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. 2019 Jun 17;9(7):52.
doi: 10.1038/s41408-019-0213-9.

Immunoglobulin gene rearrangement IGHV3-48 is a predictive marker of histological transformation into aggressive lymphoma in follicular lymphomas

María García-Álvarez  1 , Sara Alonso-Álvarez  2 , Isabel Prieto-Conde  1 , Cristina Jiménez  1 , M Eugenia Sarasquete  1   3 , M Carmen Chillón  1   3 , Alejandro Medina  1 , Ana Balanzategui  1 , Rebeca Maldonado  1 , Alicia Antón  1 , Noemí Puig  1   3 , Marta Rodríguez  4 , Oscar Blanco  4 , Pilar Tamayo  5 , Verónica González-Calle  1 , Alejandro Martín  1   3 , Ramón García-Sanz  6   7   8 , Marcos González  1   3   9 , M Dolores Caballero  1   3 , Miguel Alcoceba  1   3
Affiliations

Immunoglobulin gene rearrangement IGHV3-48 is a predictive marker of histological transformation into aggressive lymphoma in follicular lymphomas

María García-Álvarez et al. Blood Cancer J. .

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.

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Conflict of interest statement

The authors reports grants PI15/01393, PI18-00410, CAS102P17, GRS 1180/A/15, GLD17/00334, CIBERONC-CB16/12/00233 during the conduct of the study, and from Gilead Sciences (GLD15/00348, GLD16/00162), Incyte, Janssen, and Amgen outside the submitted work. M.G.A., I.P.C., C.J., V.G.C. and M.E.S. are or were supported by the Spanish government (ISCIII and/or FEHH). Consulting fees and/or non-financial support were reported from Abbvie (M.G.), Amgen (N.P., M.D.C), BMS (R.G-S., M.D.C.), Celgene (N.P., A.M., M.D.C), Gilead (A.M., M.G., M.D.C.), Incyte (R.G-S.), Janssen (N.P., A.M., R.G-S., M.G., M.D.C., M.A.), Kite (M.D.C.), MSD (M.D.C.), Novartis (S.A-A., M.D.C.), Prothena (V.G-C.), Roche (A.M., M.G., M.D.C.), Servier (A.M.), Takeda (N.P., R.G-S., M.D.C.), and Weber (N.P.). R.G-S. is the president of the Spanish Society of Haematology. The remaining authors declare no competing interests.

Figures

Fig. 1
Fig. 1. IGHV gene repertoire in follicular lymphoma (n = 138).
The 35 IGHV genes expressed in our series are presented along the X-axis
Fig. 2
Fig. 2. Comparison of the IGHV gene usage in tFL with FL without HT at 5 years and GCB/non-GCB DLBCL.
The five IGHV genes most frequently expressed in our series are shown along the X-axis. *P < 0,05. GCB, germinal center B-cell-like; non-GCB, non-germinal center B-cell-like
Fig. 3
Fig. 3. Kaplan–Meier analysis of 10-year HT by IGHV3-48 gene usage.
The absence and presence of IGHV3-48 are depicted by black and grey lines, respectively. The vertical dashed line indicates 10-year follow-up
See this image and copyright information in PMC

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