the most common indolent non-Hodgkin lymphoma (NHL, 20–30%), with an incidence of 12.5 new cases per 100 000 inhabitants/year
In order to identify unique characteristics of FL, we compared our FL dataset with the results reported for CD5-/IgM+normal B cells and other B-cell lymphoproliferative disorders (B-LPDs), namely, de novo diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), chronic lymphocytic leukemia (CLL), splenic marginal zone lymphoma (SMZL), hairy cell leukemia (HCL), multiple myeloma (MM) and Waldenström macroglobulinemia (WM) (Table 2 and Supplemental Table S6)[19,21,39,40,41,42,43,44]
Our study reports the largest FL series examined to date (n = 187) in which the use of immunoglobulin heavy chain variable (IGHV), IGHD and IGHJ genes in the clonal BCR rearrangement has been extensively characterized
Summary
Follicular lymphoma (FL) is the most common indolent non-Hodgkin lymphoma (NHL, 20–30%), with an incidence of 12.5 new cases per 100 000 inhabitants/year. FL is typically characterized by a non-aggressive nature, usually responds successfully to first-line therapy, and has a median survival of 15 to 20 years[1,2,3]. Despite the improvement in treatment effectiveness due to the incorporation of immunochemotherapy regimens, including anti-CD20 monoclonal antibody, 20% of patients experience early progression or develop a treatment-resistant disease within 2 years of receiving first-line therapy[2,4,5]. Transformed follicular lymphoma (tFL) involves a clonal relationship between the initial FL and the aggressive form and it is considered to be one of the most unfavorable events in the natural history of FL9, because transformation has customarily
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